leptin and Diabetes-Mellitus--Type-2

Probiotics or synbiotics consumption have been suggested to reduce the risk of cardiovascular disease (CVD) through a decline in inflammation and oxidative stress, however, the results from studies are conflicting. This study filled this knowledge gap by evaluating randomized controlled trials (RCTs) investigating probiotics or synbiotics intake on adipokines, inflammation, and oxidative stress in patients with prediabetes and type-2 diabetes mellitus (T2DM).. We systematically did search up to March 2022 in PubMed/Medline, Scopus, ISI Web of Science, and Cochrane library. A random-effect model was applied to estimate the weighted mean difference (WMD) and 95% confidence interval (95% CI) for each outcome.. A total of 32 RCTs were included in the meta-analysis. This intervention led to a significant decrease in levels of C-reactive protein (CRP) (WMD - 0.62 mg/l; 95% CI - 0.80, - 0.44; p < 0.001), tumor necrosis factor-α (TNF-α) (WMD - 0.27 pg/ml; 95% CI - 0.44, - 0.10; p = 0.002) and malondialdehyde (MDA) (WMD - 0.51 µmol/l; 95% CI - 0.73, - 0.30; p < 0.001), and also a significant increase in levels of glutathione (GSH) (WMD 69.80 µmol/l; 95% CI 33.65, 105.95; p < 0.001), total antioxidant capacity (TAC) (WMD 73.59 mmol/l; 95% CI 33.24, 113.95; p < 0.001) and nitric oxide (NO) (WMD 7.49 µmol/l; 95% CI 3.12, 11.86; p = 0.001), without significant alterations in interleukin-6 (IL-6) and adipokines levels.. A consumption of probiotics or synbiotics could be a useful intervention to improve cardiometabolic outcomes through a reduced inflammation and oxidative stress in patients with prediabetes and T2DM.

Topics: Adipokines; Adiponectin; Diabetes Mellitus, Type 2; Dietary Supplements; Glutathione; Humans; Inflammation; Leptin; Oxidative Stress; Prediabetic State; Probiotics; Randomized Controlled Trials as Topic; Synbiotics

This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription.. A systematic search for relevant studies was performed in 3 databases. Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included: adiponectin, apelin, brain-derived neurotrophic factor, fetuin-A, fibroblast growth factor-21, follistatin, ghrelin, interleukin (IL)-6, IL-8, IL-10, IL-15, IL-18, leptin, myostatin, omentin, resistin, retinol-binding protein 4, tumor necrosis factor-α, and visfatin.. Forty randomized controlled trials were selected for data extraction (n = 2160). Exercise training induces changes in adiponectin, fetuin-A, fibroblast growth factor-21, IL-6, IL-10, leptin, resistin, and tumor necrosis factor-α levels but has no significant effects on apelin, IL-18, and ghrelin compared to controls. Physical exercise training favored large and positive changes in pooled exerkines (i.e., an overall effect size calculated from several exerkines) (Hedge's g = 1.02, 95% confidence interval (95%CI): 0.76-1.28), which in turn were related to changes in glycated hemoglobin (mean difference (MD) = -0.81%, 95%CI: -0.95% to -0.67%), fasting glucose (MD = -23.43 mg/dL, 95%CI: -30.07 mg/dL to -16.80 mg/dL), waist circumference (MD = -3.04 cm, 95%CI: -4.02 cm to -2.07 cm), and body mass (MD = -1.93 kg, 95%CI: -2.00 kg to -1.86 kg). Slightly stronger effects were observed with aerobic, resistance, or high-intensity interval protocols at moderate- to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session.. Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.

Topics: Adiponectin; alpha-2-HS-Glycoprotein; Apelin; Diabetes Mellitus, Type 2; Exercise; Fibroblast Growth Factors; Ghrelin; Humans; Interleukin-10; Interleukin-18; Leptin; Randomized Controlled Trials as Topic; Resistin; Tumor Necrosis Factor-alpha

Obesity has recently emerged as one of the most severe health concerns. Obesity is a key autonomous risk factor for heart failure and contributes to cardiovascular disease (CVD) risk factors such as hypertension, type 2 diabetes, and metabolic abnormalities. Obesity is caused by a metabolic imbalance, which occurs when calories burnt are fewer than the number of calories consumed. There are several pathways accountable for the adverse impacts of obesity on the cardiovascular system. Inflammatory cell infiltration develops in the adipose tissue, the pancreas, and other issues similar to the progression of obesity. Inflammation is triggered by immune cells that invade dysfunctional adipose tissue. The atherosclerotic inflammation phase, related to obesity, induces coronary calcification. Obesity is linked to elevated levels of leptin and high blood pressure. Leptin causes systemic vasoconstriction, sodium retention, and increased blood pressure by influencing the synthesis of nitric oxide and activating the sympathetic nervous system. Obesity is a well-known risk factor for CVD and is one of the leading causes of the greater risk of diseases, including dyslipidemia, hypertension, depression, metabolic syndrome, atrial fibrillation, and heart failure in adults and children. When used with dietary improvements, antiobesity drugs improve the probability of experiencing clinically healthy (5%) weight loss. This review aimed to address the consequences of obesity on cardiac structure and function, risk factors, the impact of the obesity paradox, pharmacological treatment strategies for managing and recommended exercise and diet.

Topics: Adult; Cardiovascular Diseases; Child; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypertension; Inflammation; Leptin; Obesity

Microbiota dysbiosis and metabolic syndrome, consequences of a non-adequate diet, generate a feedback pathogenic state implicated in Alzheimer's disease development. The lower production of short chain fatty acids (SCFAs) under dysbiosis status leads to lipid homeostasis deregulation and decreases Angptl4 release and AMPK activation in the adipose tissue, promoting higher lipid storage (adipocyte hypertrophy) and cholesterol levels. Also, low SCFA generation reduces GPR41 and GPR43 receptor activation at the adipose tissue (increasing leptin release and leptin receptor resistance) and intestinal levels, reducing the release of GLP-1 and YPP. Therefore, lower satiety sensation and energy expenditure occur, promoting a weight gaining environment mediated by higher food intake and lipid storage, developing dyslipemia. In this context, higher glucose levels, together with higher free fatty acids in the bloodstream, promote glycolipotoxicity, provoking a reduction in insulin released, insulin receptor resistance, advanced glycation products (AGEs) and type 2 diabetes. Intestinal dysbiosis and low SCFAs reduce bacterial biodiversity, increasing lipopolysaccharide (LPS)-producing bacteria and intestinal barrier permeability. Higher amounts of LPS pass to the bloodstream (endotoxemia), causing a low-grade chronic inflammatory state characterized by higher levels of leptin, IL-1β, IL-6 and TNF-α, together with a reduced release of adiponectin and IL-10. At the brain and neuronal levels, the generated insulin resistance, low-grade chronic inflammation, leptin resistance, AGE production and LPS increase directly impact the secretase enzymes and tau hyperphosphorylation, creating an enabling environment for β-amyloid senile plaque and tau tangled formations and, as a consequence, Alzheimer's initiation, development and maintenance.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Dietetics; Dysbiosis; Humans; Insulin Resistance; Leptin; Lipopolysaccharides; Metabolic Syndrome; Microbiota

Leptin is a hormone primarily produced by the adipose tissue in proportion to the size of fat stores, with a primary function in the control of lipid reserves. Besides adipose tissue, leptin is also produced by other tissues, such as the stomach, placenta, and mammary gland. Altogether, leptin exerts a broad spectrum of short, medium, and long-term regulatory actions at the central and peripheral levels, including metabolic programming effects that condition the proper development and function of the adipose organ, which are relevant for its main role in energy homeostasis. Comprehending how leptin regulates adipose tissue may provide important clues to understand the pathophysiology of obesity and related diseases, such as type 2 diabetes, as well as its prevention and treatment. This review focuses on the physiological and long-lasting regulatory effects of leptin on adipose tissue, the mechanisms and pathways involved, its main outcomes on whole-body physiological homeostasis, and its consequences on chronic diseases.

Topics: Adipose Tissue; Diabetes Mellitus, Type 2; Homeostasis; Humans; Leptin; Obesity

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, neuronal loss, and permanent neurological impairments. The etiology of MS is not clearly understood, but genetics and environmental factors can affect the susceptibility of individuals. Obesity or a body mass index of (BMI) > 30 kg/m2 is associated with serious health consequences such as lipid profile abnormalities, hypertension, type 2 diabetes mellitus, reduced levels of vitamin D, and a systemic lowgrade inflammatory state. The inflammatory milieu can negatively affect the CNS and promote MS pathogenesis due in part to the increased blood-brain barrier permeability by the actions of adipose tissue-derived cytokines or adipokines. By crossing the blood-brain barrier, the pro-inflammatory adipokines such as leptin, resistin, and visfatin activate the CNS-resident immune cells, and promote the inflammatory responses; subsequently, demyelinating lesions occur in the white matter of the brain and spinal cord. Therefore, better knowledge of the adipokines' role in the induction of obesity-related chronic inflammation and subsequent events leading to the dysfunctional blood-brain barrier is essential. In this review, recent evidence regarding the possible roles of obesity and its related systemic low-grade inflammation, and the roles of adipokines and their genetic variants in the modulation of immune responses and altered blood-brain barrier permeability in MS patients, has been elucidated. Besides, the results of the current studies regarding the potential use of adipokines in predicting MS disease severity and response to treatment have been explored.

Topics: Adipokines; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Leptin; Lipids; Multiple Sclerosis; Neurodegenerative Diseases; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Vitamin D

Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.

Topics: Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Leptin; Mutation; Obesity

Consumption of a high calorie diet with irregular eating and sedentary behavior habits is typical of the current suboptimal lifestyle, contributing to the development of metabolic diseases such as obesity and type 2 diabetes mellitus. Most notably, the disorder of adipokine secretion in visceral adiposity is a major contributor to metabolic diseases with advancing age. In this regard, spexin and leptin are established as anorexigenic adipokines that can modulate adipogenesis and glucose metabolism by suppressing food intake or increasing energy expenditure, respectively. Emerging evidence points out that spexin levels are lower in the serum and adipose tissue of patients with obesity and/or insulin resistance, whereas circulating levels of leptin are higher in obesity and comorbidities. In turn, spexin and leptin pharmacologically induce beneficial effects on the brain's modulation of food intake and energy expenditure. On the other hand, endocrine crosstalk via spexin and leptin has also been reported in patients suffering from obesity and diabetes. Spexin plays a crucial role in the regulation of leptin secretion and leptin resistance. It should therefore be taken into account that studying the role of spexin in leptin regulation will help us combat the pathologies of obesity caused by leptin resistance.

Topics: Diabetes Mellitus, Type 2; Energy Metabolism; Feeding Behavior; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Obesity

Type II diabetes mellitus (T2DM) is one of the most prevalent diseases in the world, associated with diabetic foot ulcers and impaired wound healing. There is an ongoing need for interventions effective in treating these two problems. Pre-clinical studies in this field rely on adequate animal models. However, producing such a model is near-impossible given the complex and multifactorial pathogenesis of T2DM. A leptin-deficient murine model was developed in 1959 and relies on either dysfunctional leptin (ob/ob) or a leptin receptor (db/db). Though monogenic, this model has been used in hundreds of studies, including diabetic wound healing research. In this study, we systematically summarize data from over one hundred studies, which described the mechanisms underlying wound healing impairment in this model. We briefly review the wound healing dynamics, growth factors' dysregulation, angiogenesis, inflammation, the function of leptin and insulin, the role of advanced glycation end-products, extracellular matrix abnormalities, stem cells' dysregulation, and the role of non-coding RNAs. Some studies investigated novel chronic diabetes wound models, based on a leptin-deficient murine model, which was also described. We also discussed the interventions studied in vivo, which passed into human clinical trials. It is our hope that this review will help plan future research.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Mice; Mice, Inbred Strains; Wound Healing

The brain orchestrates whole-body metabolism through an intricate system involving interneuronal crosstalk and communication. Specifically, a key player in this complex circuitry is the hypothalamus that controls feeding behaviour, energy expenditure, body weight and metabolism, whereby hypothalamic neurons sense and respond to circulating hormones, nutrients, and chemicals. Dysregulation of these neurons contributes to the development of metabolic disorders, such as obesity and type 2 diabetes. The involvement of hypothalamic microRNAs, post-transcriptional regulators of gene expression, in the central regulation of energy homeostasis has become increasingly apparent, although not completely delineated. This review summarizes current evidence demonstrating the regulation of feeding-related neuropeptides by brain-derived microRNAs as well as the regulation of specific miRNAs by nutrients and other peripheral signals. Moreover, the involvement of microRNAs in the central nervous system control of insulin, leptin, and estrogen signal transduction is examined. Finally, the therapeutic and diagnostic potential of microRNAs for metabolic disorders will be discussed and the regulation of brain-derived microRNAs by nutrients and other peripheral signals is considered. Demonstrating a critical role of microRNAs in hypothalamic regulation of energy homeostasis is an innovative route to uncover novel biomarkers and therapeutic candidates for metabolic disorders.

Topics: Diabetes Mellitus, Type 2; Eating; Estrogens; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; MicroRNAs; Neuropeptides

To assess the effect of gender factors on serum leptin levels in patients with diabetes mellitus.. To remove any studies that indicated a relationship between leptin-based inflammatory variables and the prevalence of type 2 diabetes in particular patient categories, a comprehensive search of all articles published between July 2019 and June 2021 was performed on PubMed/MEDLINE, Web of Science, Scopus, and EBSCO Host, including Academic Search Premier, Africa-Wide Information, and Cumulative Index to Nursing and Allied Health Literature. A summary description of the combined analysis across multiple centers, regions, and continents will help us better understand the effect of gender on serum leptin levels in patients with diabetes. The meta-analysis was performed using RevMan 5.2 software on the literature that satisfied the inclusion and exclusion criteria.. Plasma CRP levels in women with type 2 diabetes were found to be no different from those in males with type 2 diabetes, with an OR of 0.12, 95 percent confidence interval (CI) of 0.12 to 0.12,. Gender factors did not affect the level of inflammatory factors and leptin level in type 2 diabetes.

Topics: Africa; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-6; Leptin; Male; Prevalence

Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.

Topics: Aged; Anti-Inflammatory Agents; Brain-Derived Neurotrophic Factor; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Humans; Insulin; Leptin; Nervous System Diseases; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Tyrosine

Type 2 diabetes mellitus (T2DM) is no longer only a disease of humans, but also of domestic animals, and it particularly affects cats. It is increasingly thought that because of its unique characteristics, T2DM may belong not only to the group of metabolic diseases but also to the group of autoimmune diseases. This is due to the involvement of the immune system in the inflammation that occurs with T2DM. Various pro- and anti-inflammatory substances are secreted, especially cytokines in patients with T2DM. Cytokines secreted by adipose tissue are called adipokines, and leptin, adiponectin, resistin, omentin, TNF-α, and IL-6 have been implicated in T2DM. In cats, approximately 90% of diabetic cases are T2DM. Risk factors include older age, male sex, Burmese breed, presence of obesity, and insulin resistance. Diagnosis of a cat requires repeated testing and is complicated compared to human diagnosis. Based on similarities in the pathogenesis of T2DM between humans and cats, adipokines previously proposed as biomarkers for human T2DM may also serve in the diagnosis of this disease in cats.

Topics: Adipokines; Adiponectin; Animals; Biomarkers; Cats; Cytokines; Diabetes Mellitus, Type 2; Humans; Interleukin-6; Leptin; Male; Resistin; Tumor Necrosis Factor-alpha

Research shows that reduced sleep duration is related to an increased risk of obesity. The relationship between sleep deprivation and obesity, type 2 diabetes, and other chronic diseases may be related to the imbalance of appetite regulation. To comprehensively illustrate the specific relationship between sleep deprivation and appetite regulation, this review introduces the pathophysiology of sleep deprivation, the research cutting edge of animal models, and the central regulatory mechanism of appetite under sleep deprivation. This paper summarizes the changes in appetite-related hormones orexin, ghrelin, leptin, and insulin secretion caused by long-term sleep deprivation based on the epidemiology data and animal studies that have established sleep deprivation models. Moreover, this review analyzes the potential mechanism of associations between appetite regulation and sleep deprivation, providing more clues on further studies and new strategies to access obesity and metabolic disease.

Topics: Animals; Appetite; Appetite Regulation; Diabetes Mellitus, Type 2; Ghrelin; Leptin; Obesity; Sleep; Sleep Deprivation

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Coffee and diabetes risk association has been demonstrated in numerous studies; however, the exact mechanism has not been clarified yet. The present meta-analysis was conducted to cover the current knowledge regarding the effect of coffee on Type 2 Diabetes (T2D), in addition to the evaluation of adiponectin, leptin, C-reactive protein (CRP) and Interleukin-6 (IL-6) levels among coffee consumers as relatively possible mediators of this effect.. A comprehensive search of the literature was carried out using search engines up to March 2020. The effect sizes were investigated using the standardised mean difference (SMD) and odds ratios (OR) or relative risk (RR) with its 95% confidence interval (CI). A total of 69 cross-sectional and cohort studies were included and divided as follows: 31 articles for T2D risk, 15 studies for adiponectin, 6 studies for leptin, 12 studies for CRP and 5 studies for IL-6.. Overall, coffee consumption was inversely associated with T2D risk with an estimated pooled RR of 0.73 (95% confidence interval [0.68, 0.80] for the highest vs lowest coffee consumption categories. The combined SMD between the different coffee intake categories, showed that coffee consumption was associated with higher adiponectin levels (P = .002), and lower level of leptin (P = .04) and CRP (P = .2), with apparently no change in IL-6 levels (P = .91).. The present meta-analysis showed strong epidemiological evidence that coffee consumption is inversely associated with the risk of T2D. Also, adiponectin, leptin concentrations appeared to be potential mediators of the coffee effect on diabetes, while IL-6 levels did not.

Topics: Adiponectin; C-Reactive Protein; Coffee; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Interleukin-6; Leptin; Risk

Emerging evidence has identified sleep as a significant, but modifiable, risk factor for metabolic syndrome, diabetes, and obesity. Leptin, an adipocyte-derived peptide and a regulator of food intake and energy expenditure, has been shown to be associated with a short sleep duration in the pathophysiology of obesity and consequently type 2 diabetes. This review focuses on the current evidence indicating the effects of a short sleep duration on the regulation of leptin concentration in association with obesity and diabetes mellitus. In summary, the evidence suggests that sleep deprivation, by affecting leptin regulation, may lead to obesity and consequently development of type 2 diabetes through increased appetite and food intake. However, findings on the role of leptin in diabetes due to sleep deprivation are contradictory, and further studies with larger sample sizes are needed to confirm previous findings.

Topics: Diabetes Mellitus, Type 2; Humans; Leptin; Obesity; Sleep; Sleep Deprivation

The existence of molecular links that facilitate colorectal cancer (CRC) development in the population with type 2 diabetes (T2D) is supported by substantial epidemiological evidence. This review summarizes how the systemic, metabolic and hormonal imbalances from T2D alter CRC cell metabolism, signalling and gene expression as well as their reciprocal meshing, with an overview of CRC molecular subtypes and animal models to study the diabetes-CRC cancer links. Metabolic and growth factor checkpoints ensure a physiological cell proliferation rate compatible with limited nutrient supply. Hyperinsulinaemia and hyperleptinaemia in prediabetes and excess circulating glucose and lipids in T2D overcome formidable barriers for tumour development. Increased nutrient availability favours metabolic reprogramming, alters signalling and generates mutations and epigenetic modifications through increased reactive oxygen species and oncometabolites. The reciprocal control between metabolism and hormone signalling is lost in diabetes. Excess adipose tissue at the origin of T2D unbalances adipokine (leptin/adiponectin) secretion ratios and function and disrupts the insulin/IGF axes. Leptin/adiponectin imbalances in T2D are believed to promote proliferation and invasion of CRC cancer cells and contribute to inflammation, an important component of CRC tumourigenesis. Disruption of the insulin/IGF axes in T2D targets systemic and CRC cell metabolic reprogramming, survival and proliferation. Future research to clarify the molecular diabetes-CRC links will help to prevent CRC and reduce its incidence in the diabetic population and must guide therapeutic decisions.

Topics: Adiponectin; Animals; Colorectal Neoplasms; Diabetes Mellitus, Type 2; Humans; Insulin; Leptin

During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer's disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.

Topics: Adiponectin; Adipose Tissue; Adiposity; Aging; Alzheimer Disease; Arthritis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Acids; Gene Expression Regulation; Humans; Leptin; Lipid Metabolism; Lipidomics; Neoplasms; Obesity; Signal Transduction

We review the effects of acute and long-term physical activity on adipokine levels in individuals with type 2 diabetes (T2D). Three electronic databases were searched. Studies made in animal models were excluded, while studies based on participants with and without T2D, and also studies with type 1 diabetes were included. Of the 2,450 citations, 63 trials, including randomised control trials, cross-sectional and longitudinal studies, met our inclusion criteria. Seventy and five percent of studies reported the effects of physical activity on tumor necrosis factor-alpha (TNFα), interleukin 6 (IL-6), adiponectin, visfatin, omentin-1, and leptin levels. There are no robust results due to variations in exercise modality, intensity, duration, and also differences in cohort characteristics in the literature. Only four studies described the effects of an acute session of physical activity on adipokine levels. Overall, physical activity improves diabetes status by regulating adipokine levels. However, long-term aerobic + resistance training combined with dietary modifications is likely to be a more effective strategy for improving adipokines profiles in patients with type 2 diabetes.

Topics: Adipokines; Adiponectin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Exercise; Humans; Leptin

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and

Topics: Animals; Blood-Brain Barrier; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Leptin; Mice, Obese; Obesity; Signal Transduction

Obstructive sleep apnea (OSA), obesity, and disturbed glucose homeostasis are usually considered distinct clinical condition, although they are tightly related to each other. The aim of our manuscript is to provide an overview of the current evidence on OSA, obesity, and disturbed glucose homeostasis providing epidemiologic evidence, biological insights, and therapeutic strategies.. The mechanisms hypothesized to be involved in this complex interplay are the following: (1) "direct weight-dependent" mechanisms, according to which fat excess compromises respiratory mechanics, and (2) "indirect weight-dependent" mechanisms such as hyperglycemia, insulin resistance and secondary hyperinsulinemia, leptin resistance and other hormonal dysregulations frequently found in subjects with obesity, type 2 diabetes, and/or sleep disorders. Moreover, the treatment of each of these clinical conditions, through weight loss induced by diet or bariatric surgery, the use of anti-obesity or antidiabetic drugs, and continuous positive airway pressure (CPAP), seems to positively influence the others. These recent data suggest not only that there are multiple connections among these diseases but also that treating one of them may result in an improvement of the others.

Topics: Bariatric Surgery; Body Weight; Continuous Positive Airway Pressure; Diabetes Mellitus, Type 2; Diet; Glucose; Homeostasis; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Risk Factors; Sleep Apnea, Obstructive; Weight Loss

Different adipokines secreted from adipose tissue, exert a range of physiological effects. The aim of present systematic review and meta-analysis was to critically investigate the consequence of bariatric surgery on circulating adipokines, that is, adiponectin, leptin, visfatin, resistin, plasminogen activator inhibitor, and chemerin. After systematically checking the following electronic databases: ISI web of Science, Scopus and PubMed without limitation in time and language up to February 2019, a pool based on a random effect model was established. Eighty-five eligible studies were entered for quantitative analysis. Our meta-analysis revealed that circulating adiponectin increased significantly after bariatric surgery [Standardized mean difference (SMD)=1.401, 95% CI: 1.101, 1.701, p<0.001]; whilst leptin (SMD=-2.178, 95% CI: -2.433, -1.923, p<0.001), PAI-1 (-14.928 ng/ml 95% CI: -21.794, -8.063, p<0.001), and chemerin (-50.238 ng/ml 95% CI: -85.708, -14.768, p<0.001) decreased. However, serum visfatin (2.05 ng/ml, 95% CI: -5.07, 9.17, p=0.573) and resistin (-2.080 ng/ml, 95% CI: -5.352, 1.192, p=0.21) were unchanged. In conclusion, bariatric surgery is associated with a reduction in specific adipokines including leptin, chemerin, and PAI-1, whereas adiponectin is raised, adaptations that could be indicative of improved fat mass and function.

Topics: Adiponectin; Adipose Tissue; Bariatric Surgery; Chemokines; Cytokines; Diabetes Mellitus, Type 2; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Organ Size; Plasminogen Activator Inhibitor 1; Postoperative Period; Resistin; Weight Loss

The epidemic of obesity has become pandemic, putting a significant burden on the world's healthcare system. While the heritability of the disease is high, all the identified genetic variants associated to obesity account for a very small percentage of phenotypic variation. The origins of the obesity pandemic cannot be explained exclusively due to genetic factors. In recent years, epigenetic studies have offered valuable information for a deeper understanding of the steep increase in global obesity rates. Existing evidence indicate that environmental exposures induce alterations to the epigenome, leading to the transmission of obesity risk across generations. In this review, we provide insight into the epigenetic disturbances associated with obesity and discuss the impact of harmful diets, particularly calorie-dense foods, in the epigenetic regulation of obesity. The epigenetics of obesity is an expanding area of research, and current reports suggest potential in the use of epigenetic mechanisms as clinical biomarkers and therapeutic candidates.

Topics: Diabetes Mellitus, Type 2; Diet; DNA Methylation; Epigenesis, Genetic; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4

We aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D).. Our study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci between trait pairs that showed significant genetic correlations in the first part. In the end, we carried out a bidirectional MR analysis to find out whether there is a causal relationship between leptin levels and T2D or glycemic traits.. Our results have shown the shared genetic architecture between leptin levels and T2D and found causality of HOMA-IR on leptin levels, shedding light on the molecular mechanisms underlying the association between leptin levels and T2D.

Topics: Diabetes Mellitus, Type 2; Female; Genome-Wide Association Study; Humans; Leptin; Mendelian Randomization Analysis; Phenotype; Pregnancy

Leptin and adiponectin are two adipokines. Their circulating concentrations, high for leptin and low for adiponectin, are predictive of insulin resistance and of an unfavorable cardiometabolic evolution in patients with obesity, metabolic syndrome or type 2 diabetes. In addition, recently, the adiponectin/leptin ratio has been proposed as an index of adipose tissue dysfunction together with threshold values for cardiometabolic risk for this index. The relevance and potential applications of the adiponectin/leptin and leptin/adiponectin ratios are discussed in the light of recent literature in this brief update.

Topics: Adiponectin; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Prognosis; Risk Factors

Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly

Topics: Adipose Tissue; Autoimmune Diseases; Diabetes Mellitus, Type 2; Humans; Infections; Leptin; Obesity; Receptors, Leptin

This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of resveratrol intake on weight loss. We searched the following databases until July 2018: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Out of 831 reports, 36 RCTs were eligible for including to our meta-analysis. The pooled results, using random-effects model showed that resveratrol supplementation significantly decreased body weight (SMD = -0.17; 95% CI, -0.33, -0.01;

Topics: Adiponectin; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Leptin; Obesity; Randomized Controlled Trials as Topic; Resveratrol; Weight Loss

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new kind of hypoglycemic drugs that improve glucose homeostasis by inhibiting renal glucose reabsorption. Recent studies have shown that SGLT2 inhibitors can also mediate body metabolism through regulation of adipokines level, but the effects of SGLT2 inhibitors on the concentration of adipokines (leptin and adiponectin) remains controversial. This meta-analysis was set out to evaluate the changes in circulating leptin and adiponectin levels in patients with type 2 diabetes mellitus (T2DM) receiving SGLT2 inhibitors therapy. Ten randomized controlled trials (RCTs), that evaluated the effects of SGLT2 inhibitors on blood leptin and adiponectin levels in patients with type 2 diabetes, were identified by performing a systematic search of Pubmed, Embase, Cochrane, and Web of science databases through July 2018. Data were calculated using a random-effects model and presented as standardized mean difference (SMD) and 95% confidence interval (CI). Compared with placebo, treatment with SGLT2 inhibitors contributed to a decreased circulating leptin levels (SMD -0.29, 95% CI -0.56, -0.03) and an increased circulating adiponectin levels (SMD 0.30, 95% CI 0.22, 0.38). SGLT2 inhibitor treatment was associated with decreased circulating leptin levels and increased circulating adiponectin levels, which might contribute to the beneficial effects of SGLT2 inhibitors on metabolic homeostasis.

Topics: Adiponectin; Biomarkers; Diabetes Mellitus, Type 2; Humans; Leptin; Prognosis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

Lipodystrophy is a disease characterized by a partial or total absence of adipose tissue leading to severe metabolic derangements including marked insulin resistance, type 2 diabetes, hypertriglyceridemia, and steatohepatitis. Lipodystrophy is also a source of major cardiovascular disorders which, in addition to hepatic failure and infection, contribute to a significant reduction in life expectancy. Metreleptin, the synthetic analog of the adipocyte-derived hormone leptin and current therapy of choice for patients with lipodystrophy, successfully improves metabolic function. However, while leptin has been associated with hypertension, vascular diseases, and inflammation in the context of obesity, it remains unknown whether its daily administration could further impair cardiovascular function in patients with lipodystrophy. The goal of this short review is to describe the cardiovascular phenotype of patients with lipodystrophy, speculate on the etiology of the disorders, and discuss how the use of murine models of lipodystrophy could be beneficial to address the question of the contribution of leptin to lipodystrophy-associated cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Hypertriglyceridemia; Insulin Resistance; Leptin; Lipodystrophy; Mice

Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism-all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.

Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipotropic Agents; Melatonin; Natriuretic Peptides; Thermogenesis; Tretinoin

Diabetes is a metabolic disorder with multiple complications, including cardiomyopathy, retinopathy, nephropathy and neuropathy. Diabetic complications are the major cause of disability and death in diabetic patients. Apelin, a recently identified adipokine peptide, has been found to play important roles in diabetic complications. Here we summarize the current knowledge on the role of apelin in the pathogenesis of different diabetic complications. We also propose that similar to insulin resistance or leptin resistance, diabetics may also show apelin resistance. Potential clinical application of apelin and its analogue peptides in treating diabetic complications is discussed.

Topics: Apelin; Diabetes Complications; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Molecular Structure; Protein Conformation; Structure-Activity Relationship

The aim of the present study was to carry out a meta-analysis of randomized controlled trials (RCTs) that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes.. Literature searches were carried out using Medline, the Cochrane Controlled Trials Registry and ClinicalTrials.gov, and RCTs that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes were selected. Standardized mean differences and 95% confidence intervals were calculated.. A total of 10 RCTs met the eligibility criteria and were included in the meta-analysis. Significantly lower blood leptin levels were observed in the pioglitazone group (standardized mean difference -0.58, 95% confidence interval -1.12 to -0.05%, P = 0.03) than in the placebo group. There was no significant difference in blood leptin levels observed between the pioglitazone and oral antidiabetic drug groups (standardized mean difference -0.01, 95% confidence interval -0.20 to 0.19%, P = 0.93).. There was a significant difference in blood leptin levels between the pioglitazone and placebo groups. However, relatively few RCTs were included in the study, and there was a high level of statistical heterogeneity; we believe that this could have affected the results.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Leptin; Male; Middle Aged; Pioglitazone; Randomized Controlled Trials as Topic; Thiazolidinediones; Treatment Outcome

Excess adiposity can induce adverse sequelae in multiple cell types and organ systems. The transition from the lean to the obese state is characterized by fundamental cellular changes at the level of the adipocyte. These changes affect the local microenvironment within the respective adipose tissue but can also affect nonadipose systems. Adipocytes within fat pads respond to chronic nutrient excess through hyperplasia or hypertrophy, which can differentially affect interorgan crosstalk between various adipose depots and other organs. This crosstalk is dependent on the unique ability of the adipocyte to coordinate metabolic adjustments throughout the body and to integrate responses to maintain metabolic homeostasis. These actions occur through the release of free fatty acids and metabolites during times of energy need - a process that is altered in the obese state. In addition, adipocytes release a wide array of signalling molecules, such as sphingolipids, as well as inflammatory and hormonal factors (adipokines) that are critical for interorgan crosstalk. The interactions of adipose tissue with the kidney - referred to as the adipo-renal axis - are important for normal kidney function as well as the response of the kidney to injury. Here, we discuss the mechanistic basis of this interorgan crosstalk, which clearly has great therapeutic potential given the increasing rates of chronic kidney disease secondary to obesity and type 2 diabetes mellitus.

Topics: Adipokines; Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Angiotensin II; Angiotensinogen; Ceramidases; Diabetes Mellitus, Type 2; Humans; Inflammation; Kidney Diseases; Leptin; Macrophages; Obesity; Receptors, Adiponectin; Signal Transduction

Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Heart; Heart Failure; Humans; Hypoglycemic Agents; Intra-Abdominal Fat; Kidney Tubules; Leptin; Models, Biological; Myocardium; Obesity; Renal Insufficiency; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume

N-3 PUFAs can potentially influence levels of inflammatory and non-inflammatory adipokines. Given the contradictory effects of n-3 PUFAs on serum levels of adipokines in type 2 diabetes, we conducted a systematic review and meta-analysis study of randomized placebo-controlled clinical trials that examined the effects of n-3 PUFAs on serum levels of leptin and adiponectin in patients with type 2 diabetes.. The electronic databases, without regard to language restrictions including PubMed/Medline, Google Scholar, SCOPUS and ISI Web of Science until August 2017, were used to identify randomized controlled trials that assessed the effect of n-3 PUFAs on serum leptin and adiponectin concentrations in type 2 diabetes. Outcomes were extracted based on the mean ± SD as effect size at baseline and end of the intervention. Between-study heterogeneity was evaluated by the I. Data from 10 eligible articles involved 494 subjects with type 2 diabetes mellitus (intervention groups = 254 and control groups = 240), with age between 44 and 70 years, treated with doses of 0.52-7.4 g/day n-3 PUFAs. Adiponectin concentration nonsignificantly increased by a MD = 0.17 µg/mL (95% CI - 0.11, 0.44). Also, leptin concentration nonsignificantly reduced by a MD = - 0.31 ng/mL (95% CI - 0.69, 0.07).. Plant and marine sources of n-3 PUFAs can modify serum leptin and adiponectin levels by increasing adiponectin and decreasing leptin levels in patients with type 2 diabetes. Due to some limitations in this study, further studies are needed to reach a definitive conclusion about the effect of n-3 PUFAs on the levels of leptin and adiponectin in T2DM.

Topics: Adiponectin; Adult; Aged; Diabetes Mellitus, Type 2; Fatty Acids, Omega-3; Humans; Leptin; Middle Aged; Randomized Controlled Trials as Topic

Anthocyanins are food compounds which belong to polyphenols and can mainly be found in dark fruits (e.g., blueberries, black currants, cranberries) and vegetables (e.g., red cabbage, radish, eggplant). The results of large research have shown that these compounds play an important role in the prevention of type 2 diabetes (T2D). In rodent studies and in studies with isolated omental adipocytes, it was observed that anthocyanins regulated the carbohydrate metabolism in the body due to the upregulation of GLUT4 (insulinregulated glucose transporter) translocation, increased activation of PPARγ (peroxisome proliferator-activated receptor-γ) in adipose tissue and skeletal muscles as well as increased secretion of adiponectin and leptin. Moreover, these compounds reduced the inflammation status in the body. Studies conducted on humans and experimental animals showed that anthocyanins decrease insulin resistance. This effect may be achieved by the upregulation of GLUT4 gene expression, activation of AMP-activated protein kinase and downregulation of retinol binding protein 4 (RBP4) expression. Anthocyanins also increased the uptake and utilization of glucose by tissues in streptozotocin-induced diabetic rats and mice, and they also protected pancreatic cells against necrosis induced by streptozotocin. Another mechanism that might explain the lower glucose level in the blood after a meal with anthocyanins compared to a meal without them is the inhibition of intestinal α-glucosidase and pancreatic α-amylase by these compounds. Moreover, anthocyanins improve insulin secretion, which can have a special meaning for people with T2D. The evidence from the presented studies suggests that foods rich in anthocyanins may be one of the diet elements supporting the prevention and treatment of T2D.

Topics: Adiponectin; Animals; Anthocyanins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose Transporter Type 4; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Muscle, Skeletal; Pancreas; PPAR gamma; Rats; Retinol-Binding Proteins, Plasma

Leptin, an adipokine that is implicated in the control of food intake via appetite suppression, may also stimulate oxidative stress, inflammation, thrombosis, arterial stiffness, angiogenesis and atherogenesis. These leptin-induced effects may predispose to the development of cardiovascular diseases. In the present review we discuss the evidence linking leptin levels with the presence, severity and/or prognosis of both coronary artery disease and non-cardiac vascular diseases such as stroke, carotid artery disease, peripheral artery disease (PAD) and abdominal aortic aneurysms (AAA) as well as with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Leptin levels have been positively associated with the presence, severity, extent and lesion complexity of coronary atherosclerosis as well as with the presence, severity and poor clinical outcomes of both ischemic and hemorrhagic strokes. But conflicting results also exist. Furthermore, leptin was reported to independently predict common carotid intima-media thickness and carotid plaque instability. A link between hyperleptinemia and PAD has been reported, whereas limited data were available on the potential association between leptin and AAA. Elevated leptin concentrations have also been related to CKD incidence and progression as well as with insulin resistance, T2DM, micro- and macrovascular diabetic complications. Statins and antidiabetic drugs (including sitagliptin, metformin, pioglitazone, liraglutide and empagliflozin) may affect leptin levels. Further research is needed to establish the potential use (if any) of leptin as a therapeutic target in these diseases.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Leptin

One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA

Topics: Diabetes Mellitus, Type 2; Humans; Hypogonadism; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Prevalence; Testosterone

Obesity is metabolic disorder that increases the risk of diabetes, heart disease, and other metabolic syndromes in human beings. One sign of diabetes is increased blood glucose levels in the body. Glucose levels increase due to problems with insulin secretion or insulin resistance. Maturity onset of diabetes of the young is more common in adults and occurs due to insulin resistance. Both diabetes and obesity are major problems that are responsible for the death of millions of individuals every year, worldwide. Leptin, a 164-KDa hormone that is secreted by white adipose tissue, is a product of the lep gene. Mutation in lep decreases leptin concentration and increases obesity and type-2 diabetes mellitus. Leptin has been shown to produce positive effects on hunger, energy expenditure, and behavior and is thus useful in the treatment of obesity and type-2 diabetes. Leptin controls appetite through its effect on the hypothalamus in the brain. Both leptin and insulin regulate appetite, body weight, and glucose levels in the body.

Topics: Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Obesity

The aim of the present study was to conduct a meta-analysis of randomized controlled trials (RCTs) that investigated the effects of metformin on blood leptin and ghrelin levels in patients with type 2 diabetes mellitus (T2DM).. Literature searches were performed using MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov, and RCTs that investigated the effects of metformin on blood leptin and ghrelin levels in patients with T2DM were selected. Standardized mean differences (SMDs) and 95 % confidence intervals (CIs) were calculated.. Twelve RCTs met the eligibility criteria and were included in the meta-analysis. There was no significant difference in blood leptin between the metformin and control groups (SMD 0.03; 95 % CI -0.35 %, 0.42 %; P = 0.86), although there was a significant difference in blood leptin levels between the metformin group and the group on oral antidiabetic drugs (OADs) other than metformin (SMD -0.39; 95 % CI -0.76 %, -0.01 %; P = 0.04). There were no significant differences in blood ghrelin levels.. Metformin treatment was not associated with a decrease in blood leptin levels in patients with T2DM compared with levels in patients in the control group. Moreover, metformin treatment was not associated with increases in blood ghrelin levels compared with the control and other OADs groups. However, blood leptin levels were significantly lower in the metformin compared with the other OADs group.

Topics: Diabetes Mellitus, Type 2; Ghrelin; Humans; Hypoglycemic Agents; Leptin; Metformin; Randomized Controlled Trials as Topic; Treatment Outcome

The central link between obesity and type 2 diabetes is the development of insulin resistance. To date, it is still not clear whether hyperinsulinemia causes insulin resistance, which underlies the pathogenesis of obesity-associated type 2 diabetes, owing to the sophisticated regulatory mechanisms that exist in the periphery and in the brain. In recent years, accumulating evidence has demonstrated the existence of insulin resistance within the hypothalamus. In this review, we have integrated the recent discoveries surrounding both central and peripheral insulin resistance to provide a comprehensive overview of insulin resistance in obesity and the regulation of systemic glucose homeostasis. In particular, this review will discuss how hyperinsulinemia and hyperleptinemia in obesity impair insulin sensitivity in tissues such as the liver, skeletal muscle, adipose tissue, and the brain. In addition, this review highlights insulin transport into the brain, signaling pathways associated with hypothalamic insulin receptor expression in the regulation of hepatic glucose production, and finally the perturbation of systemic glucose homeostasis as a consequence of central insulin resistance. We also suggest future approaches to overcome both central and peripheral insulin resistance to treat obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Hypothalamus; Insulin Resistance; Leptin; Obesity; Signal Transduction

Leptin is an adipocyte-derived hormone not only with an important role in the central control of energy metabolism, but also with many pleiotropic effects in different physiological systems. One of these peripheral functions of leptin is a regulatory role in the interplay between energy metabolism and the immune system, being a cornerstone of the new field of immunometabolism. Leptin receptor is expressed throughout the immune system and the regulatory effects of leptin include cells from both the innate and adaptive immune system. Leptin is one of the adipokines responsible for the inflammatory state found in obesity that predisposes not only to type 2 diabetes, metabolic syndrome and cardiovascular disease, but also to autoimmune and allergic diseases. Leptin is an important mediator of the immunosuppressive state in undernutrition status. Placenta is the second source of leptin and it may play a role in the immunomodulation during pregnancy. Finally, recent work has pointed to the participation of leptin and leptin receptor in the pathophysiology of inflammation in oral biology. Therefore, leptin and leptin receptor should be considered for investigation as a marker of inflammation and immune activation in the frontier of innate-adaptive system, and as possible targets for intervention in the immunometabolic mediated pathophysiology.

Topics: Adaptive Immunity; Animals; Biomarkers; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Immune System; Immunity, Innate; Immunomodulation; Inflammation; Leptin; Mice; Obesity; Receptors, Leptin

The brain leptin signaling system has a key role in regulation of feeding behavior, peripheral metabo- lism, functions of the nervous and endocrine systems, and disturbances in this system lead to metabolic disorders, including metabolic syndrome (MS) and type 2 diabetes mellitus (DM2). This system is activa- ted by leptin produced by adipocytes and then penetrates into brain through the blood-brain barrier, where leptin binds to leptin receptors OBRb. This leads to activation of tyrosine kinase JAK2, which phosphory- lates tyrosine-containing sites located in the cytoplasmic domain of the receptor, resulting in stimulation of activity of phosphatidylinositol-3-kinase, the transcription factors STAT3 and STAT5, phosphatase SHP2, and mitogen-activated protein kinase. Decrease in number of functionally active leptin receptors and disturbances in the downstream components of leptin cascades in neuronal cells lead to development of leptin resistance. Since the leptin system in hypothalamic neurons is closely linked to the insulin, mela- nocortin, dopaminergic and other signaling systems, leptin resistance induces a lot of functional disorders in the CNS and on the periphery. The restoration of the brain leptin system functions is one of the promi- sing approaches to treatment and prevention of metabolic disorders, including MS and DM2. The review analyzes data on structural and functional organization of the leptin signaling system, its functional, interaction with other brain signaling systems, the causes and effects of central leptin resistance, as well as the approaches to restore the functions of the hypothalamic leptin system in MS and DM2. Key words: leptin, leptin resistance, hypothalamus, JAK2-kinase, leptin receptor, diabetes mellitus, metabolic syndrome, melanocortin system, phosphatase inhibitor.

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Humans; Leptin; Metabolic Syndrome; Nerve Tissue Proteins; Signal Transduction

The adipocytokines leptin and adiponectin have been variously associated with diabetic microvascular complications. No comprehensive clinical data exist examining the association between adipocytokines and the presence of these complications.. This is a systematic review of cross-sectional studies comparing circulating adipocytokines in patients with type 2 diabetes mellitus (T2DM), with and without microvascular complications. Studies were retrieved from MEDLINE, EMBASE, Scopus and Cochrane databases. Study quality was evaluated using a modified Newcastle-Ottawa Scale. Meta-analysis was performed using an inverse-variance model, providing standardised mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity was determined by I(2) statistic.. Amongst 554 identified studies, 28 were included in the review. Study quality range was 3.5-9 (maximum 11). Higher leptin levels were associated with microalbuminuria (SMD=0.41; 95% CI=0.14-0.67; n=901; p=0.0003), macroalbuminuria (SMD=0.68; 95% CI=0.30-1.06; n=406; p=0.0004), and neuropathy (SMD=0.26; 95% CI=0.07-0.44; n=609; p=0.008). Higher adiponectin levels were associated with microalbuminuria (SMD=0.55; 95% CI=0.29-0.81, n=274; p<0.001), macroalbuminuria (SMD=1.37; 95% CI=0.78-1.97, n=246; p<0.00001), neuropathy (SMD=0.25; 95% CI=0.14-0.36; n=1516; p<0.00001), and retinopathy (SMD=0.38; 95% CI=0.25-0.51; n=1306; p<0.00001). Meta-regression suggested no influence of body mass index and duration of diabetes on effect size, and a weak trend in terms of age on effect size.. Our meta-analysis suggests leptin and adiponectin levels are higher in T2DM patients with microvascular complications. Studies were limited by cross-sectional design. Large prospective analyses are required to validate these findings.

Topics: Adipokines; Adiponectin; Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Leptin; Male; Middle Aged

This review discusses current and future pharmacological approaches to the treatment of obesity, with a focus on the biological control of energy balance.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Bile Acids and Salts; Body Weight; Diabetes Mellitus, Type 2; Drug Discovery; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Hypothalamus; Inflammation; Leptin; Obesity; Oxidative Phosphorylation; Pediatric Obesity

While it is well established that the adiposity hormone leptin plays a key role in the regulation of energy homeostasis, growing evidence suggests that leptin is also critical for glycaemic control. In this review we examine the role of the brain in the glucose-lowering actions of leptin and the potential mediators responsible for driving hyperglycaemia in states of uncontrolled insulin-deficient diabetes (uDM). These considerations highlight the possibility of targeting leptin-sensitive pathways as a therapeutic option for the treatment of diabetes. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Christoffer Clemmensen and colleagues, DOI: 10.1007/s00125-016-3906-7 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).

Topics: Animals; Blood Glucose; Brain; Corticosterone; Diabetes Mellitus, Type 2; Homeostasis; Humans; Leptin

Patients with type 2 diabetes have lower serum testosterone levels and a higher prevalence of hypogonadism than non-diabetic patients, independently of the metabolic control of disease. The mechanisms underlying a decrease in testosterone might be related to age, obesity and insulin resistance, often present in patients with type 2 diabetes. The increase in estrogens due to higher aromatase enzyme activity in increased adipose tissue might exert negative-feedback inhibition centrally. Insulin stimulates gonadal axis activity at all three levels and therefore insulin resistance might account for the lower testosterone production. Leptin exerts a central stimulatory effect but inhibits testicular testosterone secretion. Thus, resistance to leptin in obese subjects with type 2 diabetes determines lower central effects of leptin with lower gonadotropin-releasing hormone (GnRH) secretion and, on the other hand, hyperleptinemia secondary to leptin resistance inhibits testosterone secretion at the testicular level. However, lower testosterone levels in patients with diabetes are observed independently of age, weight and body mass index, which leads to the assumption that hyperglycemia per se might play a role in the decrease in testosterone. Several studies have shown that an overload of glucose results in decreased serum testosterone levels. The aim of this review is to assess changes in the male gonadal axis that occur in patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Estrogens; Humans; Hyperglycemia; Hypogonadism; Insulin Resistance; Leptin; Male; Prevalence

β-cell failure coupled with insulin resistance plays a key role in the development of type 2 diabetes mellitus (T2DM). Changed adipokines in circulating level form a remarkable link between obesity and both β-cell failure and insulin resistance. Some adipokines have beneficial effects,whereas others have detrimental properties. The overall contribution of adipokines to β-cell failure mainly depends on the interactions among adipokines. This article reviews the role of individual adipokines such as leptin,adiponectin,and resistin in the function,proliferation,death,and failure of β-cells. Future studies focusing on the combined effects of adipokines on β-cells failure may provide new insights in the treatment of T2DM.

Topics: Adipokines; Adiponectin; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Obesity; Resistin

Aging leads to a number of physiological alterations, specifically changes in circulating hormone levels, increases in fat deposition, decreases in metabolism, changes in inflammatory responses, and reductions in growth factors. These progressive changes in physiology and metabolism are exacerbated by modern culture and Western diet and give rise to diseases such as obesity, metabolic syndrome, and type 2 (non-insulin-dependent) diabetes (T2D). These age and lifestyle-related metabolic diseases are often accompanied by insulin and leptin resistance, as well as aberrant amylin production and signaling. Many of these alterations in hormone production and signaling are directly influenced by an increase in both oxidative stress and inflammation. Importantly, changes in hormone production and signaling have direct effects on brain function and the development of age-related neurologic disorders. Therefore, this review aims to present evidence on the effects that diet and metabolic disease have on age-related cognitive decline and the development of cognitive diseases, particularly Alzheimer disease. This review will focus on the metabolic hormones insulin, leptin, and amylin and their role in cognitive decline, as well as the therapeutic potential of these hormones in treating cognitive disease. Future investigations targeting the long-term effects of insulin and leptin treatment may reveal evidence to reduce risk of cognitive decline and Alzheimer disease.

Topics: Aging; Alzheimer Disease; Cognition; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Obesity

Metabolic homeostasis requires integration of complex signaling networks which, when deregulated, contribute to metabolic syndrome and related disorders. Protein-tyrosine phosphatase 1B (PTP1B) has emerged as a key regulator of signaling networks that are implicated in metabolic diseases such as obesity and type 2 diabetes. In this review, we examine mechanisms that regulate PTP1B-substrate interaction, enzymatic activity and experimental approaches to identify PTP1B substrates. We then highlight findings that implicate PTP1B in metabolic regulation. In particular, insulin and leptin signaling are discussed as well as recently identified PTP1B substrates that are involved in endoplasmic reticulum stress response, cell-cell communication, energy balance and vesicle trafficking. In summary, PTP1B exhibits exquisite substrate specificity and is an outstanding pharmaceutical target for obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Humans; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Thermodynamics

This year marks the 20th anniversary of the discovery of leptin, which has tremendously stimulated translational obesity research. The discovery of leptin has led to realizations that have established adipose tissue as an endocrine organ, secreting bioactive molecules including hormones now termed adipokines. Through adipokines, the adipose tissue influences the regulation of several important physiological functions including but not limited to appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion, glucose and lipid metabolism, fat distribution, endothelial function, hemostasis, blood pressure, neuroendocrine regulation, and function of the immune system. Adipokines have a great potential for clinical use as potential therapeutics for obesity, obesity related metabolic, cardiovascular and other diseases. After 20 years of intense research efforts, recombinant leptin and the leptin analog metreleptin are already available for the treatment of congenital leptin deficiency and lipodystrophy. Other adipokines are also emerging as promising candidates for urgently needed novel pharmacological treatment strategies not only in obesity but also other disease states associated with and influenced by adipose tissue size and activity. In addition, prediction of reduced type 2 diabetes risk by high circulating adiponectin concentrations suggests that adipokines have the potential to be used as biomarkers for individual treatment success and disease progression, to monitor clinical responses and to identify non-responders to anti-obesity interventions. With the growing number of adipokines there is an increasing need to define their function, molecular targets and translational potential for the treatment of obesity and other diseases. In this review we present research data on adipose tissue secreted hormones, the discovery of which followed the discovery of leptin 20 years ago pointing to future research directions to unravel mechanisms of action for adipokines.

Topics: Adipokines; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Humans; Leptin; Obesity

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease, which is often accompanied by obese and/or type II diabetes mellitus. Approximately one-third of NASH patients develop hepatic fibrosis. Hepatic stellate cells are the major effector cells during liver fibrogenesis. Advanced liver fibrosis usually proceeds to cirrhosis and even hepatocellular carcinoma, leading to liver failure, portal hypertension and even death. Currently, there are no approved agents for treatment and prevention of liver fibrosis in human beings. Curcumin, the principal curcuminoid of turmeric, has been reported to show antitumor, antioxidant, and anti-inflammatory properties both in in vitro and in vivo systems. Accumulating data shows that curcumin plays a critical role in combating liver fibrogenesis. This review will discuss the inhibitory roles of curcumin and update the underlying mechanisms by which curcumin targets in inhibiting hepatic stellate cell activation.

Topics: Animals; Curcumin; Diabetes Mellitus, Type 2; Disease Models, Animal; Hepatic Stellate Cells; Humans; In Vitro Techniques; Leptin; Lipid Metabolism; Liver Cirrhosis; Oxidative Stress; Signal Transduction

Obesity and diabetes represent a significant healthcare concern. In contrast to genome-wide association studies that, some exceptions notwithstanding, have offered modest clues about pathomechanism, the dissection of rare disorders in which obesity represents a core feature have highlighted key molecules and structures critical to energy regulation. Here we focus on the primary cilium, an organelle whose roles in energy homeostasis have been underscored by the high incidence of obesity and type II diabetes in patients and mouse mutants with compromised ciliary function. We discuss recent evidence linking ciliary dysfunction to metabolic defects and we explore the contribution of neuronal and nonneuronal cilia to these phenotypes.

Topics: Animals; Cilia; Diabetes Mellitus, Type 2; Energy Metabolism; Hypothalamus; Leptin; Microtubule-Associated Proteins; Obesity; Receptors, Leptin; STAT3 Transcription Factor

Obesity is a central health issue due to its epidemic prevalence and its association with type 2 diabetes and other comorbidities. Obesity is not just being overweight. It is a metabolic disorder due to the accumulation of excess dietary calories into visceral fat and the release of high concentrations of free fatty acids into various organs. It represents a state of chronic oxidative stress and low-grade inflammation whose intermediary molecules may include leptin, adiponectin and cytokines. It may progress to hyperglycemia, leading to type 2 diabetes. Whether or not dietary antioxidant supplements are useful in the management of obesity and type 2 diabetes is discussed in this review. Only the benefits for obesity and diabetes are examined here. Other health benefits of antioxidants are not considered. There are difficulties in comparing studies in this field because they differ in the time frame, participants' ethnicity, administration of antioxidant supplements, and even in how obesity was measured. However, the literature presents reasonable evidence for marginal benefits of supplementation with zinc, lipoic acid, carnitine, cinnamon, green tea, and possibly vitamin C plus E, although the evidence is much weaker for omega-3 polyunsaturated fatty acids, coenzyme Q10, green coffee, resveratrol, or lycopene. Overall, antioxidant supplements are not a panacea to compensate for a fast-food and video-game way of living, but antioxidant-rich foods are recommended as part of the lifestyle. Such antioxidant foods are commonly available.

Topics: Adipose Tissue; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Antioxidants; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Dietary Supplements; Fatty Acids, Nonesterified; Genetic Predisposition to Disease; Humans; Inflammation; Leptin; Obesity; Overweight; Oxidative Stress; Proprotein Convertase 1; Proteins; Reactive Oxygen Species; Receptor, Melanocortin, Type 4; Vitamins

Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies.

Topics: Carcinoma, Hepatocellular; Chemoprevention; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Incidence; Inflammation; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Leptin; Liver Neoplasms; Metformin; Non-alcoholic Fatty Liver Disease; Obesity; Risk Factors; S-Adenosylmethionine; Toll-Like Receptors

Leptin (Lep) is emerging as a pivotal molecule involved in both the early events and the terminal phases of Alzheimer's disease (AD). In the canonical pathway, Lep acts as an anorexigenic factor via its effects on hypothalamic nucleus. However, additional functions of Lep in the hippocampus and cortex have been unravelled in recent years. Early events in the sporadic form of AD likely involve cellular level alterations which can have an effect on food intake and metabolism. Thus, AD can be conceivably interpreted as a multiorgan pathology that not only results in a dramatic neuronal loss in brain areas such as the hippocampus and the cortex (ultimately leading to a significant cognitive impairment) but as a disease which also affects body-weight homeostasis. According to this view, body-weight control disruptions are to be expected in both the early- and late-stage AD, concomitant with changes in serum Lep content, alterations in Lep transport across the blood-brain barrier (BBB) and Lep receptor-related signalling abnormalities. Lep is a member of the adipokine family of molecules, while the Lep receptor belongs to the class I cytokine receptors. Since cellular response to adipokine signalling can be either potentiated or diminished as a result of specific ligand-receptor interactions, Lep interactions with other members of the adipokine family including amylin, ghrelin and hormones such as prolactin require further investigation. In this review, we provide a general perspective on the functions of Lep in the brain, with a particular focus on the sporadic AD.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Ghrelin; Humans; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Life Style; Obesity; Prolactin; Protein Binding

Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of α-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity.

Topics: Animals; Appetite; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exercise; Gene-Environment Interaction; Humans; Hypertension; Leptin; Obesity; Potassium, Dietary; Protective Factors; Receptor, Melanocortin, Type 4; Sodium, Dietary; Sympathetic Nervous System

After the discovery of the db gene in 1966, it was determined that a blood-borne satiety factor was produced excessively, but was not responded to, in db/db mice. This model for type 2 diabetes is widely used since it phenocopies human disease and its co-morbidities including obesity, progressive deterioration in glucose tolerance, hypertension and hyperlipidaemia. Db/db mice, unlike their non-diabetic controls, have consistently elevated levels of liver glycogen, most likely due to hyperphagia. In transmission electron micrographs, liver glycogen usually shows a composite cauliflower-like morphology of large "α particles" (with a wide range of sizes) made up of smaller "β particles" bound together. New studies have explored the size distribution of liver glycogen molecules and found that α particles in db/db mice are more chemically fragile than those in healthy mice, and can readily break apart to smaller β particles. There is evidence that smaller glycogen particles have a higher association with glycogen phosphorylase, a key enzyme involved in glycogen degradation, as well as being degraded more rapidly in vitro; therefore the inability to form stable large glycogen α particles is predicted to result in a faster, less controlled degradation into glucose. The implications of this for glycaemic control remain to be fully elucidated. However, "rescuing" the more fragile diabetic glycogen to decrease hepatic glucose output in type 2 diabetes, may provide a potential therapeutic target which is the subject of this review.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Leptin; Liver Glycogen; Mice, Mutant Strains; Microscopy, Electron, Transmission

Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.

Topics: Animals; Cilia; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Homeostasis; Humans; Insulin; Leptin; Metabolic Diseases; Mice; Microtubules; Obesity; Signal Transduction

Links between short sleep duration and obesity, type 2 diabetes, hypertension, and cardiovascular disease may be mediated through changes in dietary intake. This review provides an overview of recent epidemiologic studies on the relations between habitual short sleep duration and dietary intake in adults from 16 cross-sectional studies. The studies have observed consistent associations between short sleep duration and higher total energy intake and higher total fat intake, and limited evidence for lower fruit intake, and lower quality diets. Evidence also suggests that short sleepers may have irregular eating behavior deviating from the traditional 3 meals/d to fewer main meals and more frequent, smaller, energy-dense, and highly palatable snacks at night. Although the impact of short sleep duration on dietary intake tends to be small, if chronic, it may contribute to an increased risk of obesity and related chronic disease. Mechanisms mediating the associations between sleep duration and dietary intake are likely to be multifactorial and include differences in the appetite-related hormones leptin and ghrelin, hedonic pathways, extended hours for intake, and altered time of intake. Taking into account these epidemiologic relations and the evidence for causal relations between sleep loss and metabolism and cardiovascular function, health promotion strategies should emphasize improved sleep as an additional factor in health and weight management. Moreover, future sleep interventions in controlled studies and sleep extension trials in chronic short sleepers are imperative for establishing whether there is a causal relation between short sleep duration and changes in dietary intake.

Topics: Adult; Aged; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet; Dietary Fats; Dietary Fiber; Energy Intake; Feeding Behavior; Female; Fruit; Ghrelin; Health Promotion; Health Status; Humans; Hypertension; Leptin; Male; Middle Aged; Nutritive Value; Obesity; Sleep; Sleep Deprivation; Snacks; Time Factors

The insulin signaling system of the brain has a key role in the regulation of fundamental cell processes in neurons and controls metabolic processes in the CNS and periphery. In hypothalamic neurons insulin signaling system interacts closely with the other signaling systems regulated by leptin, melanocortin peptides, dopamine, serotonin, and is the key component of the hypothalamic signaling network, which integrates and transforms the central and peripheral signals. The disturbances in the brain insulin system lead to central insulin resistance, which is one of the primary causes of type 2 diabetes mellitus (DM), metabolic syndrome and Alzheimer's disease. The early restoration of the functions of this system provides an effective approach to prevent and treat type 2 DM and neurodegenerative diseases associated to it. In this review the literature data and own results on structural functional organization of the brain insulin signaling system, causes and functional consequences of central insulin resistance, abnormalities of insulin signaling in the CNS and approaches to its restoration in type 2 DM are analyzed and discussed.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Dopamine; Humans; Hypoglycemic Agents; Hypothalamus; Insulin; Insulin Resistance; Leptin; Melanocortins; Metabolic Syndrome; Neurons; Serotonin; Signal Transduction

Random mutagenesis of mouse leptin antagonist (L39A/D40A/F41) followed by selection of high-affinity mutants by yeastsurface display indicated that replacing residue D23 with a non-negatively charged amino acid (most specifically with Leu) leads to dramatically enhanced affinity of leptin toward LEPR leading to development of superactive mouse, human, ovine and rat leptin antagonists (D23L/L39A/D40A/F41A). Superactive leptin antagonist mutants of mouse, human, rat or ovine leptins were developed in our laboratory, expressed in E. coli, refolded and purified to homogeneity as monomeric proteins. Pegylation of leptin antagonists resulted in potent and effective long-acting reagents suitable for in vivo studies or therapies. In the present review we explain the mechanism of leptin inhibition and summarize the possible use of leptin antagonists as possible leptin blockers in various human pathologies such as antiinflammatory and anti-autoimmune diseases, uremic cachexia, and cancer. We also suggest the use of leptin antagonists as research reagents for creation of a novel, fast and reversible model of T2DM in mice.

Topics: Amino Acid Substitution; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Autoimmunity; Diabetes Mellitus, Type 2; Drug Design; Drugs, Investigational; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Leptin; Ligands; Mutant Proteins; Receptors, Leptin; Recombinant Proteins

This meta-analysis aimed to assess the gender-specific differences in the relationship between circulating leptin levels and risk of type 2 diabetes. Published prospective studies that reported the association of leptin levels with risk of type 2 diabetes for a certain gender or those that reported gender-specific associations were considered. Dose-response relationships were assessed by the generalized least squares trend estimation and summary relative risks (RRs) with 95% confidence interval (CI) were computed with the random-effects model. Stratified and sensitivity analyses were also performed to investigate potential sources of heterogeneity. Overall, 11 prospective studies were identified. The summary RR for an increment in leptin levels of 1-log ng mL(-1) was 1.37 (95% CI, 1.13-1.66) for men and 0.96 (95% CI, 0.90-1.03) for women. The differences between genders were statistically significant (P for interaction = 0.006). Subgroup and sensitivity analyses generally confirmed the robustness of these findings. Furthermore, the increased risk in men appeared non-linear, with a tendency to plateau at high levels (P for non-linearity = 0.03). Little evidence of publication bias was found. Collectively, higher leptin levels were found to be associated with elevated risk of type 2 diabetes in men but not in women.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Obesity; Prospective Studies; Risk Factors; Sex Factors

Both reduction in total sleep duration with slow-wave sleep (SWS) largely preserved and alterations of sleep quality (especially marked reduction of SWS) with preservation of total sleep duration are associated with insulin resistance without compensatory increase in insulin secretion, resulting in impaired glucose tolerance and increased risk of type 2 diabetes. When performed under rigorously controlled conditions of energy intake and physical activity, sleep restriction is also associated with a decrease in circulating levels of leptin (an anorexigenic hormone) and an increase in circulating levels of ghrelin (an orexigenic hormone), hunger and appetite. Furthermore, sleep restriction is also associated with a stimulation of brain regions sensitive to food stimuli, indicating that sleep loss may lead to obesity through the selection of high-calorie food. There is also evidence that sleep restriction could provide a permissive environment for the activation of genes that promote obesity. Indeed, the heritability of body mass index is increased in short sleepers. Thus, chronic sleep curtailment, which is on the rise in modern society, including in children, is likely to contribute to the current epidemics of type 2 diabetes and obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Sleep

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Topics: Animals; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Rats; Rats, Inbred Strains; Rats, Zucker; Receptors, Leptin

Clozapine is, and will remain in the coming years, an irreplaceable drug in psychiatry which has elective indication in treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. Unfortunately, the drug is largely underused for many and serious side effects. Only a good knowledge of these side effects and of the main strategies to prevent their occurrence or minimize their impact can allow overcoming the underutilization of this valuable therapy. The article describes the clinical and epidemiological features of the non-motor side effects of clozapine including blood dyscrasias, constipation, diabetes, enuresis, fever, hepatitis, hypersalivation, ileus, myocarditis, nephritis, priapism, seizures, serositis, weight gain and metabolic syndrome. The paper suggests several strategies, supported by scientific evidence, in the management of these side effects. The neuropsychiatric side effects of clozapine are not discussed in this review.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Electroencephalography; Humans; Leptin; Metabolic Syndrome; Paraproteinemias; Receptor, Serotonin, 5-HT2C; Seizures; Weight Gain

The molecular mechanisms of body weight and body composition regulation have long been a research focus in the hopes of identifying tractable pathways for therapeutic interventions for obesity and diabetes, as well as related disorders such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and polycystic ovary syndrome. The metabolic consequences of obesity and type 2 diabetes (T2D) were already a focus of the world's attention in 1994 when the discovery of leptin generated enormous enthusiasm for the potential to treat common (non-monogenic) obesity and its associated metabolic disorders with an adipokine hormone that regulated body weight as well as lipid and carbohydrate metabolism. Recombinant human leptin and many leptin analogs were developed and studied in animals and a few in human clinical trials. Overall, the opportunity for leptin as a therapeutic in unselected patients with obesity and T2D has not been substantiated in clinical trials. The potential for combination therapy suggested by clinical studies with leptin and pramlintide supports a path toward obesity treatment through the leptin pathway. The profound metabolic benefits seen with leptin in numerous forms of leptin deficiency, including lipodystrophy, provide hope for the opportunity to identify selected subsets of patients who could benefit from leptin treatment. This review provides a comprehensive overview of the clinical data on a subset of the potential utilities of leptin, specifically as a therapeutic for general or common obesity and its metabolic consequences including T2D and NAFLD/NASH.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Leptin; Lipodystrophy; Non-alcoholic Fatty Liver Disease; Obesity; Treatment Outcome

Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues.. Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue.. Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.

Topics: Appetite Depressants; Diabetes Mellitus, Type 2; Eating; Humans; Hypoglycemic Agents; Hypothalamus; Insulin Resistance; Leptin; Metformin; Obesity; Risk Reduction Behavior; Signal Transduction; Treatment Outcome; Weight Loss

Osteocalcin is a bone matrix protein that has been associated with several hormonal actions on energy and glucose metabolism. Animal and experimental models have shown that osteocalcin is released into the bloodstream and exerts biological effects on pancreatic beta cells and adipose tissue. Undercarboxylated osteocalcin is the hormonally active isoform and stimulates insulin secretion and enhances insulin sensitivity in adipose tissue and muscle. Insulin and leptin, in turn, act on bone tissue, modulating the osteocalcin secretion, in a traditional feedback mechanism that places the skeleton as a true endocrine organ. Further studies are required to elucidate the role of osteocalcin in the regulation of glucose and energy metabolism in humans and its potential therapeutic implications in diabetes, obesity and metabolic syndrome.

Topics: Adipose Tissue; Animals; Bone and Bones; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Metabolic Syndrome; Muscles; Obesity; Osteocalcin

The adipose tissue is an endocrine organ that produces a variety of protein hormones. One of them is leptin, which regulates several critical functions at the central nervous system such as caloric intake, basal energy expenditure, reproduction, glucose and lipid metabolism and osteogenesis. Acting at a local level, leptin modulates the immune system and promotes liver fibrogenesis. The most promising therapeutic implications of leptin will possibly be in type 1 diabetes mellitus (DM1). Its supplementation in animal models of DM1 prevents hyperglycemia and ketoacidosis. These actions depend on the activation of leptin receptors in the central nervous system and the suppression of glucagon signaling in the liver.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Leptin; Mice; Rats; Receptors, Leptin

The metabolic syndrome comprises a cluster of cardiometabolic risk factors, with insulin resistance and adiposity as its central features. Identifying individuals with metabolic syndrome is important due to its association with an increased risk of coronary heart disease and type 2 diabetes mellitus. Attention has focused on the visceral adipose tissue production of cytokines (adipokines) in metabolic syndrome and type 2 diabetes mellitus, as the levels of the anti-inflammatory adipokine adiponectin are decreased, while proinflammatory cytokines are elevated, creating a proinflammatory state associated with insulin resistance and endothelial dysfunction. In this review, we will give special attention to the role of the leptin/adiponectin ratio. We have previously demonstrated that in individuals with severe coronary artery disease, abdominal obesity was uniquely related to decreased plasma concentrations of adiponectin and increased leptin levels. Leptin/adiponectin imbalance was associated with increased waist circumference and a decreased vascular response to acetylcholine and increased vasoconstriction due to angiotensin II. Leptin and adiponectin have opposite effects on subclinical inflammation and insulin resistance. Leptin upregulates proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6; these are associated with insulin resistance and type 2 diabetes mellitus. In contrast, adiponectin has anti-inflammatory properties and downregulates the expression and release of a number of proinflammatory immune mediators. Therefore, it appears that interactions between angiotensin II and leptin/adiponectin imbalance may be important mediators of the elevated risk of developing type 2 diabetes mellitus and cardiovascular diseases associated with abdominal obesity.

Topics: Adiponectin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Leptin; Metabolic Syndrome; Obesity, Abdominal

One of the crucial factors leading to the development of pre-diabetes and type 2 diabetes mellitus (DM2) are the disturbances in the brain hormonal signaling systems regulated by insulin, insulin-like growth factor-1 (IGF-1) and leptin. The causes of these disturbances are the changes in the redox balance and lipid metabolism leading to lipotoxicity and endoplasmic reticulum stress in neuronal cells, as well as the dysfunctions in neurotransmitter systems of the brain that are functionally associated with insulin, IGF-1 and leptin signaling systems. The identification of molecular disturbances in insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 can be used for early diagnostics of these diseases, and to develop new strategies for preventive treatment of DM2 at the pre-diabetic stage. In the review, the literature data and the results of own investigations concerning the changes in the insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 and their role in the etiology and pathogenesis of DM2 are analyzed, and the approaches to restore the functional activity of these systems are discussed.

Topics: Animals; Asymptomatic Diseases; Blood Glucose; Brain; Diabetes Mellitus, Type 2; Disease Progression; Gene Expression Regulation; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Neurons; Oxidative Stress; Signal Transduction

The purposeful use of plant minor biologically active food substances (with demonstrated evident hypoglycemic, hypocholesterolemic and antioxidant action) in the composition of specialized dietary products can become the inno- vative approach for the dietary treatment of type 2 diabetes mellitus. Clinical testing of minor biologically active food substances of plant origin and their further use in the composition of specialized dietary products should be preceded by the stage of complex physiological and biochemical studies in vivo. It all turns on the question: to which extent the results obtained with the biomodel can be extrapolated on the human body. Hence, this review comparatively evaluates the rat models of type 2 diabetes. In this paper, we overview the most frequently used monogenic models of obesity with the damage of the leptin signaling path- way, when the animal loses control over saturation, hyperphagia and subsequent obesity appear. We describe polygenic models of obesity-related diabetes with fatty rats, which are more approximated to type 2 diabetes mellitus in humans. The characteristic of the type 2 diabetes model without obesity is given in the article: the SDT (Spontaneously Diabetic Torii) rats are genetically predisposed to glucose intolerance. Spontaneously Diabetic Torii-fa/fa (SDT fatty) rat is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a younger age as compared with SDTrats. In conclusion, the SDT fatty rats are useful as a model for the development of new drugs and/or specialized dietary products to reduce body fat mass.

Topics: Animal Feed; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Genetic Testing; Glucose Intolerance; Insulin Resistance; Leptin; Micronutrients; Nutritional Status; Obesity; Rats; Signal Transduction

Peptide hormones and proteins control body weight and glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of body weight and euglycaemia. The development of obesity, often in association with type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic, anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM. Here, we review advances in the science of co-agonist therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of glucagon-like peptide 1, glucagon, gastric inhibitory polypeptide, gastrin, islet amyloid polypeptide and leptin, which enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation.

Topics: Animals; Blood Glucose; Body Weight; Central Nervous System; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Leptin; Obesity

Obesity is a chronic disease, and it requires chronic therapy. Hypertension, dyslipidemia, diabetes and cardiovascular diseases are leading causes of mortality in the modern world. All of them are strongly linked to obesity. While treating obesity, those conditions are also managed. Obese patients should always be treated through lifestyle interventions, though the results of such interventions are modest. Pharmacotherapy is a second step in the treatment of obesity, approved only when weight loss targets were not reached through lifestyle intervention. During the history of antiobesity drugs, many of them were withdrawn because of their side effects. Various guidelines recommend prescribing drug therapy for obesity through consideration of the potential benefits and limitations. Orlistat deactivates intestinal lipase and inhibits intestinal fat lipolysis. It is actually the only drug on the European market approved for the treatment of obesity. Orlistat therapy reduces weight to a modest extent, but it reduces the incidence of diabetes beyond the result achieved with lifestyle changes. Recently, some effective antiobesity drugs like sibutramine and rimonabant have been removed from the market due to their side effects. The new combination of topimarate and fentermine is approved in the US but not in Europe. The cost effectiveness of long-term pharmacotherapy of obesity is still an unresolved question.

Topics: Anti-Obesity Agents; Appetite; Combined Modality Therapy; Comorbidity; Cost-Benefit Analysis; Cyclobutanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Combinations; Exercise Therapy; Fructose; Gastrointestinal Hormones; Humans; Incretins; Insulin; Insulin Secretion; Intestines; Lactones; Leptin; Life Style; Models, Biological; Neuropeptides; Obesity; Orlistat; Phentermine; Phytotherapy; Piperidines; Plant Preparations; Pyrazoles; Rimonabant; Topiramate

An increase in adiposity is associated with altered levels of biologically active proteins. These include the hormones adiponectin and leptin. The marked change in circulating concentrations of these hormones in obesity has been associated with the development of insulin resistance and metabolic syndrome. Variations in dietary lipid consumption have also been shown to impact obesity. Specifically, omega-3 fatty acids have been correlated with the prevention of obesity and subsequent development of chronic disease sequalae. This review explores animal and human data relating to the effects of omega-3 fatty acids (marine lipids) on adiponectin and leptin, considering plausible mechanisms and potential implications for obesity management. Current evidence suggests a positive, dose-dependent relationship between omega-3 fatty acid intake and circulating levels of adiponectin. In obese subjects, this may translate into a reduced risk of developing cardiovascular disease, metabolic syndrome and diabetes. In non-obese subjects, omega-3 is observed to decrease circulating levels of leptin; however, omega-3-associated increases in leptin levels have been observed in obese subjects. This may pose benefits in the prevention of weight regain in these subjects following calorie restriction.

Topics: Adiponectin; Animals; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dietary Supplements; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Health Promotion; Humans; Inflammation; Leptin; Metabolic Syndrome; Obesity; Randomized Controlled Trials as Topic

There is a pressing need for new effective therapeutic strategies for addressing the epidemic of type 2 diabetes. Leptin has been shown to reduce hyperglycaemia in rodent models of type 1 diabetes and has recently been shown to normalize fasting plasma glucose concentrations in a rodent model of polygenic obesity and type 2 diabetes. Overall, these findings suggest that leptin may be an effective therapeutic option for both type 1 and type 2 diabetes. However, short-term human clinical studies in overweight and obese patients with recently diagnosed type 2 diabetes have reported minimal efficacy of leptin administration to lower blood glucose levels. Herein, the role of leptin in the maintenance of glucose homeostasis and the potential use of leptin in the treatment of type 2 diabetes are discussed.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Leptin; Obesity

Obesity and diabetes are major causes of CKD and ESRD, and are thus enormous health concerns worldwide. Both obesity and diabetes, along with other elements of the metabolic syndrome including hypertension, are highly interrelated and contribute to the development and progression of renal disease. Studies show that multiple factors act in concert to initially cause renal vasodilation, glomerular hyperfiltration, and albuminuria, leading to the development of glomerulopathy. The coexistence of hypertension contributes to the disease progression, which, if not treated, may lead to ESRD. Although early intervention and management of body weight, hyperglycemia, and hypertension are imperative, novel therapeutic approaches are also necessary to reduce the high morbidity and mortality associated with both obesity-related and diabetes-related renal disease.

Topics: Adiponectin; Animals; Cardiovascular Diseases; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Early Medical Intervention; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Leptin; Medication Therapy Management; Mice; Models, Animal; Obesity; Risk Reduction Behavior

Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Animals; Chronic Disease; Clinical Trials as Topic; Cytokines; Diabetes Mellitus, Type 2; Exercise; Female; Humans; Inflammation; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Serpins

It is well known that adverse conditions during intrauterine life, such as intrauterine growth restriction (IUGR), can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased risk of disease in adulthood (fetal origin of adult disease hypothesis). In the first part of this review the epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed are reported. The second part of the review is focused on metabolomics studies that have revealed an altered metabolism in IUGR patients compared to controls. Together with more classic biomarkers of IUGR, such as endothelin-1, leptin, protein S100B and visfatin, the new holistic metabolomics approach has assumed a crescent role in the identification of disorders in the neonatal metabolic profile, determined by the interconnection of the different processes.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Epigenomics; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Genotype; Humans; Infant, Low Birth Weight; Infant, Newborn; Leptin; Metabolomics; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors

Most of the drugs available to treat type 2 diabetes mellitus (T2DM) act either in the pancreas by increasing insulin secretion or in tissues such as the liver or muscle by improving insulin sensitivity. However, recent studies have shown that the brain also plays a critical role in the regulation of glucose homeostasis. For example, central leptin administration reduces hyperglycemia and improves the survival of mice with type 1 diabetes mellitus (T1DM). In addition, several pieces of evidence show that the brain can control the insulin sensitivity in different tissues and the pancreatic secretion of insulin and glucagon. Therefore, the brain emerges as a promising new target of drugs aiming to treat both T1DM and T2DM. An exciting finding is that there is a partial overlap between neuronal populations that regulate energy balance and glucose homeostasis. Therefore, obesity and T2DM may have similar origins that are related to dysfunctions in the central nervous system. Likewise, future drugs that target the brain to treat T2DM may have beneficial effects in reducing body weight, and vice versa. In this review, the recent data showing how the brain is able to have an important regulatory effect over blood glucose levels as well as the possible neuronal circuitries involved in the control of glucose homeostasis will be summarized. The opportunities and challenges of using synthetic drugs or natural compounds that act in the central nervous system to treat diabetes mellitus will also be discussed.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Insulin; Leptin; Lipodystrophy; Signal Transduction

During the development of type 2 diabetes mellitus, skeletal muscle is a major site of insulin resistance. The latter has been linked to mitochondrial dysfunction and impaired fatty acid oxidation. Some hormones like insulin, thyroid hormones and adipokines (e.g., leptin, adiponectin) have positive effects on muscle mitochondrial bioenergetics through their direct or indirect effects on mitochondrial biogenesis, mitochondrial protein expression, mitochondrial enzyme activities and/or AMPK pathway activation--all of which can improve fatty acid oxidation. It is therefore not surprising that treatment with these hormones has been proposed to improve muscle and whole body insulin sensitivity. However, treatment of diabetic patients with leptin and adiponectin has no effect on muscle mitochondrial bioenergetics showing resistance to these hormones during type 2 diabetes. Furthermore, treatment with most thyroid hormones has unexpectedly revealed negative effects on muscle insulin sensitivity. Future research should focus on development of agents that improve metabolic dysfunction downstream of hormone receptors.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Insulin; Insulin Resistance; Leptin; Mitochondria, Muscle; Muscle, Skeletal; Obesity

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

Topics: Adiponectin; Adipose Tissue; Alcoholic Intoxication; Animals; Carbohydrate Metabolism; Cell Death; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids; Fatty Liver; Genetic Predisposition to Disease; Genome, Mitochondrial; Hepatitis C; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Models, Biological; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Reactive Oxygen Species

Several peptides are involved in the regulation of food intake and energy expenditure, among which are leptin, adiponectin, ghrelin and neuropeptide Y (NPY). These peptides may be implicated in the obesity seen in the majority of patients with type 2 diabetes mellitus (T2DM).. The present review considers: i) the role of leptin, adiponectin, ghrelin and NPY in patients with T2DM, and, ii) the effect of insulin as well as oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet agents on these peptides in patients with T2DM.. Patients with T2DM have either lower or similar leptin levels, decreased adiponectin and ghrelin levels, and increased NPY circulating levels compared with nondiabetic controls. Treatment with insulin, oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet drugs may influence the levels of these peptides. It is not widely appreciated that several drugs commonly administered to patients with T2DM can influence adipokine levels. The clinical relevance of these effects needs to be evaluated.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Hypoglycemic Agents; Leptin; Male; Neuropeptide Y

Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis.

Topics: Animals; Autonomic Nervous System; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Neurons; Parasympathetic Nervous System; Sympathetic Nervous System

Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance.

Topics: Adipocytes; Adipose Tissue; Animals; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Metabolic Syndrome; Obesity; Signal Transduction; Toll-Like Receptors

Resistance to the hormones insulin and leptin are hallmarks in common for type 2 diabetes mellitus and obesity. Both conditions are associated with increased activity and expression of protein tyrosine phosphatase (PTP)1B. Therefore, inhibition of PTP1B activity or down-regulation of its expression should ameliorate insulin and leptin resistance, and may hold therapeutic utility in type 2 diabetes mellitus and obesity control. This background has motivated the fervent search for PTP1B inhibitors, carried out in the recent years. The purpose of this review is to provide the most recent advances in understanding the structural details of PTP1B molecule relevant to the interactions with inhibitors, and the progress towards compounds with enhanced membrane permeability, affinity, specificity, and potency on intracellular PTP1B; several inhibitors of benefit in type 2 diabetes mellitus and obesity control are presented and discussed.

Topics: Diabetes Mellitus, Type 2; Enzyme Inhibitors; Humans; Insulin Resistance; Leptin; Molecular Structure; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1

In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR γ2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARγ agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic β-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures.

Topics: Animals; Bone and Bones; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Leptin; Lipid Peroxidation; Osteocalcin; Osteogenesis; Oxidative Stress; PPAR gamma; Signal Transduction; Wnt1 Protein

The present review evaluates the role of sleep and its alteration in triggering problems of glucose metabolism and the possible involvement of adipokines in this process. A reduction in the amount of time spent sleeping has become an endemic condition in modern society, and a search of the current literature has found important associations between sleep loss and alterations of nutritional and metabolic contexts. Studies suggest that sleep loss is associated with problems in glucose metabolism and a higher risk for the development of insulin resistance and type 2 diabetes mellitus. The mechanism involved may be associated with the decreased efficacy of regulation of the hypothalamus-pituitary-adrenal axis by negative feedback mechanisms in sleep-deprivation conditions. In addition, changes in the circadian pattern of growth hormone (GH) secretion might also contribute to the alterations in glucose regulation observed during sleep loss. On the other hand, sleep deprivation stress affects adipokines - increasing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and decreasing leptin and adiponectin -, thus establishing a possible association between sleep-debt, adipokines and glucose metabolism. Thus, a modified release of adipokines resulting from sleep deprivation could lead to a chronic sub-inflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes mellitus. Further studies are necessary to investigate the role of sleep loss in adipokine release and its relationship with glucose metabolism.

Topics: Adipokines; Adiponectin; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Insulin Resistance; Interleukin-6; Leptin; Sleep Deprivation; Tumor Necrosis Factor-alpha

Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptin's role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to a number of hypothalamic-pituitaryendocrine axes, including adrenal, gonadal, growth hormone, pancreatic islets, and thyroid. The pleiotropic nature of leptin has been confirmed by demonstration of a role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, reproduction, and wound healing. Unfortunately, the results of the majority of clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only to the management of those rare forms of human obesity caused by mutation in the ob gene. Failure of leptin in the clinic, and withdrawal of phentermine from Europe, and fenfluramine and sibutrimine from clinical use in the United States, have stimulated new approaches in the development of anti-obesity and anti-diabetes pharmacophores. These efforts are focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptin-related synthetic peptide analogs or mimetics. This review summarizes patents on leptin-related peptide analogs, antagonists and mimetics.

Topics: Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Leptin; Obesity; Patents as Topic; Peptides

Obesity plays a major role in the development of type 2 diabetes mellitus, and it has long been accepted that weight loss plays a significant role in diabetes therapy. This weight loss has traditionally been accomplished through lifestyle changes including diet and exercise. What has only more recently gained acceptance is that bariatric surgery may have a role to play in diabetes therapy as well. This article discusses the pathophysiology of type 2 diabetes mellitus and obesity and provides a basic understanding of these diseases, which forms the basis for understanding the importance of weight loss in their treatment.

Topics: Animals; Bariatric Surgery; Body Mass Index; Comorbidity; Diabetes Mellitus, Type 2; Disease Progression; Energy Intake; Energy Metabolism; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors; Weight Loss

The clinical outcomes achieved by bariatric surgery have been impressive. However, the physiologic mechanisms and complex metabolic effects of bariatric surgery are only now beginning to be understood. Ongoing research has contributed a large amount of data and shed new light on the science behind obesity and its treatment, and this article reviews the current understanding of metabolic and bariatric surgery physiology.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Neuropeptide Y; Obesity, Morbid; Peptide YY; Weight Loss

Obesity in men, particularly when central, is associated with lower total testosterone [TT], free testosterone [FT] and sex hormone-binding globulin [SHBG], and a greater decline in TT and FT with increasing age compared with lean men. Obesity-related conditions such as obstructive sleep apnea, insulin resistance and type 2 diabetes mellitus are independently associated with decreased plasma testosterone. Possible mechanisms include decreased LH pulse amplitude, inhibitory effects of oestrogen at the hypothalamus and pituitary and the effects of leptin and other peptides centrally and on Leydig cells. Obese men have reduced sperm concentration and total sperm count compared to lean men but sperm motility and morphology appear unaffected. The cause and effect relationships between low plasma androgen levels, obesity and the metabolic syndrome, and associated cardiometabolic risk remain unclear. While weight loss normalizes TT and FT in obese men, androgen replacement in the short term does not significantly improve cardiometabolic risk profile despite reducing fat mass.

Topics: Aging; Animals; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Leptin; Luteinizing Hormone; Male; Metabolic Syndrome; Obesity; Risk Factors; Signal Transduction; Sleep Apnea, Obstructive; Spermatogenesis; Testis; Testosterone; Weight Loss

Diabetes mellitus complicates 1-2% of all pregnancies but is associated with high perinatal morbidity and mortality. Gestational diabetes affects up to 4% of pregnancies and is associated with fetal macrosomia (large for dates). Fetal growth is a complex process influenced by determinants such as genetics, maternal factors, uterine environment and maternal and fetal hormones. Infants of pre-gestational diabetic mothers have an additional influence of maternal fluctuations in glycaemia. The purpose of this paper is to review maternal and fetal growth factors, including insulin, in the aetiology of macrosomia in diabetic pregnancy. Placental Growth Hormone is the major growth hormone secreted during human pregnancy. Leptin may have a role in satiety. Resistin was originally proposed as the link between obesity and diabetes but is now thought to have a more complex role. These hormones and their actions on human in-utero growth are reviewed in depth with particular reference to both pre-gestational (type 1 and type 2 diabetes) and gestational diabetes. Previously increased fetal weight in infants of diabetic mothers was thought to be as a result of maternal hyperglycaemia. It is now evident that control of fetal growth, in normal as well as diabetic pregnancies, is far more complex than previously thought.

Topics: Adult; Birth Weight; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Macrosomia; Fetus; Growth Hormone; Humans; Hyperglycemia; Infant; Insulin; Leptin; Placental Hormones; Pregnancy; Pregnancy in Diabetics; Resistin

Topics: Animals; Cloning, Molecular; Diabetes Mellitus, Type 2; Energy Metabolism; Genetic Predisposition to Disease; Humans; Leptin; Mice; Models, Genetic; Obesity; Phenotype; Publications; Receptors, Leptin; Thinness

The intrauterine environment supports the development and health of offspring. Perturbations to this environment can have detrimental effects on the fetus that have persistent pathological consequences through adolescence and adulthood. The developmental origins of the health and disease concept, also known as the "Barker Hypothesis", has been put forth to describe the increased incidence of chronic disease such as cardiovascular disease and diabetes in humans and animals exposed to a less than ideal intrauterine environment. Maternal infection, poor or excess nutrition, and stressful events can negatively influence the development of different cell types, tissues and organ systems ultimately predisposing the organism to pathological conditions. Although there are a variety of conditions associated to exposure to altered intrauterine environments, the focus of this review will be on the consequences of stress and high fat diet during the pre- and perinatal periods and associated outcomes related to obesity and other metabolic conditions. We further discuss possible neuroendocrine and epigenetic mechanisms responsible for the metabolic programming of offspring. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

Topics: Animals; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Susceptibility; Energy Metabolism; Environment; Epigenesis, Genetic; Female; Glucocorticoids; Humans; Insulin; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors

Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion. Chronically increased levels of plasma nonesterified fatty acids (NEFA) and triglyceride-rich lipoproteins impair beta-cell function, a process referred to as lipotoxicity. Furthermore, when NEFA supply exceeds metabolic capacity, lipids accumulate in nonadipose tissues, such as pancreatic islets, inducing organ dysfunction. The purpose of this review is to describe the mechanisms underlying lipotoxicity in vitro, to discuss the evidence for lipotoxicity in vivo and to address whether pancreatic lipid accumulation interferes with insulin secretion in humans.. Although numerous in-vitro studies have shown that chronically elevated NEFA levels induce beta-cell dysfunction and apoptosis, studies in humans are less conclusive. It has been acknowledged that concurrent hyperglycaemia amplifies the adverse effects of elevated plasma NEFA levels on beta-cell function; therefore glucolipotoxicity should be the preferred term. Lipid accumulation in pancreatic islets impaired beta-cell secretory capacity in leptin-deficient rodents. In humans, recent studies employing noninvasive magnetic resonance-technology and computed tomography-technology, lipid accumulation in the pancreas was increased in individuals with impaired glucose metabolism and T2DM. However, there was no clear association with beta-cell dysfunction.. To date, it is difficult to provide evidence that intraislet lipid accumulation truly exists in humans and that it is indeed causal to beta-cell dysfunction. Additional research is warranted to further detail the nature and role of pancreatic lipid content in humans, its consequence for the postulated processes pertinent to glucolipotoxicity and its contribution to the progressive nature of beta-cell dysfunction in prediabetes.

Topics: Animals; Apoptosis; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Lipid Metabolism Disorders; Pancreas; Pancreatic Diseases

Adipocytokines, such as adiponectin, TNF-alpha, and leptin, are cytokines secreted by visceral adipocytes, and they are associated with metabolic syndrome. Adiponectin is one of the adipocytokines, and is a protein comprised of 244 amino acids. It is known as ACRP30, GBP28, and AdipoQ. Adiponectin is secreted by adipocytes, has three different isoforms, including trimers (low-molecular weight: LMW), hexamers (middle-molecular-weight: MMW), and higher-order oligomeric (high-molecular-weight: HMW) structures, and affects the biological activity. Adiponectin is a clinically relevant parameter measured routinely in subjects at risk of type 2 diabetes and metabolic syndrome. We investigated the adiponectin levels using a number of ELISA assay kits.

Topics: Adipokines; Adiponectin; Biomarkers; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Ghrelin; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Plasminogen Activator Inhibitor 1; Reagent Kits, Diagnostic; Resistin; Risk; Tumor Necrosis Factor-alpha

The frequency of obesity has been increasing worldwide for 20 years. Many epidemiological studies support a correlation between obesity and increased risk of cancer, particularly digestive cancers in both genders, and gynaecological cancer in women. Currently, about 5% of cancers could be directly related to overweight. Carcinogenesis mechanisms induced by obesity involve insulin resistance, adipokine and angiogenic factor secretions, and inflammation. Experimental and clinical evidence suggest that insulin resistance plays a major role in carcinogenesis. Insulin and non-protein banded IGF-1, whose levels are increased in type 2 diabetes, stimulate cellular growth and inhibit apoptosis. Abnormalities in adipokine secretion by the central adipose tissue play a role at different stages of obesity-induced carcinogenesis. Excess of leptin and PAI-1, associated with a decrease in adiponectin secretion in obese people, contributes to carcinogenesis through cellular growth and angiogenesis stimulation. Remodelling of the extracellular matrix due to metalloproteinase stimulation by PAI-1 is also able to promote cell migration. Obesity not only increases cancer frequency, but is also liable to modify the prognosis and the response to antiangiogenic therapy of digestive cancers. This data suggests the need for clinicians to take into account overweight in cancer risk evaluation and to consider obesity and metabolic disorders as confounding factors in designing therapeutic studies.

Topics: Adipokines; Adipose Tissue; Biological Factors; Body Mass Index; Diabetes Complications; Diabetes Mellitus, Type 2; Evidence-Based Medicine; France; Gastrointestinal Neoplasms; Global Health; Humans; Incidence; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metalloproteases; Obesity; Plasminogen Activator Inhibitor 1; Prevalence; Prognosis; Risk Assessment; Risk Factors; Serine Proteinase Inhibitors

Obstructive sleep apnea (OSA) is a chronic disease characterized by repetitive partial or complete closure of the upper airway during sleep. OSA tends to be associated with components of metabolic syndrome sharing a common ground of metabolic changes with metabolic syndrome itself. Recent studies showed that subjects with OSA were 6-9 times more likely to have metabolic syndrome than subjects without OSA. Intermittent hypoxia and sleep fragmentation in OSA can initiate intermediary mechanisms (oxidative stress, neurohumoral changes, inflammation) leading to the components of metabolic syndrome. OSA has been suggested to be a novel risk factor, inside the metabolic syndrome, contributing to increased cardiovascular risk. Several studies report that continuous positive airway pressure (CPAP) treatment can reverse pathophysiological changes in OSA, increasing insulin sensitivity and reducing blood pressure. Recent evidences show that CPAP treatment reduces the risk of cardiovascular events and mortality in subjects with OSA. Some subjects with metabolic syndrome can be affected by undiagnosed OSA: CPAP treatment could significantly reduce cardiovascular risk in this subgroup of patients.

Topics: Age Factors; Aged; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Continuous Positive Airway Pressure; Death, Sudden, Cardiac; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Hypertension; Insulin Resistance; Leptin; MEDLINE; Metabolic Syndrome; Obesity; Randomized Controlled Trials as Topic; Risk Factors; Sleep Apnea, Obstructive; Stroke

Gastric bypass surgery (GBP), in addition to weight loss, results in dramatic remission of type 2 diabetes (T2DM). The mechanisms by which this remission occurs are unclear. Besides weight loss and caloric restriction, the changes in gut hormones that occur after GBP are increasingly gaining recognition as key players in glucose control. Incretins are gut peptides that stimulate insulin secretion postprandially; the levels of these hormones, particularly glucagon-like peptide-1, increase after GBP in response to nutrient stimulation. Whether these changes are causal to changes in glucose homeostasis remain to be determined. The purpose of this review is to assess the evidence on incretin changes and T2DM remission after GBP, and the possible mechanisms by which these changes occur. Our goals are to provide a thorough update on this field of research so that recommendations for future research and criteria for bariatric surgery can be evaluated.

Topics: Animals; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Gastric Bypass; Gastric Emptying; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose; Homeostasis; Humans; Incretins; Intestine, Small; Leptin; Liver; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Weight Loss

Adipose tissue cells express and secrete numerous proteins influencing the signal transduction pathways of insulin receptor by auto-, para- and endocrine manner. Several cytokines, tumor necrosis factor-alpha and its soluble receptor forms, sTNFR1 and sTNFR2, resistin, retinol-binding protein 4, plasminogen activator inhibitor, lipocain 1 inhibit the signalization of insulin receptor causing insulin resistance in target tissues, mainly in adipose, liver and muscle, brain, endothelial as well as in pancreatic beta-cells. However, many other proteins produced by the fat tissue, such as adiponectin, visfatin, vaspin, apelin, omentin and chemerin enhance the signal transmission of the receptor. Recently discovered common mechanisms leading to insulin and cytokine resistance in obesity and type 2 diabetes mellitus, e.g. protein family of suppressor of cytokine signaling (SOCS) are also discussed.

Topics: Adipokines; Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Lipocalin 1; Mutation; Obesity; Plasminogen Inactivators; Receptor, Insulin; Resistin; Retinol-Binding Proteins, Plasma; Signal Transduction; Transcription, Genetic; Tumor Necrosis Factor-alpha

Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain.. To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes.. A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified.

Topics: Adult; Animals; Child; Diabetes Mellitus, Type 2; Drug Delivery Systems; Drug Evaluation, Preclinical; Energy Metabolism; Female; Ghrelin; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Obesity; Receptors, Ghrelin; Receptors, Leptin

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Energy Metabolism; Feedback, Physiological; Ghrelin; Glucose; Glucose Intolerance; Humans; Hypothalamus; Insulin; Leptin; Neurotransmitter Agents; Nutritional Status; Obesity

Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans.

Topics: Animals; Appetite Regulation; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Humans; Hypothalamus; Insulin; Leptin; Obesity; Signal Transduction

Diabetes is an important health problem since the incidence of diabetes is continuously increasing. Early diagnosis is important as type 2 diabetes begins long before we diagnose it, leading to a complicated course of the disease. In order to prevent delay in the diagnosis of type 2 diabetes, novel predictors and pathways for type 2 diabetes are mounting. Diabetic complications are common cause of morbidity and mortality among subjects with diabetes. In the pathogenesis of diabetic complications some factors other than chronic hyperglycemia may be involved. Adipocytokines play important roles in the pathogenesis of diabetes mellitus, insulin resistance, and associated metabolic conditions such as hypertension and dyslipidemia. The investigations on the role of adipocytokines in developing diabetes and its complications have been made. In this review, we discussed the implications of adipocytokines in predicting diabetes and diabetic complications, with particular attention on the roles of adiponectin, leptin, visfatin, and vaspin.

Topics: Adipokines; Adiponectin; Age of Onset; Cytokines; Diabetes Complications; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Prognosis; Serpins

Cardiovascular diseases are currently the most frequent cause of death in Poland and their incidence continually rises. This is related to the high incidence of obesity associated with insulin resistance, which is present in type 2 diabetes mellitus. Adipose tissue produces multiple cytokines(TNF-alpha, IL-6, PAI-1, CRP, angiotensinogen, leptin, adiponectin, visfatin, apelin, resistin)which decrease insulin sensitivity and induce inflammatory processes, endothelial dysfunction,and atherosclerosis. This article presents the link between obesity, insulin resistance, and type 2 diabetes mellitus according to studies conducted in vitro and in animal models. In human studies, the influence of resistin on the development of insulin resistance is controversial. The article underlines the role of resisitin in the development of inflammatory processes and endothelial dysfunction in humans. In clinical studies, resistin was shown to be a predictive factor of coronary artery disease and mortality connected with cardiovascular diseases.

Topics: Adipose Tissue; Animals; Biomarkers; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Inflammation; Inflammation Mediators; Leptin; Metabolic Diseases; Metabolic Syndrome; Obesity; Resistin

The incidence of type 2 diabetes (T2D) is rapidly expanding. Some of the more obvious pathologies associated with it include: defective glucose metabolism, obesity, cardiovascular disease and an inability to mount an effective immune response to infection by certain pathogenic organisms, leading to sepsis and death. A common tie linking these seemingly disparate complications is chronic inflammation. Today we know that inflammation is regulated locally and systemically by numerous biochemical signals. One of the most important of these signals is a class of molecules called cytokines. Cytokines can be generally classified as proinflammatory or anti-inflammatory and allow an organism to respond rapidly to an immune challenge by coordinating an appropriate immune response. In T2D, the balance between proinflammatory and anti-inflammatory cytokines is shifted toward proinflammation, potentially causing or exacerbating the health complications found in T2D. Over-nutrition has been shown to trigger the innate immune system but activation of the innate immune system, itself, induces hyperglycemia and insulin resistance. In all likelihood, diabetes and chronic inflammation are inseparable and act as a reciprocal feed-forward loop.

Topics: Anti-Inflammatory Agents; Cytokines; Diabetes Mellitus, Type 2; Humans; Incidence; Inflammation; Interleukin-1beta; Interleukin-6; Leptin; Tumor Necrosis Factor-alpha

There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardiometabolic risk. Although the basis of this differential risk has not been established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Adipose tissue is, in fact, now recognized not simply a store of excess energy but a major endocrine and secretory organ, releasing a wide range of protein factors and signals, termed adipokines, in addition to fatty acids and other lipid moieties. These factors are derived from adipocyte or non-adipocyte fractions, and include proteins, metabolites and hormones. This paper reviews some of the advances in the understanding of biologically active molecules produced by adipose tissue and how dysregulated production of these factors could be implicated in the association between central adiposity, cardiovascular pathology and comorbidities, including metabolic syndrome, type 2 diabetes and systemic inflammation.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Leptin; Metabolic Syndrome; Obesity; Systemic Inflammatory Response Syndrome

The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.

Topics: Adipocytes; Adipose Tissue; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Energy Metabolism; Female; Humans; Intra-Abdominal Fat; Leptin; Male; Metabolic Syndrome; Obesity; Risk Reduction Behavior; Subcutaneous Fat, Abdominal; Transcription Factors

Obesity has been recognized as a worldwide public health problem. It significantly increases the chances of developing several diseases, including Type II diabetes. The roles of insulin and leptin in obesity involve reactions that can be better understood when they are presented step by step. The aim of this work was to design software with data from some of the most recent publications on obesity, especially those concerning the roles of insulin and leptin in this metabolic disturbance. The most notable characteristic of this software is the use of animations representing the cellular response together with the presentation of recently discovered mechanisms on the participation of insulin and leptin in processes leading to obesity. The software was field tested in the Biochemistry of Nutrition web-based course. After using the software and discussing its contents in chatrooms, students were asked to answer an evaluation survey about the whole activity and the usefulness of the software within the learning process. The teaching assistants (TA) evaluated the software as a tool to help in the teaching process. The students' and TAs' satisfaction was very evident and encouraged us to move forward with the software development and to improve the use of this kind of educational tool in biochemistry classes.

Topics: Biochemistry; Computer-Assisted Instruction; Diabetes Mellitus, Type 2; Education, Distance; Health Education; Humans; Insulin; Leptin; Multimedia; Obesity; Program Evaluation; Software; Teaching; Teaching Materials

The integrated central actions of hormones secreted from pancreatic islets, the gut and adipocytes regulate both energy homeostasis and body weight. Dysregulation in these neurohormonal pathways probably contributes to pathogenesis of obesity and type 2 diabetes.. To examine hormone-based therapies targeting these interrelated pathways as potential treatments for obesity and diabetes.. Preclinical and clinical data on therapies based on hormones secreted from the pancreas (glucagon, insulin, amylin and pancreatic polypeptide), gut (glucagon-like peptide-1, glucose dependent insulinotropic polypeptide, cholecystokinin and peptide YY) and adipose tissue (leptin and adiponectin) as potential treatments for diabetes and obesity are reviewed.. In diabetes, hormone-based treatments have translated into new clinical platforms including insulin analogs, the GLP-1-like peptide receptor agonist exenatide and amylinomimetic pramlintide, which due to their complex interplay and the progressive nature of diabetes, can be utilized in different settings. Various peptide hormones and agonists/antagonists are currently under investigation as new approaches to treatment of obesity and diabetes.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Amyloid; Animals; Body Weight; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Homeostasis; Hormones; Humans; Intestinal Mucosa; Islet Amyloid Polypeptide; Leptin; Mice; Obesity; Pancreas

Nonalcoholic fatty liver disease (NAFLD) spans a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Simple steatosis is the substrate upon which the more serious entities in the spectrum develop; it is the first "hit" in the multistep pathogenesis of NASH, which is considered the hepatic manifestation of the metabolic syndrome. Demonstration of the existence of regulatable fatty acid transport mechanisms has contributed to clarifying the role of fatty acid disposition in obesity, the various components of NAFLD, and the metabolic syndrome. Hepatic steatosis is closely linked to obesity. This linkage is based on the fact that obesity results in marked enlargement of the intraabdominal visceral fat depots. The eventual development of insulin resistance leads to continuous lipolysis within these depots, releasing fatty acids into the portal circulation, where they are rapidly translocated to the liver and reassembled into triglycerides. Reactive oxygen species, generated in the liver from oxidation of fatty acids, are precipitating factors in the cascade of events leading from simple steatosis to NASH. Dysregulation of fatty acid disposition, with ectopic lipid accumulation in other tissues, is a major contributing factor to other components of the metabolic syndrome. Bariatric surgery is an effective treatment for severe obesity, but its role in the management of the various forms of fatty liver disease is unclear. Our review of the literature that includes both initial and follow-up liver biopsies suggests that most obese patients with simple steatosis and NASH who undergo bariatric surgery will achieve improvement in hepatic histology, but that occasional patients, especially those who lose weight very rapidly, may show worsening of either fibrosis or steatohepatitis.

Topics: Abdominal Fat; Adipocytes; Animals; Bariatric Surgery; Comorbidity; Diabetes Mellitus, Type 2; Fatty Acids; Fatty Liver; Gastrointestinal Hormones; Humans; Insulin Resistance; Leptin; Lipolysis; Liver; Metabolic Syndrome; Obesity; Obesity, Morbid

The metabolic syndrome represents a major public health burden because of its high prevalence in the general population and its association with cardiovascular disease and type 2 diabetes. Accumulated evidence based on biochemical, neurophysiologic, and indirect measurements of autonomic activity indicate that visceral obesity and the metabolic syndrome are associated with enhanced sympathetic neural drive and vagal impairment. The mechanisms linking metabolic syndrome with sympathetic activation are complex and not completely understood, and cause-effect relationships need further clarification from prospective trials. Components of the metabolic syndrome that may directly or indirectly enhance sympathetic drive include hyperinsulinemia, leptin, nonesterified fatty acids, proinflammatory cytokines, angiotensinogen, baroreflex impairment, and obstructive sleep apnea. beta-Adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic activity. Because chronic sympathetic activation contributes to hypertension and its target-organ damage, sympathoinhibition remains an important goal in the therapeutic management of the metabolic syndrome.

Topics: Adipokines; Cytokines; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Risk Assessment; Sensitivity and Specificity; Sleep Apnea, Obstructive; Sympathetic Nervous System

Recently more and more evidences have emerged about the oncogenic effect of type 2 diabetes and metabolic syndrome. Among these evidences epidemiological data are in first line. There is a causal relationship according to gender, ethnicity and geographic situation between different tumors and type 2 diabetes/metabolic syndrome as well. Supposed pathomechanisms are obesity, cytokines, secreted excessively in adipose tissue, permanent and postprandial hyperglycemia, hyperinsulinism and insulin resistance, other growth factors, like proinsulin, insulin like growth factor-1, reactive oxygen species, angiogenesis, inflammation, and the multiple effects of inflammatory cytokines. It proved to be evident that both peroxisome-proliferator-activated receptors and the regulatory ubiquitin proteasome system have significant role in insulin sensitivity and in co-ordinating cell proliferation and angiogenesis. These mechanisms in metabolic syndrome are risk factors towards atherosclerosis and cancer diseases as well. This newly emerged knowledge may open new pathways in treating and preventing the above-mentioned pathologic processes.

Topics: Adiponectin; Adipose Tissue; Animals; Cell Proliferation; Cytokines; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metabolic Syndrome; Neoplasms; Neovascularization, Pathologic; Obesity; Peroxisome Proliferator-Activated Receptors; Reactive Oxygen Species; Risk Factors; Ubiquitins; Vascular Endothelial Growth Factor A

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Topics: Animals; Atherosclerosis; Bone Density; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Hematocrit; Humans; Hypogonadism; Inflammation Mediators; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Models, Biological; Obesity; Prostatic Neoplasms; Sexual Dysfunction, Physiological; Testosterone

Acute hypoxia is experienced by a variety of individuals (neonates to the elderly) and in an assortment of conditions and diseases (terrorist bomb attack to decompensated heart failure). Increasingly, elaboration of inflammatory cytokines appears key to the brain-based response to hypoxia, as evidenced by the biobehaviors of malaise, fatigue, lethargy, and loss of interest in the physical and social environment. These sickness symptoms implicate hypoxia-dependent activation of the neuroimmune system as a key component of acute hypoxia. Type 2 diabetes (T2D) is associated with increased incidence, severity, and delayed recovery from hypoxic events. Why T2D negatively affects acute hypoxia is not well understood. Recent work, however, reveals that anti-inflammatory pathways tied to the interleukin (IL)-1beta arm of the neuroimmune system may be critical. In this review, the authors examine the link between acute hypoxia, T2D, and neuroimmunity.

Topics: Animals; Autoimmune Diseases of the Nervous System; Brain; Diabetes Mellitus, Type 2; Encephalitis; Humans; Hypoxia, Brain; Interleukin-1beta; Leptin; Neuroimmunomodulation; Signal Transduction

Obesity and type 2 diabetes are the most prevalent metabolic diseases in the western world. Alarmingly, the cluster of pathologies characteristic of obesity-induced disease have started to emerge in children, a phenomenon that up until a decade ago was inconceivable. Hence, the development of new strategies to treat 'metabolic disease' is most warranted. Growing evidence suggests that during type 2 diabetes, a state of chronic low-grade inflammation exists in metabolically active tissues such as the liver, adipose tissue and skeletal muscle. This inflammation is often secondary to lipid accumulation in insulin-responsive tissues. Recent studies have focused on the therapeutic potential of ciliary neurotrophic factor (CNTF). CNTF is a pluripotent neurocytokine and, has shown promise as a potential anti-obesogenic therapy. CNTF acts both centrally and peripherally, mimics the biological actions of leptin while overcoming "leptin resistance", remains effective even after termination of therapy if administered centrally, and appears to reduce inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. The advantages and disadvantages of CNTF as a therapeutic strategy to alleviate obesity-associated diseases will be highlighted in this review.

Topics: Brain; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Leptin; Obesity; Receptor, Ciliary Neurotrophic Factor; Signal Transduction; Weight Loss

Decreases in both mass and secretory function of insulin-producing beta-cells contribute to the pathophysiology of type 2 diabetes. The histology of islets from patients with type 2 diabetes displays an inflammatory process characterized by the presence of cytokines, apoptotic cells, immune cell infiltration, amyloid deposits, and eventually fibrosis. This inflammatory process is probably the combined consequence of dyslipidemia, hyperglycemia, and increased circulating adipokines. Therefore, modulation of intra-islet inflammatory mediators, in particular interleukin-1 beta, appears as a promising therapeutic approach.

Topics: Cytokines; Diabetes Mellitus, Type 2; Dyslipidemias; Glucose; Humans; Hypoglycemic Agents; Inflammation; Insulin-Secreting Cells; Interleukin-1beta; Islets of Langerhans; Leptin; Obesity; Pancreatic Diseases

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

Current explanations for obesity center around a predisposition in genotype and phenotype, possibly triggered by an inflammatory process or event, and exacerbated by environmental and psychological factors. It is likely that a variety of physiologic factors may act in combination to produce clinical obesity. Leptin resistance may be an important neurochemical cause of obesity; elevated leptin levels have been correlated with weight gain over extended time periods. Genetic studies support the postulate that a gene originating with our cave-dwelling ancestors, critical to survival when food was scare, has evolved into a trigger for obesity and related diseases. A variety of biochemical markers are prevalent in obesity and obesity-linked disease states. C-reactive protein, interleukin-6, and others are elevated in obesity, supporting the hypothesis that inflammation plays a role in the condition. Tumor necrosis factor-alpha is overexpressed in obesity and diabetes, suggesting that it may be part of the link between the 2 conditions.

Topics: Appetite; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Causality; Cost of Illness; Diabetes Mellitus, Type 2; Dietary Fats; Genetic Predisposition to Disease; Genotype; Humans; Inflammation; Interleukin-6; Leptin; Life Style; Neoplasms; Obesity; Phenotype; Tumor Necrosis Factor-alpha; United States

Examination of individuals with 'extreme phenotypes' has revealed some rare monogenic disorders that were previously unknown. This identification can shed light on physiological pathways that are also important in normal physiology and how their impairment leads to more common, milder, multigenic forms of the disease. Ultimately, this is a potential route to treatment of both disease types. This approach is discussed in relation to Type 2 diabetes, arising from both insufficient insulin production and insulin resistance.

Topics: Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Humans; Insulin; Insulin Resistance; Leptin; Metabolic Diseases; Models, Biological; Obesity; Phenotype; PPAR gamma; Receptor, Melanocortin, Type 4

Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Leptin; Metabolic Syndrome; NF-kappa B; Obesity; Risk Factors; Sleep Apnea Syndromes

The unparalleled global rates of obesity and type 2 diabetes, together with the associated cardiovascular morbidity and mortality, are referred to as the "diabesity pandemic". Changes in lifestyle occurring worldwide, including the increased consumption of high-caloric foods and reduced exercise, are regarded as the main causal factors. Central obesity and insulin resistance have emerged as important linking components. Understanding the aetiology of the cluster of pathologies that leads to the increased risk is instrumental in the development of preventive and therapeutic strategies. Historically, skeletal muscle, adipose tissue and liver were regarded as key insulin target organs involved in insulin-mediated regulation of peripheral carbohydrate, lipid and protein metabolism. The consequences of impaired insulin action in these organs were deemed to explain the functional and structural abnormalities associated with insulin resistance. The discovery of insulin receptors in the central nervous system, the detection of insulin in the cerebrospinal fluid after peripheral insulin administration and the well-documented effects of intracerebroventricularly injected insulin on energy homeostasis, have identified the brain as an important target for insulin action. In addition to its critical role as a peripheral signal integrating the complex network of hypothalamic neuropeptides and neurotransmitters that influence parameters of energy balance, central nervous insulin signalling is also implicated in the regulation of peripheral glucose metabolism. This review summarizes the evidence of insulin action in the brain as part of the multifaceted circuit involved in the central regulation of energy and glucose homeostasis, and discuss the role of impaired central nervous insulin signalling as a pathogenic factor in the obesity and type 2 diabetes epidemic.

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Disease Outbreaks; Energy Intake; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Life Style; Obesity; Physical Exertion; Receptor, Insulin; Signal Transduction

An imbalance between pro- and anti-inflammatory molecules occurs in metabolic syndrome X. High-energy diet, saturated fats and trans-fats during perinatal period could suppress Delta(6) and Delta(5) desaturases both in the maternal and fetal tissues, resulting in a decrease in the concentrations of long-chain polyunsaturated fatty acids (LCPUFAs): arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that have a negative feedback control on inflammation. EPA, DHA and AA augment endothelial nitric oxide synthesis, potentiate insulin action both in the peripheral tissues and brain and alter leptin production. LCPUFAs are essential for brain growth and development and synaptogenesis and modulate the action of several neurotransmitters and hypothalamic peptides. This suggests that metabolic syndrome X could be a disorder of the brain due to suboptimal LCPUFAs during perinatal period that triggers low-grade systemic inflammation, implying that perinatal strategies are needed to prevent its development.

Topics: Animals; Appetite Regulation; Arachidonic Acid; Brain; Diabetes Mellitus, Type 2; Docosahexaenoic Acids; Dopamine; Eicosapentaenoic Acid; Fatty Acids, Essential; Fatty Acids, Unsaturated; gamma-Aminobutyric Acid; Humans; Hypothalamus, Middle; Infant, Newborn; Inflammation; Insulin; Leptin; Metabolic Syndrome; N-Methylaspartate; Neurons; Qa-SNARE Proteins; Receptor, Insulin; Receptors, Retinoic Acid; Serotonin; Synapses

Topics: Adiponectin; Adiposity; Atherosclerosis; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Leptin; Lipid Metabolism; Lipid Metabolism Disorders; Obesity; Peptide Hormones; Resistin

The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.

Topics: Adiponectin; Adipose Tissue; Angiotensin II; Animals; Cardiovascular Diseases; Complement Activation; Complement C3a; Complement Factor D; Cytokines; Diabetes Mellitus, Type 2; Fibrinolysis; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Plasminogen Activator Inhibitor 1; Renin-Angiotensin System; Resistin; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Risk Factors; Tumor Necrosis Factor-alpha

Adipokines, the bioactive factors derived mainly from adipocytes, regulate pancreatic beta-cell function including insulin secretion, gene expression and apoptosis. In this review, we propose that adipokines influence beta-cell function through three interdependent pathways. The first is through regulating lipid and glucose metabolism in beta-cells. The second implicates the change of ion channel opening and closing in beta-cells. The third pathway is via the modification of insulin sensitivity of beta-cells. The endocrine function of adipocytes is dynamic, and the secretion of various adipokines changes under different metabolic conditions. During the progression from the normal state to obesity and to type 2 diabetes, adipokines contribute to the occurrence and development of beta-cell dysfunction in type 2 diabetes.

Topics: Adipocytes; Adiponectin; Animals; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin-Secreting Cells; Leptin; Lipid Metabolism

Growing evidence suggests that food intake, energy expenditure and endogenous glucose production are regulated by hypothalamic areas that respond to a variety of peripheral signals. Therefore, in response to a reduction in energy stores or circulating nutrients, the brain initiates responses in order to promote positive energy balance to restore and maintain energy and glucose homeostasis. In contrast, in times of nutrient abundance and excess energy storage, key hypothalamic areas activate responses to promote negative energy balance (i.e. reduced food intake and increased energy expenditure) and decreased nutrient availability (reduced endogenous glucose production). Accordingly, impaired responses or 'resistance' to afferent input from these hormonal or nutrient-related signals would be predicted to favour weight gain and insulin resistance and may contribute to the development of obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Feedback, Physiological; Glucose; Homeostasis; Humans; Hypothalamus; Insulin Resistance; Leptin; Liver; Obesity; Signal Transduction; Weight Gain

Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.

Topics: Adiponectin; Body Composition; Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Obesity; Risk Factors

The fact that fat issue is an endocrine gland secreting several hormones participating in the pathogenesis of type 2 diabetes mellitus (DM2) is universally recognized. Fat issue secretes leptin, tumor necrosis factor alpha, resistin, adiponectin, interleukin-6, free fatty acids, visfatin, omentin, perilipin, and other substances that influence the condition of insulinoresistance, one of the main factors responsible for DM2. Subcutaneous fat and visceral depot fat tissue differ in the spectrum of hormones they produce; the list of these hormones is presented in the article. The presence of abdominal or visceral obesity is combined with significant insulinoresistance, which, in its turn, increases the risk of vascular complications of diabetes. The article also cover the participation of other mechanisms - insulin secretion defect, oxidation stress, low secretion of glucagon-like peptide 1, apoptosis, an increased quantity of amyloid and the fl-cell pull in the pancreatic island--in DM2 pathogenesis. The authors present data on the secretion of leptin, resistin, adiponectin, and tumor necrosis factor a, as well as the condition of the functional activity of beta-cells and the degree of insulinoresistance in 30 DM2 patients receiving dietotherapy.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Disease Progression; Humans; Insulin Resistance; Interleukin-6; Leptin; Obesity; Tumor Necrosis Factor-alpha

The increasing prevalence of type 2 diabetes has sparked interest in the development of agents that treat and prevent the disease. Mounting evidence indicates that protein tyrosine phosphatase (PTP)1B negatively regulates insulin and leptin signaling making it a prime target for enhancing insulin sensitivity and controlling body mass. Despite intense efforts, development of orally bioavailable small-molecule PTP1B inhibitors has been a challenge. This review focuses on recent advances in the validation of PTP1B and in the development of approaches to modulate its activity.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Leptin; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction

A cluster of risk factors associated with obesity defines the metabolic syndrome and identifies cardiometabolic risk. Accumulation of fat in the visceral depot is a more reliable predictor of cardiovascular disease than is total body mass or body mass index. The recent discovery of the endocannabinoid-CB1 receptor system and its impact on the regulation of energy metabolism represents a significant advance that will help target visceral fat and its metabolic implications. As a highly active endocrine organ, visceral fat secretes many bioactive molecules, known as adipokines. Dysregulation of these adipokines contributes to the pathogenesis of the obesity-associated metabolic syndrome, resulting in insulin resistance, type 2 diabetes, hypertension, hyperlipidemia, and vascular disease. Even modest weight reduction leads to reduced cardiometabolic risk by affecting the individual components comprising the metabolic syndrome.

Topics: Adiponectin; Anti-Obesity Agents; Blood Coagulation; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Dyslipidemias; Exercise; Fatty Acids; Humans; Hypertension; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Life Style; Metabolic Syndrome; Obesity; Practice Guidelines as Topic; Risk Factors; Weight Loss

The global epidemic of obesity and type-2 diabetes mellitus (T2DM) has highlighted the need for new therapeutic approaches. The association of insulin resistance with these disorders and the knowledge that insulin receptor signaling is mediated by tyrosine (Tyr) phosphorylation have generated great interest in the regulation of the balance between Tyr phosphorylation and dephosphorylation. Several protein Tyr phosphatases (PTPs) have been implicated in the regulation of insulin action, with the most convincing data for PTP1B. Murine models targeting PTP1B, PTP1B(-/-)mice, demonstrate enhanced insulin sensitivity without the weight gain seen with other insulin sensitizers such as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, probably due to a second action of PTP1B as a negative regulator of leptin signaling. Despite intensive efforts and recent progress, a safe, selective and efficacious PTP1B inhibitor has yet to be identified.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Design; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Receptor, Insulin; Signal Transduction; Structure-Activity Relationship; Substrate Specificity

Since adipose tissue was shown to be more than a storage organ, the many cytokines it produces have been identified, along with their roles in energy homeostasis, appetite, and insulin resistance. Concurrently, numerous gut hormones with a diversity of effects have been discovered. They include, amongst many others, peptide YY, ghrelin and oxyntomodulin. As these peptides have been investigated, the potential for their use as novel anti-obesity and antidiabetic therapies has been realized. In this chapter we describe the actions of four of the peptides that have been proposed as the basis for promising new therapies for diabetes: leptin, adiponectin, obestatin and peptide YY. They each have an effect on appetite and, directly or indirectly, on glucose metabolism. We synthesize available data for these peptides and consider the therapeutic potential of each.

Topics: Adiponectin; Animals; Appetite; Diabetes Mellitus, Type 2; Ghrelin; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Leptin; Oxyntomodulin; Peptide YY

Unique genetic traits appear to play a role in the increased rates of hypertension (HTN), glucose dysregulation/diabetes (T2DM), and obesity in persons of African descent. Indeed, with increasing rates of westernization/urbanization and concomitant increases in obesity and T2DM, a similar predisposition to the cardiometabolic syndrome and cardiovascular disease (CVD) can be seen in Africans compared with persons of African descent, with CVD reaching epidemic proportions in many areas of Africa. In addition, the complex relationships of metabolic abnormalities that are unique to individuals of African descent have also been demonstrated in Africans. These include: (1) a dissociation of HTN to insulin resistance; (2) relative favorable lipid profile in the setting of increasing rates of CVD; (3) low levels of visceral adiposity in the setting of obesity and insulin resistance; and (4) a dissociation of insulin sensitivity and adiponectin when compared with Caucasians. Although not well understood, these unique relationships suggest that conventional parameters for CVD do not apply to Africans of persons of African descent.

Topics: Adiponectin; Africa; Diabetes Mellitus, Type 2; Dyslipidemias; Genetic Predisposition to Disease; Humans; Hypertension; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Obesity; Risk Factors

Millions of people worldwide suffer from type 2 diabetes mellitus. There are two major factors that play a role in its pathogenesis: insulin resistance and impaired secretion of insulin by beta-cells. Impaired insulin action is closely linked to the phenomenon of obesity. The adipose tissue releases free fatty acids but also hormones and cytokines such as leptin, adiponectin, resistin, TNF-alpha and others. All those particles modify insulin action. This review article summarizes contemporary opinions on the role of obesity in the generation of resistance to insulin and subsequently impaired glucose tolerance as well as overt type 2 diabetes mellitus.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Resistin; Tumor Necrosis Factor-alpha

Obesity and its related metabolic diseases, including type 2 diabetes, are associated with alterations in the circulating levels of various peptides. These include the adipocytokines (peptides released by adipocytes which circulate, such as leptin, adiponectin and resistin), and other peptides whose levels are altered in association with obesity (such as ghrelin, neuropeptide Y, interleukin-1 beta and tumour necrosis factor-alpha). While the primary action of these peptides is linked with the regulation and maintenance of energy balance and metabolism, many of them have also been shown to possess vasoactive, inflammatory and other properties that influence vascular biology, vascular physiology and atherogenesis. As such, they may form an important mechanistic link between obesity and cardiovascular disease. In this review, we will outline the vasoactive properties of adipocytokines and other obesity-related peptides. In particular, as pharmacotherapies suggested to achieve weight loss will alter the pathways associated with these peptides, such treatments might have either beneficial or deleterious effects on the incidence and progression of cardiovascular disease.

Topics: Adiponectin; Adipose Tissue; Atherosclerosis; Diabetes Mellitus, Type 2; Ghrelin; Humans; Leptin; Muscle, Smooth, Vascular; Obesity; Peptide Hormones

To survey the latest state of knowledge concerning the regulation of regional adipocytes and their role in the development of insulin resistance and type 2 diabetes.. Data from the English-language literature on regional adipocytes, including abdominal, intramyocellular, intrahepatic and intra-islet fat as well as the adipokines and their relations to insulin resistance and type 2 diabetes, were reviewed.. It is not the total amount of fat but the fat that resides within skeletal muscle cell (intramyocellular fat), hepatocytes and intra-abdominally (visceral fat), via systemic and local secretion of several adipokines, that influences insulin resistance. Among the adipokines that relate to insulin resistance, adiponectin and leptin appear to have clinical relevance to human insulin resistance and others may also contribute, but their role is still inconclusive. The intra-islet fat also adversely affects beta-cell function and number (beta-cell apoptosis), eventually leading to deterioration of glucose tolerance. The abnormal location of fat observed in patients with type 2 diabetes and their relatives is conceivably partly the results of the genetically determined, impaired mitochondrial fatty acid oxidative capacity. Restriction or elimination of the fat load by weight control, regular exercise and thiazolidinediones has been shown to improve insulin resistance and beta-cell function and to delay the development of type 2 diabetes.. These data support the plausibility of an essential role of regional adipose tissue in the development of insulin resistance and type 2 diabetes.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Lipids; Muscle Cells

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts

Topics: Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Lipid Metabolism; Macrophages; Obesity; Resistin; Signal Transduction; Tumor Necrosis Factor-alpha

Topics: Adipocytes; Adiponectin; Antibody Formation; Chronic Disease; Diabetes Mellitus, Type 2; Humans; Leptin

Onset expression of Type 2 (NIDDM) diabetes and obesity metabolic syndromes (DOS) are characterized by premature, progressive cytoatrophy and organo-involution induced by dysregulated cellular gluco- and lipo-metabolic cascades. The consequential systemic, interstitial and intracellular hyperlipidemia disrupts normal cytointegrity and metabolic responsivity to the established hypercaloric pericellular environments. The sequential cytostructural, metabolic and endocrine disturbances associated with the development of progressive DOS-associated hypercytolipidemia compromises cellular metabolic response cascades and promotes cytochemical disturbances which culminate with nuclear lipoapoptosis and cytoatrophy. The dramatic alterations in interstitial glucose and lipid (free fatty acids/triglycerides) concentrations are recognized to influence interstitial and cytoplasmic microchemical environments, which markedly alter cellular nutrient diffusion and active trans-membrane flux rates. The progressive exacerbation of interstitial and cytoplasmic lipid imbibition has been demonstrated to be associated with DNA fragmentation by lipo-infiltration into the chromatin matrix, inducing structural disruption and physical dissolution, indexed as nuclear lipoapoptosis. Therapeutic reduction of the severity of hypercytolipidemia-induced structural and cytochemical compromise promotes the restoration of homeostatic metabolic support for normalized cytostructural indices and supportive cellular gluco- and lipo-metabolic cascades. The re-establishment of a homeostatic interstitial microenvironment moderates the severity of cytolipidemic compromise within affected cell types, reduces nuclear lipo-infiltration and DNA lipo-dissolution, resulting in the preservation of cytostructural integrity. Through the therapeutic restoration of extra- and intra-cellular microchemical environments in genetically dysregulated metabolic syndrome models, the coincident cytochemical, endocrine and metabolic disturbances associated with progressive hypercytolipidemia, resulting from the expressed systemic hypercaloric environmental and hepato-pancreatic endometabolic disturbances which characterize Type 2 (NIDDM) diabetes-obesity and metabolic (X) syndromes, may be ameliorated.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Hyperlipidemias; Leptin; Mutation; Obesity; Receptors, Cell Surface; Receptors, Leptin; Syndrome

The worldwide increase in the prevalence of obesity is becoming one of the most important clinical-epidemiological phenomena of the present days. Environmental factors such as changes in life-style and feeding behavior associated with poorly characterized genetic determinants are though to play the most important roles in the pathogenesis of this disease. During the last ten years, since the discovery of leptin, great advances were obtained in the characterization of the hypothalamic mechanisms involved in the control of food intake and thermogenesis. Such advances are unveiling a complex and integrated system and are opening a wide perspective for the finding of novel therapeutic targets for the treatment of this harming condition. This review will present some of the most recent findings in this field. It will be focused on the actions of leptin and insulin in the hypothalamus and will explore the hypothesis that hypothalamic resistance to the action of these hormones may play a role in the development of obesity and may act as a molecular link between obesity, type 2 diabetes mellitus and other clinical conditions on which insulin resistance plays an important pathogenetic role.

Topics: Diabetes Mellitus, Type 2; Eating; Humans; Hypothalamus; Insulin Resistance; Leptin; Life Style; Obesity; Thermogenesis; Transcription, Genetic

Type 2 diabetes is a polygenic disease that can lead to severe complications in multiple tissues. Rodent models have been used widely for investigating the pathophysiology underlying type 2 diabetes and for examining the potential link with obesity, largely due to the limitations of invasive testing and of studying detailed molecular mechanisms in human tissues. Among rodents, the mouse model is especially popular because mice are easy to manipulate genetically, have a short generation time, and are relatively inexpensive. The most commonly used inbred mouse strains are reviewed in addition to several genetically engineered mouse models that have been generated to study type 2 diabetes in the context of obesity, with a focus on insulin, leptin, and peroxisome proliferator-activated receptor (PPAR) signaling pathways.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose; Homeostasis; Humans; Insulin; Leptin; Mice

Traditionally, nutrients such as glucose and amino acids have been viewed as substrates for the generation of high-energy molecules and as precursors for the biosynthesis of macromolecules. However, it is now apparent that nutrients also function as signaling molecules in functionally diverse signal transduction pathways. Glucose and amino acids trigger signaling cascades that regulate various aspects of fuel and energy metabolism and control the growth, proliferation, and survival of cells. Here, we provide a functional and regulatory overview of three well-established nutrient signaling pathways-the hexosamine signaling pathway, the mTOR (mammalian target of rapamycin) signaling pathway, and the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Nutrient signaling pathways are interconnected, coupled to insulin signaling, and linked to the release of metabolic hormones from adipose tissue. Thus, nutrient signaling pathways do not function in isolation. Rather, they appear to serve as components of a larger "metabolic regulatory network" that controls fuel and energy metabolism (at the cell, tissue, and whole-body levels) and links nutrient availability with cell growth and proliferation. Understanding the diverse roles of nutrients and delineating nutrient signaling pathways should facilitate drug discovery research and the search for novel therapeutic compounds to prevent and treat various human diseases such as diabetes, obesity, and cancer.

Topics: Adiponectin; Amino Acids; AMP-Activated Protein Kinase Kinases; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Hexosamines; Homeostasis; Humans; Insulin; Leptin; Metabolism; Neoplasms; Obesity; Protein Kinases; Signal Transduction; TOR Serine-Threonine Kinases

To review the potential role of leptin, hyperleptinaemia and leptin resistance in the cardiovascular and endocrine complications of metabolic syndrome.. Review of literature listed in Medline.. Hyperleptinaemia is common in obesity and reflects increased adiposity and leptin resistance. Nevertheless, leptin resistance may not be complete as several actions of leptin, such as cardiovascular sympatho-activation, might be preserved in obese subjects known to be resistant to the metabolic effects of leptin (i.e. selective leptin resistance). Notably, the renal and sympathetic actions of leptin may play an important role in the pathogenesis of hypertension related to obesity and metabolic syndrome. Furthermore, the lipotoxic effect of leptin resistance may cause insulin resistance and beta cell dysfunction, increasing the risk of type 2 diabetes. Leptin has also been shown to possess proliferative, pro-inflammatory, pro-thrombotic, and pro-oxidative actions.. Hyperleptinaemia and leptin resistance may contribute to hypertension, impaired glucose metabolism, and pro-atherogenic state in obesity and metabolic syndrome.

Topics: Animals; Atherosclerosis; Blood Pressure; Diabetes Mellitus, Type 2; Drug Resistance; Humans; Hypertension; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity

Topics: Animals; Cytokines; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-18; Leptin; Male; Mice

The incidence of type 1 and type 2 diabetes mellitus in the pediatric population has increased over the past decade. The practitioner is often faced with the challenge of differentiating between type 1 and type 2 diabetes at the time of initial diagnosis because of the overlap of clinical and laboratory characteristics between these two entities. Adipokines are proteins secreted by the adipose tissue. Leptin and adiponectin are two adipokines that have been extensively studied in vitro, in animal studies, and in human subjects with type 1 and type 2 diabetes. Leptin and adiponectin play a significant role in the regulation of lipid and carbohydrate metabolism. Adiponectin increases insulin sensitivity in both the liver and skeletal muscle. Leptin decreases appetite, increases energy expenditure, suppresses insulin synthesis and secretion and increases insulin sensitivity. Changes in the secretion or sensitivity to leptin and adiponectin may contribute to the development of type 1 and type 2 diabetes. Adiponectin is higher in adult and pediatric patients with type 1 diabetes compared to those with type 2 diabetes. Data regarding leptin levels are contradictory. Most studies report decreased serum leptin at the time of diagnosis in type 1 diabetes compared to type 2 diabetes subjects and non-diabetic controls. This paper will review basic research and clinical evidence supporting the role of adiponectin and leptin in the development of type 1 and type 2 diabetes and discuss their potential use as tools in the differential diagnosis of pediatric diabetes.

Topics: Adiponectin; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diagnostic Techniques, Endocrine; Humans; Immune System; Insulin Resistance; Leptin; Metabolic Networks and Pathways; Models, Biological; Obesity

Impairment in the regulation of energy homeostasis and imbalance between energy intake and energy expenditure lead to many metabolic disorders and diseases such as obesity and type 2 diabetes. AMP-activated protein kinase (AMPK) is considered as a "fuel-gauge" in the cell and plays a key role in the regulation of energy metabolism. Activated by an increase in the AMP/ATP ratio, AMPK switches on catabolic pathways such as fatty acid oxidation and switches off anabolic pathways such as lipogenesis or gluconeogenesis. Insulin-sensitizing adipokines (leptin and adiponectin) and anti-diabetic drugs (thiazolidinediones and biguanides) are acting in part through the activation of AMPK. More recent findings indicate that AMPK plays also a major role in the control of whole body energy homeostasis by integrating, at the hypothalamus level, nutrient and hormonal signals that regulate food intake and energy expenditure. AMPK provides therefore a potential target for the treatment of metabolic diseases such as obesity and type II diabetes.

Topics: Adenylate Kinase; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids; Homeostasis; Humans; Insect Hormones; Insulin; Leptin; Models, Biological; Oligopeptides; Prevalence; Pyrrolidonecarboxylic Acid

Fatty tissue synthesizes and secretes a wide range of products that may be directly involved in the pathogenesis of the complications associated with obesity. These so-called adipokines may trigger or sustain a chronic inflammatory process. By manipulating the secretory function of fat cells, it might in future be possible to prevent the development of the metabolic and cardiovascular complications of obesity. Current data already suggest that weight reduction and certain substances with an anti-inflammatory action reduce the risk for the metabolic and cardiovascular complications of obesity. To date, however, the evidence available is only indirect, and is insufficient to definitively establish causal relationships between certain secretory products of adipocytes and the comorbidities of adiposity. Further clinical studies are needed.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hypertension; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Metabolic Syndrome; Obesity; Plasminogen Inactivators; Risk Factors; Thromboembolism; Weight Loss

Among the atypical antipsychotics, clozapine and olanzapine are known to cause significant weight gain. Along with quetiapine, they may impair glucose metabolism and increase the risk for type 2 diabetes. They are also associated with a rise in triglyceride levels and an increased risk for coronary artery disease. Clinicians should take these risks seriously in prescribing these antipsychotics and employ intelligent safeguards if and when they use them.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypertriglyceridemia; Leptin; Neurotransmitter Agents; Olanzapine; Weight Gain

Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Disease Progression; Endothelial Cells; Glucose Intolerance; Humans; Hypertension; Insulin Resistance; Leptin; Life Style; Obesity

The role of adipocytes as protein secreting cells has been known for almost 15 years. Most of these proteins have known biological activity and are called adipokines. However, only a few of the adipokines have been shown to regulate insulin sensitivity. The latter effects are direct or indirect. The adipokines regulating insulin sensitivity are tumor necrosis factor alpha, adiponectin, interleukin-6, resistin and leptin. This review examines the mechanism how these adipokines influence insulin sensitivity, how the adipocyte production of the adipokines is regulated and if genetic variance in the genes encoding for adipokines is important for the development of type 2 diabetes mellitus.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Cytokines; Diabetes Mellitus, Type 2; Genetic Variation; Hormones, Ectopic; Humans; Inflammation; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Models, Biological; Nicotinamide Phosphoribosyltransferase; Resistin; Tumor Necrosis Factor-alpha

Fructose intake and the prevalence of obesity have both increased over the past two to three decades. Compared with glucose, the hepatic metabolism of fructose favors lipogenesis, which may contribute to hyperlipidemia and obesity. Fructose does not increase insulin and leptin or suppress ghrelin, which suggests an endocrine mechanism by which it induces a positive energy balance. This review examines the available data on the effects of dietary fructose on energy homeostasis and lipid/carbohydrate metabolism. Recent publications, studies in human subjects, and areas in which additional research is needed are emphasized.

Topics: Beverages; Diabetes Mellitus, Type 2; Energy Metabolism; Fructose; Ghrelin; Glucose; Humans; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Obesity; Peptide Hormones

Topics: Adiponectin; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Intercellular Signaling Peptides and Proteins; Leptin

In an era of rapidly increasing prevalence of human obesity and associated health problems, leptin gene polymorphisms have drawn much attention in biomedical research. Leptin gene polymorphisms have furthermore drawn much attention from animal scientists for their possible roles in economically important production and reproduction traits. Of the polymorphisms reported for exonic, intronic, and promoter regions of the leptin gene, 16 have been included in association studies in humans, 19 in cattle, and 6 (all exonic or intronic) in pigs. In humans, associations have been found with overweight or (early-onset) obesity, non-insulin-dependent diabetes mellitus, prostate cancer, and non-Hodgkin's lymphoma. In cattle, associations have been found with feed intake, milk yield traits, carcass traits, and reproduction-related traits, and in pigs with feed intake, average daily gain, carcass traits (backfat/leanness), and reproduction performance traits. Many of the polymorphisms were only included in a limited number of association studies, or the phenotypes studied varied largely for a given polymorphism between studies. Therefore, many of the associations found for these polymorphisms need to be confirmed in future studies before firm conclusions can be drawn.

Topics: Animals; Cattle; Diabetes Mellitus, Type 2; DNA, Complementary; Exons; Humans; Introns; Leptin; Lymphoma, Non-Hodgkin; Male; Obesity; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Prostatic Neoplasms; Swine

Topics: Animals; Bacterial Infections; Blood Glucose; Chemokines; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Humans; Immunity; Leptin; Listeriosis; Liver; Obesity; Risk; Weight Loss

In the past decade, epidemiological findings and data from experimental studies in animals have shown that the structure and function of the organism can be programmed during critical periods of development which can lead to detrimental long-term consequences for the health of an individual. Low birth weight has been linked to many adult diseases in humans including type 2 diabetes. The full detrimental effects of early growth restriction are often accompanied by the presence of obesity, which itself might be a manifestation of programmed appetite regulation in fetal and neonatal life. The understanding of interactions between leptin and insulin and their roles in glucose and body weight regulation provides clues towards mechanisms underlying altered appetite regulation and increased risk of type 2 diabetes in low birth weight individuals. Molecular mechanisms involved might include epigenetic alteration of the fetal genome in response to maternal nutrition.

Topics: Animals; Appetite; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Humans; Infant, Low Birth Weight; Infant, Newborn; Insulin; Insulin Secretion; Leptin; Obesity; Rodentia

A decrease in the number of functional insulin-producing beta-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in beta-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of beta-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-kappaB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of beta-cell secretory function and cell turnover. Thus, the mechanisms regulating beta-cell proliferation, apoptosis, and function are inseparable processes.

Topics: Animals; Cell Death; Diabetes Mellitus, Type 2; Disease Models, Animal; Dyslipidemias; Humans; Immunity, Innate; Inflammation; Insulin-Secreting Cells; Leptin; Risk Factors

In this work, I stand out the rich endocrine role of adipocytes, that together with its function of lipidic deposit and regulating of metabolism, this confers them a central place in physiology and pathology.

Topics: Adipocytes; Adiponectin; Adolescent; Adult; Aged; Animals; Child; Diabetes Mellitus, Type 2; Female; Humans; Hypothalamus; Infant, Newborn; Insulin Resistance; Interleukins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Obesity; Osteoporosis; Osteoporosis, Postmenopausal; Puberty; Rats; Tumor Necrosis Factor-alpha

Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects associated to environmental factors in any part of this system can lead to metabolic disorders such as the syndrome X which is presently a frequent syndrome in industrialized countries. It is characterized by a cluster of risk factors of atherosclerosis including insulin resistance, hyperinsulinemia, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, and coagulation abnormalities. Its pathophysiology is likely to involve insulin resistance at the level of both skeletal muscle and visceral adipose tissue and altered fluxes of metabolic substrates between these tissues that in turn impair liver metabolism. Therapeutic intervention favours at present diet and exercise prescriptions. In addition, if necessary, specific treatment of the metabolic disorders is required. In the treatment of insulin resistance, new promising drugs are likely to be used in the next future. In this regard, adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. Here, we review new advances in our understanding of mechanisms leading to insulin resistance and type 2 diabetes from the perspective of the role and interactions of recently identified adipocyte-specific chemical messengers, the adipocytokines, such as adiponectin, tumor necrosis factor-alpha, interleukin 6, and resistin.

Topics: Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Incidence; Insect Hormones; Insulin Resistance; Leptin; Mice; Obesity; Oligopeptides; Pyrrolidonecarboxylic Acid; Resistin

The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described to act on the satiety center in the hypothalamus through specific receptors (leptin receptor [ObR]) to restrict food intake and enhance energy expenditure. Important peripheral actions of leptin involve inhibition of insulin biosynthesis and secretion in pancreatic beta-cells. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop-the so-called "adipo-insular axis." Multiple signal transduction pathways are involved in leptin signaling in pancreatic beta-cells. We have identified the proinsulin gene and protein phosphatase 1 gene as leptin repressed genes and the gene for the suppressor of cytokine signaling 3 protein as a leptin-induced gene in pancreatic beta-cells. The molecular effects of leptin culminate to restrict insulin secretion and biosynthesis to adapt glucose homeostasis to the amount of body fat. In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing "leptin resistance." This leptin resistance at the level of the pancreatic beta-cell may contribute to dysregulation of the adipo-insular axis and promote the development of hyperinsulinemia and manifest type 2 diabetes in overweight patients.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Models, Biological

Adipose tissue has evolved as a complex organ with functions far beyond the mere storage of energy. Chronic oversupply of calories, common to Western-style diets, frequently goes hand-in-hand with an altered secretion pattern of adipokines and elevated plasma free fatty acid levels, known to modulate insulin sensitivity in skeletal muscle. Intramyocellular accumulation of lipids directly attenuates insulin signaling within myocytes via distinct kinases. Obesity is also accompanied by an enhanced basal inflammatory tone, originating from adipocytes and adipose tissue-associated macrophages. In addition, adipocytes accumulate within the skeletal muscle and exert direct paracrine effects on muscle insulin sensitivity.

Topics: Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Inflammation; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Proteins

Topics: Adiponectin; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Proteins; Tumor Necrosis Factor-alpha

PTP1B is a ubiquitously expressed intracellular protein tyrosine phosphatase. Several lines of evidence support an important role for protein tyrosine phosphatase 1B(PTP1B) in metabolism, and specially in type 2 diabetes and obesity. Overexpression of PTP1B protein has been observed in insulin-resistant states associated with obesity. PTP1B is a negative regulator of insulin and leptin signaling, PTP1B inhibitors might be efficacious in the treatment of type 2 diabetes and obesity by increasing insulin and leptin sensitivity.

Topics: Animals; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Insulin; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction

Isomers of conjugated linoleic acid (CLA) are found in beef, lamb and dairy products. Diets containing CLA reduce adipose mass in various depots of experimental animals. In addition, CLA delays the onset of diabetes in the ZDF rat model for obesity-linked type 2 diabetes mellitus. We hypothesize that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes mellitus. In this double-blind study, subjects with type 2 diabetes mellitus were randomized into one of two groups receiving either a supplement containing mixed CLA isomers (CLA-mix; 8.0 g daily, 76% pure CLA; n = 12) or a supplement containing safflower oil (placebo; 8.0 g daily safflower oil, n = 9) for 8 wk. The isomers of CLA in the CLA-mix supplement were primarily c9t11-CLA ( approximately 37%) and t10c12-CLA ( approximately 39%) in free fatty acid form. Plasma levels of CLA were inversely associated with body weight (P < 0.05) and serum leptin levels (P < 0.05). When levels of plasma t10c12-CLA isomer were correlated with changes in body weight or serum leptin, t10c12-CLA, but not c9t11-CLA, was inversely associated with body weights (P < 0.05) and serum leptin (P < 0.02). These findings strongly suggest that the t10c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in subjects with type 2 diabetes. Future studies are needed to determine a causal relationship, if any, of t10c12-CLA or c9t11-CLA to modulate body weight and composition in subjects with type 2 diabetes. Furthermore, determining the ability of CLA isomers to influence glucose and lipid metabolism as well as markers of insulin sensitivity is imperative to understanding the role of CLA to aid in the management of type 2 diabetes and other related conditions of insulin resistance.

Topics: Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Humans; Leptin; Linoleic Acid; Obesity; Randomized Controlled Trials as Topic

It is generally accepted that obesity is associated with many other multiple-risk factor syndromes such as hypertension, hyperlipidemia, type 2 diabetes mellitus, and periodontal disease. The number of obese people is increasing rapidly in both western and eastern countries. Adipocytes in the adipose tissues of obese people produce large quantities of biologically active molecules such as leptin, an important molecule regulating energy expenditure and body weight. Therefore, adipocyte-derived active molecules, named adipocytokines, are candidate molecules accounting for the close association between obesity and other multiple-risk factor syndromes. The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is produced by adipocytes, and its blood concentration is elevated in obese patients and declines with weight loss. Studies have demonstrated that TNF-alpha suppresses insulin action via its specific receptor; hence, it exacerbates insulin resistance. In addition to adipocytes, monocytes/macrophages produce large quantities of TNF-alpha. Thus, TNF-alpha, produced from monocytic cells due to inflammatory diseases, may have an additive influence on insulin sensitivity to adipocyte-derived TNF-alpha. Here, we hypothesized that 1) TNF-alpha produced by the adipose tissues of obese patients acts as a risk factor for periodontal inflammation, and 2) TNF-alpha produced due to periodontal inflammation may be an additional important factor influencing insulin sensitivity in both obese and type 2 diabetic patients. We believe that this interaction is a possible mechanism accounting for a 2-way relationship between type 2 diabetes and periodontal disease.

Topics: Adipocytes; Cytokinins; Diabetes Mellitus, Type 2; Humans; Inflammation Mediators; Insulin Resistance; Leptin; Macrophages; Monocytes; Obesity; Periodontal Diseases; Periodontitis; Risk Factors; Syndrome; Tumor Necrosis Factor-alpha

Topics: Adipocytes; Adipose Tissue; Diabetes Mellitus, Type 2; Energy Metabolism; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Receptors, Cell Surface; Receptors, Cytokine; Resistin

Early onset obesity and type II diabetes is rapidly becoming an epidemic, especially within the United States. This dramatic increase is likely due to many factors including both prenatal and postnatal environmental cues. The purpose of this review is to highlight some of the recent advances in our knowledge of the development of the hypothalamic circuits involved in the regulation of energy balance, with a focus on the neuropeptide Y (NPY) system. Unlike the adult rat, during the postnatal period NPY is transiently expressed in several hypothalamic regions, along with the expected expression within the arcuate nucleus (ARH). These transient populations of NPY neurons during the postnatal period may provide local NPY production to sustain the necessary energy intake during this critical growth phase. This may be physiologically important since ARH-NPY projections do not fully develop until the 3rd postnatal week. The significance of this ontogeny is that many peripheral metabolic signals have little effect of feeding prior to the development of the ARH projections. The essential questions now are whether prenatal and/or postnatal exposure to high levels of insulin or leptin during development can cause permanent changes in the function of hypothalamic circuits. It is vital to understand not only the natural development of the hypothalamic circuits that regulate energy homeostasis, but also their abnormal development caused by maternal and postnatal environmental cues. This will be pivotal for designing intervention and therapeutics to treat early onset obesity/type II diabetes, which may very well need to be different from those designed to prevent/treat adult onset obesity/type II diabetes.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Hypothalamus; Insulin; Leptin; Male; Nerve Net; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains

Diabetes mellitus and hypertension are often associated with each other, and both are risk factors for cardiovascular diseases. Insulin resistance has been noted as an etiology for diabetes, hypertension and atherosclerosis. Insulin resistance often accompanied hyperinsulinemia and it is thought to elevate blood pressure through stimulation of the sympathetic nervous system and renin-angiotensin system, promotion of sodium retention in the renal tubules, and proliferation of vascular smooth muscle cells via insulin-like growth factor. Also high blood glucose may impair vascular endothelial cells and produce oxidant stress. To prevent the occurrence of hypertension in diabetes patients, improving insulin resistance have to be considered, and primary care such as reducing body weight, salt and alcohol restriction, exercise and non-smoking are important.

Topics: Arteriosclerosis; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Leptin; Life Style; Oxidative Stress; Primary Prevention; Renin-Angiotensin System; Sympathetic Nervous System

Obesity is important in the aetiology of type 2 diabetes, and presents a major barrier to its successful prevention and management. Obesity develops when energy intake exceeds energy expenditure over time. A complex system has evolved to maintain energy homeostasis, but this is biased towards weight gain. Meal size is controlled by a series of short-term hormonal and neural signals that derive from the gastrointestinal tract, such as cholecystokinin whereas others may initiate meals, such as the recently discovered hormone, ghrelin. Other hormones such as insulin and leptin, together with circulating nutrients, indicate long-term energy stores. All these signals act at several central nervous system (CNS) sites but the pathways converge on the hypothalamus, which contains a large number of peptide and other neurotransmitters that influence food intake. As energy deficit is most likely to compromise survival, it is not surprising that the most powerful of these pathways are those that increase food intake and decrease energy expenditure when stores are depleted. When energy stores are low, production of leptin from adipose tissue, and thus circulating leptin concentrations fall, leading to increased production of hypothalamic neurotransmitters that strongly increase food intake, such as neuropeptide Y (NPY), galanin and agouti-related protein (AGRP) and decreased levels of alpha-melanocyte-stimulating hormone (alpha-MSH), cocaine and amphetamine-regulated transcript (CART) and neurotensin that reduce food intake and increase energy expenditure. The finding that mutations in leptin and POMC lead to severe early onset obesity in humans has highlighted the importance of these peptides in humans. This new understanding may eventually lead to new treatments for obesity that will be of particular benefit in the prevention and treatment of type 2 diabetes.

Topics: Appetite; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Homeostasis; Humans; Leptin; Neuropeptides; Obesity

Non-alcoholic steatohepatitis (NASH) is a disease of emerging identity and importance. It is frequently associated with obesity, especially visceral fat, and is intimately related to fatty liver and markers of the insulin resistance syndrome. Both the prevalence and the severity of liver steatosis are related to body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance or type 2 diabetes. The identification of obese patients who may progress from steatosis to NASH and from NASH to fibrosis/cirrhosis is an important clinical challenge. Substantial weight loss is accompanied by a marked attenuation of insulin resistance and related metabolic syndrome and, concomitantly, by a remarkable regression of liver steatosis in most patients, although increased inflammation may be detected in some subjects. Thus, NASH may be considered as another disease of affluence, as is the insulin resistance syndrome, and perhaps being part of it, especially in obese patients.

Topics: Cytokines; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Fatty Liver; Humans; Insulin Resistance; Leptin; Obesity; Oxidative Stress; Prognosis; Weight Loss

Obesity has become the most prevalent nutritional disorder in post-industrialised societies and it is associated with the development of severe and costly complications such as type 2 diabetes mellitus and coronary heart disease or cancer. A large proportion of the risk of obesity is determined by the genetic susceptibility of an individual, but environmental factors conducive for the disorder play an important role in its phenotypic expression. Several candidate genes emerged from studies in animal models of obesity, but human pathophysiology is likely to be more complex. Thus, most cases of human obesity probably result from subtle interactions of susceptibility genes with environmental factors favouring deposition of excess calories as fat. The recent surge of obesity may relate to past evolutionary pressure which favoured selection of mechanisms defending body-weight against caloric restriction rather than against caloric excess. Rapidly developing new techniques in quantitative genetics and growing information from functional genomics will help to understand the interaction of environmental factors with signalling networks that regulate energy metabolism. The role of previously unknown pathways in the aetiology of obesity will be uncovered. The typing of numerous genetic variants will become possible and allow individual risk assessment for obesity and/or its associated disorders. Thus, rational and individually tailored therapies may be developed to combat obesity and its associated disorders.

Topics: Adult; Animals; Body Mass Index; Child; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Environment; Female; Genetic Predisposition to Disease; Humans; Hyperphagia; Leptin; Male; Mice; Mice, Knockout; Mutation; Obesity; Phenotype; Polymorphism, Genetic; Prevalence; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; Risk Assessment; Risk Factors; Thermogenesis

Leptin is a small peptide hormone that is mainly, but not exclusively, produced in adipose tissue. The circulating leptin concentration therefore directly reflects the amount of body fat. Leptin was identified through positional cloning of the obese (ob) gene, which is mutated in the massively obese ob/ob mouse, and it has a pivotal role in regulating food intake and energy expenditure. It binds to the so-called long receptor (Ob-Rb) in the hypothalamus and regulates food intake through the release of other neurotransmitters. Moreover, leptin exerts several other important metabolic effects on peripheral tissue, including modification of insulin action, induction of angiogenesis, and modulation of the immune system. As a small peptide, leptin is cleared principally by the kidney. Not surprisingly, serum leptin concentrations are increased in patients with chronic renal failure and those undergoing maintenance dialysis. Whether the hyperleptinemia of chronic renal failure contributes to some uremic manifestations, such as anorexia and weight loss, requires additional investigation. The kidney expresses abundant concentrations of the truncated isoform of the leptin receptor Ob-Ra, but only a small amount of the full-length receptor Ob-Rb. We recently discovered that leptin has direct effects on renal pathophysiological characteristics. Both cultured glomerular endothelial cells and mesangial cells obtained from the diabetic db/db mouse possess the Ob-Ra receptor, but whether biological effects of leptin are transduced through this receptor remains unknown. In glomerular endothelial cells, leptin stimulates cellular proliferation, transforming growth factor-beta1 (TGF-beta1) synthesis, and type IV collagen production. Conversely, in mesangial cells, leptin upregulates synthesis of the TGF-beta type II receptor, but not TGF-beta1, and stimulates glucose transport and type I collagen production through signal transduction pathways involving phosphatidylinositol-3-kinase. These data suggest that leptin triggers a paracrine interaction in which glomerular endothelial cells secrete TGF-beta, to which sensitized mesangial cells may respond. Both cell types increase their expression of extracellular matrix in response to leptin. Infusion of leptin into normal rats for 3 weeks fosters the development of focal glomerulosclerosis and proteinuria. Additional previously described direct and indirect effects of leptin on the kidney include natriuresis, increased sympathe

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Humans; Kidney Diseases; Leptin; Obesity

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose; Humans; Leptin; Obesity; Pregnancy

Skeletal muscle contains the majority of the body's glycogen stores and a similar amount of readily accessible energy as intramyocellular triglyceride (imTG). While a number of factors have been considered to contribute to the pathogenesis of insulin resistance (IR) in obesity and type 2 diabetes mellitus (DM), this review will focus on the potential role of skeletal muscle triglyceride content. In obesity and type 2 DM, there is an increased content of lipid within and around muscle fibers. Changes in muscle in fuel partitioning of lipid, between oxidation and storage of fat calories, almost certainly contribute to accumulation of imTG and to the pathogenesis of both obesity and type 2 DM. In metabolic health, skeletal muscle physiology is characterized by the capacity to utilize either lipid or carbohydrate fuels, and to effectively transition between these fuels. We will review recent findings that indicate that in type 2 DM and obesity, skeletal muscle manifests inflexibility in the transition between lipid and carbohydrate fuels. This inflexibility in fuel selection by skeletal muscle appears to be related to the accumulation of imTG and is an important aspect of IR of skeletal muscle in obesity and type 2 DM.

Topics: Adipose Tissue; Diabetes Mellitus, Type 2; Glycogen; Humans; Insulin Resistance; Leptin; Muscle, Skeletal; Obesity; Triglycerides

The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta-cells to compensate by adequate insulin secretion.. Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance.. Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue-specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue-specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin-responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic beta-cells and brain in the development of insulin deficiency and obesity.

Topics: Adipose Tissue; Animals; Brain; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin Resistance; Islets of Langerhans; Leptin; Lipid Metabolism; Liver; Mice; Mice, Knockout; Models, Animal; Muscle, Skeletal; Obesity; Receptor, Insulin; Receptors, Somatomedin; Research Design

Leptin deficiency, found in transgenic lipodystrophic mice and in obese (ob/ob) mice, was shown to cause increased lipogenesis in liver, through action of the sterol regulatory element-binding protein-1c, and increased liver gluconeogenesis, through a decline in the insulin receptor substrate-2. The resulting stimulation of insulin secretion by the pancreas owing to high blood glucose initiates a vicious cycle of insulin resistance.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Mice; Mice, Obese; Models, Biological

The first unifying definition for the metabolic syndrome was proposed by WHO in 1998. In accordance to this, patients with type 2 diabetes mellitus or impaired glucose tolerance have the syndrome if they fulfil two of the criteria: hypertension, dyslipidaemia, obesity/abdominal obesity and microalbuminuria. Persons with normal glucose tolerance (NGT) should also be insulin resistant. About 40% of persons with impaired glucose tolerance (IGT) and 70% of patients with type 2 diabetes have features of the syndrome. Importantly, presence of the dysmetabolic syndrome is associated with reduced survival, particularly because of increased cardiovascular mortality. The dysmetabolic syndrome most likely results from interplay between several genes and an affluent environment. Compatible with the thrifty gene theory, common variants in genes regulating lipolysis, thermogenesis and glucose uptake in skeletal muscle account for a large part of such thrifty genes. However, hitherto unknown genes may still be identified by random gene approaches.

Topics: Abdomen; Adult; Age Distribution; Aged; Animals; Carrier Proteins; Diabetes Mellitus, Type 2; Genotype; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Leptin; Middle Aged; Mutation; Obesity; Phenotype; Prevalence; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Receptors, Peptide; Syndrome

Poor periodontal health is known to be associated with Type 2 diabetes mellitus (DM). This relationship and underlying mechanisms are discussed elsewhere in this issue. Less is known concerning the link between the metabolic precursors to DM, including insulin resistance (IR), and its possible association with periodontitis. Indeed, there has been relatively little research to date in human populations concerning periodontal disease, IR, and the subsequent risk of chronic diseases, including DM. This paper will present an epidemiologist's view of how IR may link periodontal disease with DM and suggest several avenues of investigation to help clarify some of the outstanding issues.

Topics: Adipocytes; Animals; Chronic Disease; Diabetes Mellitus, Type 2; Disease Models, Animal; Epidemiologic Methods; Forecasting; Glucose Clamp Technique; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Models, Biological; Periodontal Diseases; Periodontitis; Research Design; Risk Factors; Tumor Necrosis Factor-alpha

The autonomic nervous system modulates glucose and fat metabolism through both direct neural effects and hormonal effects. This review presents recent concepts on the sympathetic regulation of glucose and fat metabolism. Focally released norepinephrine from sympathetic nerves is likely to increase glucose uptake in skeletal muscle and adipose tissues independent of insulin but norepinephrine does not contribute so much as epinephrine to hepatic glucose production. Epinephrine increases hepatic glucose production and inhibits insulin secretion and the glucose uptake by tissues that is induced by insulin. Additionally, catecholamines can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. It is likely that beta-(beta3)-adrenergic receptors mediate these responses. Alterations of central neurotransmission and environmental factors can change the relative contribution of sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissues, leading to the modulation of glucose and fat metabolism. Recent studies have proposed that leptin, an adipocyte hormone, affects the central nervous system to increase sympathetic outflow independent of feeding. The effects of leptin on glucose and fat metabolism could be in part mediated by the sympathetic nervous system. Studies using mice with a genetic disruption of serotonin 5-HT2c receptor indicate that central neural mechanisms in the regulation of sympathetic outflow and satiety could be dissociated. Abnormalities of sympathetic effects, including disturbances of leptin and beta3-adrenergic receptor signalling, are likely to cause obesity and impaired glucose tolerance in rodents and humans. These findings indicate that dysfunction of the sympathetic nervous system could predispose to obesity and Type II (non-insulin-dependent) diabetes mellitus.

Topics: Adipose Tissue; Animals; Autonomic Nervous System; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Glucose; Humans; Leptin; Lipid Metabolism; Liver; Muscle, Skeletal; Norepinephrine; Obesity; Sympathetic Nervous System

The clustering of cardiovascular risk factors such as abdominal obesity, hypertension, dyslipidaemia and glucose intolerance in the same persons has been called the metabolic or insulin-resistance syndrome. In 1998 WHO proposed a unifying definition for the syndrome and chose to call it the metabolic syndrome rather than the insulin-resistance syndrome. Although insulin resistance has been considered as a common denominator for the different components of the syndrome, there is still debate as to whether it is pathogenically involved in all of the different components of the syndrome. Clustering of the syndrome in families suggests a genetic component. It is plausible that so-called thrifty genes, which have ensured optimal storage of energy during periods of fasting, could contribute to the phenotype of the metabolic syndrome. Common variants in a number of candidate genes influencing fat and glucose metabolism can probably, together with environmental triggers, increase susceptibility to the syndrome. Among these, the genes for beta 3-adrenergic receptor, hormone-sensitive lipase, lipoprotein lipase, IRS-1, PC-1, skeletal muscle glycogen synthase, etc. appear to increase the risk of the metabolic syndrome. In addition, novel genes may be identified by genome-wide searches.

Topics: Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Glycogen Synthase; Humans; Hypertension; Insulin Resistance; Leptin; Male; Obesity; Receptors, Adrenergic, beta; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Transcription Factors

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Gene Expression; Humans; Hypertension; Leptin; Obesity; Signal Transduction

Leptin is a hormone produced primarily by the adipocytes. It works through different receptors and seems to provide information to the hypothalamus about the energy status of the body. Although leptin appears to exert its anti-obesity effect through its central action, the full spectrum of its action is yet to be determined. Most obese subjects in studies have high serum levels of leptin, suggesting that the major problem is leptin resistance rather than leptin deficiency. Consequently, these patients may not respond to exogenous leptin. Recent trials have indicated, however, that leptin may have therapeutic potential in leptin-deficient as well as leptin-resistant states.

Topics: Animals; Diabetes Mellitus, Type 2; Gene Expression; Humans; Leptin; Neuropeptide Y; Obesity, Morbid; Receptors, Cell Surface; Receptors, Leptin

Topics: Adipose Tissue; Anti-Obesity Agents; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Muscle, Skeletal; Obesity; Risk Factors; Weight Loss

The peroxisome proliferator-activated receptor gamma (PPARgamma) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARgamma in obesity and diabetes.

Topics: Adipose Tissue; Cell Differentiation; Diabetes Mellitus, Type 2; Humans; Leptin; Obesity; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Necrosis Factor-alpha

Since the discovery of leptin, a boom of scientific knowledge became available about the OB-protein gene and its role and significance in weight regulation. Both from animal and human research data, serum leptin can probably be considered as one of the best biological markers to reflect total body fat, and this finding is true over a wide range of body mass indexes (BMIs) and in different pathologies: in normal weight, anorexic and obese subjects; in non insulin-dependent diabetes mellitus (NIDDM) patients, PCO women, Prader-Willi children and subjects with hypogonadism and growth hormone deficiency. Gender differences clearly exist, probably related to sex hormone differences, and from fat distribution studies it could be shown that subcutaneous fat is much more related to serum leptin concentrations than visceral fat: also leptin messenger-RNA (m-RNA) expression is significantly higher in subcutaneous fat from human obese subjects. Leptin is not only correlated to a series of endocrine parameters such as insulin, insulin-like growth factor, (IGF) and SHBG, it seems involved as a mediator in some endocrine mechanisms (onset of puberty, insulin secretion, etc) as well. Weight loss will reduce human leptin concentrations, whereas the administration of human recombinant leptin seems to show only limited effects.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Obesity; Proteins; Puberty; Risk Factors; Sex Characteristics

It is now believed that the GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes have an important role in the development of obesity and non-insulin dependent diabetes mellitus (NIDDM). The protein encoded by daf-2 is 35% identical to the human insulin receptor, daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 can enhance superoxide dismutase (SOD) expression. EFAs and their metabolites can alter the cell membrane fluidity and enhance the expression of GLUT-4 and insulin receptors. EFAs can suppress TNF-alpha production and secretion, a mechanism that may have relevance to the role of these fatty acids in the pathogenesis of insulin resistance, obesity and NIDDM. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Based on this evidence, it is proposed that GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin interact with each other in ways which may have relevance to the development or abrogation of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.

Topics: Caenorhabditis elegans Proteins; Diabetes Mellitus, Type 2; Fatty Acids, Essential; Glucose; Glucose Transporter Type 4; Homeostasis; Humans; Insulin Resistance; Leptin; Melatonin; Models, Biological; Monosaccharide Transport Proteins; Multigene Family; Muscle Proteins; Proteins; Receptor, Insulin; Tumor Necrosis Factor-alpha

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Humans; Insulin Resistance; Leptin; Male; Proteins; Research

Topics: Diabetes Mellitus, Type 2; Gene Expression Regulation; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Obesity; Proteins

It has been increasingly recognised in recent years that type 2 (non-insulin-dependent) diabetes is part of a cluster of cardiovascular risk factors known as the metabolic syndrome, but also endorsed with such names as the deadly quartet, syndrome X and the insulin resistance syndrome. Atherosclerosis is the most common complication of type 2 diabetes among Europeans, and coronary artery, cerebrovascular and peripheral vascular disease are 2 to 5 times more common in people with this condition than in those without diabetes. These observations indicate that the treatment of type 2 diabetes requires agents that do more than simply lower blood glucose levels, and a therapy with both antihyperglycaemic effects and beneficial effects on dyslipidaemia, hypertension, obesity, hyperinsulinaemia and insulin resistance is likely to be most useful. In this respect, metformin has an important and established role: this drug has been shown to lower blood glucose and triglyceride levels, and to assist with weight reduction and to reduce hyperinsulinaemia and insulin resistance. Studies in the Israeli sand rat, Psammomys obesus, have indicated hyperinsulinaemia/insulin resistance to be the initial and underlying metabolic disorder in obesity and type 2 diabetes. Thus, the well established effect of metformin in reducing insulin resistance makes this drug an excellent candidate for the prevention of progression of impaired glucose tolerance to type 2 diabetes, and for the reduction of mortality associated with cardiovascular disease.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Chromans; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metformin; Rats; Risk Factors; Thiazoles; Thiazolidinediones; Troglitazone

The article summarizes the endocrinology axis in relation to leptin in the obesity. There is a glucocorticoid hypothesis in the obesity origin. Human plasma leptin levels are elevated in Cushing's syndrome and there is a robust leptin secretory responses to dexamethasone. Obesity impacts on reproductive function in man and women. Leptin levels are higher in women than in men and a critical blood leptin level is necessary to trigger reproductive ability in women. The relationship between body mass index and circulating leptin varies during the course of spontaneous cycles in women, the best correlation occurring during the luteal phase when progesterone and leptin concentrations are highest. Obesity is associated with a decrease in growth hormone (GH) and reversible with weight loss. The influence of body composition on GH secretion in the obesity may be mediated through leptin, acting as a peripheral signal from adipose tissue. Thyroid dysfunction appear not associated with alterations in serum leptin levels. There is a significant relationship between insulin and leptin, but it is not immediate, since type 2 diabetics show similar leptin levels to those of nondiabetic humans of the same body mass index.

Topics: Adult; Animals; Body Mass Index; Cushing Syndrome; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Human Growth Hormone; Humans; Hyperinsulinism; Hypertension; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Menstrual Cycle; Mice; Mice, Obese; Middle Aged; Obesity; Pituitary-Adrenal System; Progesterone; Rats; Reproduction; Sex Factors

An accumulation of evidence implicates leptin, insulin, glucocorticoids, proopiomelanocortin (POMC), and neuropeptide Y (NPY) interactions as being integral to metabolic control associated with neuroendocrine-endocrine functioning. Dysfunction of neuroendocrine-endocrine interactions contributes to the metabolic disturbances of diabetes mellitus type 2 (DM-2). Since Zn has a direct impact on the healthy functioning of hormonal and neuropeptide balance, it is possible that altered Zn status and metabolism in DM-2 are involved in some of the metabolic dysfunctions of DM-2.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endocrine System; Glucocorticoids; Humans; Insulin; Leptin; Neuropeptides; Neurosecretory Systems; Pro-Opiomelanocortin; Zinc

Obesity and Type 2 diabetes are now major public health issues in developed nations and have reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican-Americans, African-Americans, and Australian Aborigines. These groups all show hyperinsulinemia and insulin resistance, which have been demonstrated to be future predictors of Type 2 diabetes and have also been suggested as key factors in the etiology of the Metabolic Syndrome. It is now increasingly recognized that Type 2 diabetes is part of a cluster of cardiovascular disease (CVD) risk factors comprising the Metabolic Syndrome. This group is at very high risk of atherosclerosis because each of the risk factors in the Metabolic Syndrome cluster in its own right is an important CVD risk factor. They also contribute cumulatively to atherosclerosis. A key strategy in reducing macrovascular disease lies in the better understanding of the Metabolic Syndrome--glucose intolerance, hypertension, hyperlipidemia, and central obesity. Although it has been suggested that hyperinsulinemia/insulin resistance is the central etiological factor for the Metabolic Syndrome, epidemiological data do not support the idea that this can account for all of the cluster abnormalities. We have animal and human data suggesting that hyperleptinemia rather than, or synergistically with, hyperinsulinemia may play a central role in the genesis of the CVD risk factor cluster that constitutes the syndrome. Studies in Psammomys obesus (the Israeli sand rat) suggest hyperinsulinemia/insulin resistance is an early metabolic lesion in the development of obesity and Type 2 diabetes. This animal also develops other features of the Metabolic Syndrome, making it an excellent model to investigate etiology. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes, and dyslipidemia. It also develops hyperleptinemia and leptin insensitivity, and hyperleptinemia is correlated with insulin resistance independent of changes in body weight. It is likely that a similar sequence occurs in the transition from the prediabetic state to Type 2 diabetes in humans. More recently, other potential players in the etiology of the Metabolic Syndrome have been suggested including endothelial dysfunction and acetylation-stimulating protein (ASP). It has been suggested that endothelial dysfunction may be an antecedent fo

Topics: Acetylation; Animals; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Risk Factors

The authors reviewed the most recent literature on leptin, a protein produced by adipocytes which exerts its action on hypothalamus, modifying eating behavior and inhibiting the lust for food consumption. This one appeared to be the main, if not the only, physiologic action of leptin. Later leptin has been acknowledged a major role in the homeostasis. The regulation of the synthesis, and the mechanisms by which the protein modulates both food intake and energetic balance have been evaluated, and the hypotheses on the regulatory function exerted by leptin on the homeostasis, by acting on neuroendocrine system, on sexual maturity and fertility, on the sympathetic nervous system, on hemopoiesis and hydroelectrolytic balance have been discussed, some of which being already supported by experimental evidences.

Topics: Adipose Tissue; Animals; Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Proteins

Topics: Adipose Tissue; Body Composition; Brain; Diabetes Mellitus, Type 2; Energy Metabolism; Food; Humans; Insulin; Leptin; Neurotransmitter Agents; Obesity; Proteins

The basic premise of the thrifty gene hypothesis is that certain populations may have genes that determine increased fat storage, which in times of famine represent a survival advantage, but in a modern environment result in obesity and type 2 diabetes. The concept finds support in a unique animal model (Psammomys obesus) as well as among high type 2 diabetes susceptibility populations, such as North American Indians and South Pacific islanders. However, in some developing communities (e.g., Black South Africans) the thrifty phenotype hypothesis of perinatal malnutrition causing beta-cell dysfunction seems a better explanation, but this remains a contentious issue. Several genes have already been identified as candidates for the thrifty genotype, including those encoding proteins of the insulin-signaling and leptin pathways, as well as intermediary fat metabolism. Particular interest lies in the peroxisome-proliferator activated receptors. An innovative approach might be to focus on the "mirror image" of the thrifty genotype-congenital lipoatrophic diabetes mellitus, whose molecular defect remains enigmatic. We conclude that the genetic basis of the thrifty genotype probably derives from the multiplicative effects of polymorphisms at several sites mentioned above, rather than a single regulatory abnormality.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 2; Genotype; Humans; Insulin; Leptin; Obesity; Phenotype; Proteins; Signal Transduction

Topics: Animals; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Mice, Obese; Proteins

This review considers recent findings and ideas on the impact of dietary carbohydrates on insulin sensitivity in the context of the prevention of diabetes and cardiovascular disease. We assess the evidence for benefits in insulin sensitivity following high starch as distinct from high sucrose intakes when the diet is low in fat. We consider relationships between obesity, leptin and carbohydrate intake. We conclude that reducing the rate of carbohydrate digestion in the small bowel may be the key stage at which to intervene to reduce insulinaemia and so prevent downregulation of insulin receptors and insulin resistance.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Humans; Insulin Resistance; Leptin; Obesity; Rats; Starch

Topics: Animals; Carrier Proteins; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome; Humans; Insulin Resistance; Ion Channels; Leptin; Membrane Proteins; Mice; Mice, Mutant Strains; Mitochondrial Proteins; Obesity; Receptors, Adrenergic, beta-2; Receptors, Cell Surface; Receptors, Leptin; Tumor Necrosis Factor-alpha; Uncoupling Protein 1

Topics: Animals; Carrier Proteins; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Genotype; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Mutation; Obesity; Proteins; Receptors, Adrenergic, beta; Receptors, Cell Surface; Receptors, Leptin; Risk

Topics: Diabetes Mellitus, Type 2; Food; Humans; Leptin; Obesity; Proteins; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Tumor Necrosis Factor-alpha

A highly conserved protein called 'leptin' was recently discovered to play a role in regulation of the energy balance in humans and rodents. This 167-amino-acid-containing protein is only produced and secreted by mature adipocytes. Absence of the protein in mutant ob/ob mice and resistance to its effects in db/db mice lead to extreme obesity and type II diabetes mellitus. No mutation of the ob-gene encoding for leptin has been found in obese humans so far. ob mRNA in adipocytes and serum leptin levels are positively related to adipose tissue mass. Receptors for leptin have been found in the choroid plexus and hypothalamus. A feedback inhibition of leptin on hypothalamic neuropeptide Y (NY) production is postulated, as hypothalamic NY concentrations are increased in ob/ob mice and NY induces food intake, insulin secretion and autonomic nervous system activity. Insulin increases triglyceride stores in fat cells and could thereby stimulate leptin secretion. The ultimate intracellular pathway within the adipocyte that stimulates or shuts off ob mRNA expression and consequent leptin production and secretion remains to be elucidated. Whether leptin will ever come to play a role in the treatment of human obesity remains an unanswered question at the present time.

Topics: Adipocytes; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Humans; Leptin; Male; Mice; Mice, Obese; Obesity; Proteins

There is evidence that reduced sleep duration increases hunger, appetite, and food intake, leading to metabolic diseases, such as type 2 diabetes and obesity. However, the impact of sleep timing, irrespective of its duration and on the regulation of hunger and appetite, is less clear. We aimed to evaluate the impact of sleep loss during the late vs. early part of the night on the regulation of hunger, appetite, and desire for food.. Fifteen normal-weight ([mean ± SEM] body-mass index: 23.3 ± 0.4 kg/m. Ghrelin and feelings of hunger and appetite, as well as the desire for food, were increased after 'late-night sleep loss', but not 'early-night sleep loss', whereas leptin remained unaffected by the timing of sleep loss.. Our data indicate that timing of sleep restriction modulates the effects of acute sleep loss on ghrelin and appetite regulation in healthy men. 'Late-night sleep loss' might be a risk factor for metabolic diseases, such as obesity and type 2 diabetes. Thereby, our findings highlight the metabolic relevance of chronobiological sleep timing.

Topics: Appetite Regulation; Diabetes Mellitus, Type 2; Ghrelin; Humans; Leptin; Male; Obesity; Sleep

Topics: Adiponectin; Cholesterol; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucose; Humans; Leptin; Metabolic Syndrome; Obesity; Obesity, Morbid

High carbohydrate, lower fat (HCLF) diets are recommended to reduce cardiometabolic disease (CMD) but low carbohydrate high fat (LCHF) diets can be just as effective. The effect of LCHF on novel insulin resistance biomarkers and the metabolome has not been fully explored. The aim of this study was to investigate the impact of an ad libitum 8-week LCHF diet compared with a HCLF diet on CMD markers, the metabolome, and insulin resistance markers. n = 16 adults were randomly assigned to either LCHF (n = 8, <50 g CHO p/day) or HCLF diet (n = 8) for 8 weeks. At weeks 0, 4 and 8, participants provided fasted blood samples, measures of body composition, blood pressure and dietary intake. Samples were analysed for markers of cardiometabolic disease and underwent non-targeted metabolomic profiling. Both a LCHF and HCLF diet significantly (p < 0.01) improved fasting insulin, HOMA IR, rQUICKI and leptin/adiponectin ratio (p < 0.05) levels. Metabolomic profiling detected 3489 metabolites with 78 metabolites being differentially regulated, for example, an upregulation in lipid metabolites following the LCHF diet may indicate an increase in lipid transport and oxidation, improving insulin sensitivity. In conclusion, both diets may reduce type 2 diabetes risk albeit, a LCHF diet may enhance insulin sensitivity by increasing lipid oxidation.

Topics: Adiponectin; Adult; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dietary Carbohydrates; Dietary Fats; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Metabolome

Obesity impairs metabolic function and increases the risk of cardiovascular disease and type 2 diabetes mellitus. Evidence suggests that high-protein diets help to increase weight loss and protect against weight gain. Milk protein concentrate (MPC) is a dairy product with a high protein content with a ratio of casein and whey protein similar to skim milk. This trial aims to evaluate the effect of MPC supplementation in obese women under a weight-loss diet.. We will conduct a 2-month open-label, parallel-group, randomised controlled trial to determine the effect of MPC supplementation on levels of glycaemic and lipid profile, leptin, adiponectin, appetite, waist circumference, body mass index and body composition in 44 premenopausal obese women on a weight-loss diet.. This protocol, approved by the Medical Ethics Committee of Ahvaz University of Medical Sciences, is in accordance with the Declaration of Helsinki (approval number: IR.AJUMS.REC.1399.795). The trial results will be published in peer-reviewed journals.. Iranian Registry of Clinical Trials (IRCT20201223049804N1).

Topics: Adipokines; Adiponectin; Body Composition; Caseins; Diabetes Mellitus, Type 2; Diet, Reducing; Dietary Supplements; Female; Humans; Iran; Leptin; Lipids; Milk Proteins; Obesity; Randomized Controlled Trials as Topic; Whey Proteins

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Exercise; Fibronectins; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Resistance Training; Young Adult

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; 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Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; 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Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; 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Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

The present research aimed to investigate the anti-inflammatory potential of dietary anthocyanin (ACN) in type 2 diabetic (T2D), T2D-at-risk and healthy individuals. Furthermore, dietary inflammatory index (DII) was used to study the association of diet with biomarkers of inflammation.. An open-label clinical trial was conducted at Griffith University investigating the efficacy of 320 mg ACN supplementation per day over the course of 4 weeks. Diabetes-associated inflammatory biomarkers and relevant biochemical and physical parameters were tested pre-and post-intervention, and participants' dietary inflammatory potential was estimated.. A significant reduction in the pro-inflammatory biomarkers' interleukin-6, interleukin-18, and tumour necrosis factor-α was observed in the T2D group. In addition, some, but not all, biochemical parameters including fasting blood glucose, low-density lipoprotein cholesterol and uric acid were significantly improved in T2D-at-risk group. Moreover, a significant difference was detected between the DII scores of the healthy and T2D groups. DII score for the T2D group was consistent with an anti-inflammatory diet.. Anti-inflammatory potential of dietary ACN in T2D participants was evidenced in the present study. Although, anti-inflammatory dietary patterns of T2D participants may have accelerated the anti-inflammatory effect of the ACN capsules supplemented in this trial.

Topics: Adult; Aged; Anthocyanins; Anti-Inflammatory Agents; Biomarkers; Blood Glucose; Cholesterol, LDL; Cytokines; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Inflammation; Leptin; Middle Aged; Uric Acid

This study aimed to compare cytokine and adipokine levels in patients with obesity with and without type 2 diabetes (T2D) at baseline and 6 months after Roux-en-Y gastric bypass (RYGB) with healthy controls.. A total of 34 patients (21 with T2D) with BMI of 30 to 45 kg/m. Significant decreases in weight and glycated hemoglobin A. The altered cytokine profile of patients with obesity persisted after RYGB despite large weight loss and improved metabolic status, thus reflecting an inherent inflammatory state.

Topics: Adipokines; Adult; Case-Control Studies; Cytokines; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Inflammation Mediators; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Postoperative Period; Preoperative Period; Weight Loss

Growing evidence suggests that leptin is critical for glycemic control. Impaired leptin signaling may also contribute to low adiponectin expression in obese individuals. We assessed the association of leptin and adiponectin with incident type 2 diabetes (T2D), their interactions with sex and obesity status, and mediation by insulin resistance.. We included study participants from the Jackson Heart Study, a prospective cohort of adult African Americans in Jackson, Mississippi, that were free of T2D at the baseline Exam 1. Incident T2D was defined as new cases at Exam 2 or Exam 3. We created separate Cox regression models (hazard ratios per log-transformed ng/mL of leptin and adiponectin) with and without insulin resistance, HOMA-IR. Mediation by insulin resistance was analyzed. Several interactions were assessed, including by sex, HbA1c, and obesity.. Among our 3363 participants (mean age 53 years, 63% women), 584 developed incident T2D. Leptin was directly associated with incident T2D when modeled without HOMA-IR (HR = 1.29, 95% CI = 1.05-1.58). This direct association between leptin and T2D was significant among men (HR = 1.33, 95% CI = 1.05-1.69), but nonsignificant among women (HR = 1.24, 95% CI = 0.94-1.64); statistical interaction with sex was nonsignificant (p = 0.65). The associations in all participants and in men were nullified by HOMA-IR (HR = 0.99, 95% CI = 0.80-1.22; HR = 1.00, 95% CI = 0.78-1.28, respectively), indicating mediation through insulin resistance (proportion mediated: 1.04), and were not observed in abdominally obese participants. Adiponectin was inversely associated with T2D even after adjustment for HOMA-IR in women (HR = 0.68, 95% CI = 0.55-0.84), but not in men (HR = 0.80, 95% CI = 0.62-1.04). The inverse association was present only among abdominally obese participants, and persisted after adjustment for HOMA-IR.. Among African Americans in the Jackson Heart Study the association of leptin with incident type 2 diabetes was mediated by insulin resistance. This association was present only among abdominally non-obese participants. Differences by sex appeared: men showed a significant association mediated by insulin resistance. Among abdominally obese participants, adiponectin was inversely associated with incident T2D even after adjustment for HOMA-IR. Our results should inform future clinical trials that aim to reduce the burden of type 2 diabetes through the modification of serum levels of leptin and adiponectin.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; Black or African American; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Incidence; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Prognosis; Prospective Studies; Risk Factors; United States; Young Adult

Interval walking training has demonstrated more pronounced positive effects on physical fitness and metabolism in type 2 diabetes (T2D), compared to continuous walking. One of the pathogenic mechanisms of T2D is associated with derangements in leptin/adiponectin axis, which might predispose affected individuals to vascular inflammation and albuminuria. The aim of this study was to investigate the effects of interval walking training delivered through smart mobile devices upon albuminuria and leptin/adiponectin ratio in patients with T2D.. Patients with T2D aged 35-75 were randomized into control (n = 26) and interval training (IT, n = 14) groups. Patients in IT group had to perform three 60-min interval walking sessions (3 min intervals of slow and fast walking with the intensity of 40% and 70% of the peak energy expenditure) per week delivered by smartphone application for four months. The adherence to training was monitored remotely. Outcome measures were albuminuria, leptin/adiponectin ratio, obesity indicators, and glycaemic control. Leptin and adiponectin concentration was measured in serum samples by Luminex technology.. In the IT group compared to control group, we observed a statistically significant decrease in albuminuria (p = .002) and leptin/adiponectin ratio (p = .01), as well as a decrease in HbA1c close to statistical significance (p = .09). In IT group, changes in leptin/adiponectin ratio correlated significantly with changes in hip circumference (p = .024).. Interval walking training is beneficial for vascular health in T2D via impact on albuminuria and leptin/adiponectin ratio.

Topics: Adiponectin; Adult; Aged; Albuminuria; Diabetes Mellitus, Type 2; Exercise Therapy; Female; Humans; Leptin; Male; Middle Aged; Mobile Applications; Smartphone; Walking

Elevation of the plasma concentration of plasminogen activator inhibitor-1 (PAI-1), a rapid-acting inhibitor of fibrinolysis, is associated with development of vascular thrombotic diseases, including coronary artery disease and stroke. We investigated the effects of empagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on the plasma concentration of PAI-1 and fibrinolytic activity in patients with type 2 diabetes.. In a randomized, active-controlled, open-label trial, 51 patients with type 2 diabetes were randomly allocated at a 2:1 ratio to receive empagliflozin (10 mg/day, n = 31) or standard therapy (n = 18) for 12 weeks. We measured the plasma concentrations of PAI-1 and plasmin-α2-antiplasmin complex (PAP) as indicators of fibrinolytic activity. Serum leptin and high-molecular weight (HMW) adiponectin were also measured.. In 49 patients who completed the trial, baseline plasma PAI-1 showed a positive correlation with body weight, visceral fat area (VFA), γ-glutamyltranspeptidase (GGT), leptin, and the platelet count, while it showed a negative correlation with HDL cholesterol and PAP. Body weight and VFA decreased significantly in the empagliflozin group, but not in the control group. The serum level of GGT showed a significant decrease at 12 weeks in the empagliflozin group, while it was unchanged in the control group. Serum HMW adiponectin increased significantly in the empagliflozin group. Plasma PAI-1 decreased significantly by 25% in the empagliflozin group, but not in the control group. In the empagliflozin group, the change of plasma PAI-1 was positively correlated with the changes of body weight and leptin, but was negatively correlated with the change of PAP.. Empagliflozin reduced the plasma PAI-1 concentration through its synergistic actions of a glucose-lowering effect, VFA loss, and restoring the adipokine balance. (Clinical trial registry: UMIN000025418).

Topics: Adiponectin; Benzhydryl Compounds; Body Weight; Diabetes Mellitus, Type 2; Fibrinolysis; Glucosides; Humans; Leptin; Plasminogen Activator Inhibitor 1

To investigate the association of leptin, resistin, and tumour necrosis factor α (TNF-α) with prognosis in type 2 diabetes (T2D).. Analysis included 284 T2D patients. Apart from routine laboratory parameters, baseline leptin, resistin, and TNF-α concentrations were measured. Patients were followed for a median of 5.4 years. The primary endpoint was all-cause death at follow-up. The secondary endpoint was a composite of death, acute coronary syndrome, and stroke or transient ischemic attack.. At baseline, median age was 68 years, and 48% of patients were female. Data on the primary endpoint were obtained for all patients: 32 (11%) died during follow-up. Data on the secondary endpoint were available for 230 patients, of whom 45 (20%) reached the secondary endpoint. In univariate analyses, older age, heart failure, lower-glomerular filtration rate, and higher resistin, TNF-α and NT-proBNP concentrations were predictors of the study endpoints. Of these variables, only resistin remained an independent predictor of both study endpoints in multivariate models. In receiver-operating characteristic analysis, area under the curve for resistin was 0.7. Resistin concentration of greater than or equal to 11.4 ng/mL had sensitivity of 41% and specificity of 91% for prediction of death at follow-up (Youden's index).. Higher resistin is associated with reduced survival in T2D, irrespectively of TNF-α. Resistin concentration of above 11 ng/mL indicates T2D patients at an increased risk of unfavourable outcomes. Leptin was not a prognostic factor. These results suggest that in T2D, association of resistin with unfavourable outcomes might, at least in part, result from its pro-inflammatory properties.

Topics: Aged; Biomarkers; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Resistin; Survival Rate; Tumor Necrosis Factor-alpha

Bariatric surgery (BS) promotes carotid intima-media thickness (C-IMT) regression as early as 6 months post-surgery. To verify whether C-IMT regression occurs even earlier, we aimed at the effect of Roux-en-Y gastric bypass (RYGBP) and biliopancreatic diversion (BPD) on C-IMT 1-2 months and 12 months post-surgery.. Prospective trial. BS was performed on 109 patients either with (RYGBP = 42; BDP = 40) or without type 2 diabetes (RYGBP = 27). Healthy volunteers served as control group.. baseline, 1-2 months, 12 months post-surgery.. changes (∆) in C-IMT, weight, body mass index, fat mass, waist and neck circumferences, blood pressure, HbA1c, glucose, insulin, insulin sensitivity [HOMA-IR; OGIS, from meal tolerance test], lipids, C-reactive protein, leptin, adiponectin, MCP-1.. All surgery subgroups had similar levels of ∆-C-IMT. C-IMT in the pooled surgery group reduced from [mean (95% confidence interval)] 0.81 (0.77-0.84) mm to 0.66 (0.63-0.69) mm, p < 0.001 [-17.1 (-20.4 to -13.8)%] at 1-2 months, and to 0.63 (0.59-0.66) mm, p < 0.001 [-21.8 (-25.3 to -18.4)%] at 12 months post-surgery. ∆-C-IMT 1-2 months and 12 months post-surgery correlated to baseline C-IMT, and with ∆-leptin at 1-2 months, but not at 12 months post-surgery. In linear regression analysis, ∆-leptin and baseline C-IMT were predictors of ∆-C-IMT 1-2 months post-surgery.. A remarkable C-IMT regression occurred as early as 1-2 months after BS in obese patients either with or without type 2 diabetes, which was associated to the early reduction in leptin, (at least partially) independent of weight loss. Whether this is a causative or correlative association needs further investigation.

Topics: Adult; Bariatric Surgery; Body Mass Index; Carotid Arteries; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Obesity, Morbid; Time Factors; Tunica Intima; Weight Loss; Young Adult

Hypogonadism frequently occurs in male patients with type 2 diabetes (T2DM) and is linked to insulin resistance and inflammation. Testosterone levels rise acutely in obese patients following bariatric surgery, though long-term changes have not been investigated in a randomized controlled trial. This study evaluated obese men with T2DM randomized to either bariatric surgery or medical therapy. Testosterone, gonadotropins, body composition, insulin sensitivity, and inflammatory markers were evaluated in 32 patients at baseline and at 5 years. Surgical patients had 47.4% increase in free testosterone compared to medical therapy patients who had 2.2% decrease (P = 0.013). Increase in free testosterone correlated with reduction in body weight, high-sensitivity C-reactive protein (hsCRP), and leptin levels. Prolonged improvements in testosterone levels after bariatric surgery in T2DM are found to be related to reduction in body weight and adipogenic inflammation.

Topics: Adult; Bariatric Surgery; Blood Glucose; Body Composition; C-Reactive Protein; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Hypogonadism; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Testosterone

Type 2 diabetes and obesity are pro-inflammatory states associated with increased risk of cardiovascular disease. Canagliflozin, an SGLT2 inhibitor, demonstrated superiority in lowering HbA1c versus glimepiride with less hypoglycemia and greater weight reduction via loss of fat mass in a 52-week trial of type 2 diabetes patients. This post hoc, exploratory analysis assessed the effects of canagliflozin versus glimepiride on select adipokines, inflammatory biomarkers, and chemokines.. Changes from baseline to Week 52 in serum leptin, adiponectin, IL-6, TNFα, CRP, PAI-1, VCAM-1, and MCP-1 were measured in a randomly selected subset of type 2 diabetes patients on metformin receiving canagliflozin 300 mg (n = 100) or glimepiride (n = 100) in the overall study. Correlations between change in biomarkers and change in select metabolic and anthropometric variables were assessed.. At Week 52, canagliflozin decreased median serum leptin by 25% (95% CI: -34%, -15%) and increased median serum adiponectin by 17% (95% CI: 11%, 23%) compared with glimepiride. There was a 22% reduction in median serum IL-6 (95% CI: -34%, -10%) and a 7% increase in median serum TNFα (95% CI: 1%, 12%) with canagliflozin versus glimepiride. No between-group differences were observed with the other biomarkers. The decrease in serum leptin with canagliflozin was correlated with change in weight (r ≥ 0.3) only; the increase in adiponectin and decrease in IL-6 with canagliflozin occurred independently of changes in HbA1c, weight, or lipids.. These results indicate that canagliflozin may improve adipose tissue function and induce changes in serum leptin, adiponectin, and IL-6 that favorably impact insulin sensitivity and cardiovascular disease risk.

Topics: Adiponectin; Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Leptin; Male; Metformin; Middle Aged; Molybdoferredoxin; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Treatment Outcome; Tumor Necrosis Factor-alpha

The purpose of this study was to investigate the pleiotropic effects of 12 weeks of supervised exercise training at maximal fat oxidation (FATmax) intensity on body composition, lipid profile, glycemic control, insulin sensitivity and serum adipokine levels in older women with type 2 diabetes. Thirty-one women with type 2 diabetes, aged 60 to 69 years, were randomly allocated into exercise and control groups. Body composition, lipid profile, blood glucose, insulin resistance and serum leptin and adiponectin concentrations were measured before and after the intervention. Exercise group (n=16) walked at individualized FATmax intensities for 1 h/day for 3 days/week over 12 weeks. No dietary intervention was introduced during the experimental period. Maximal fat oxidation rate was 0.37±0.10 g/min, and occurred at 37.3±7.3% of the estimated VO

Topics: Adiponectin; Adipose Tissue; Aged; Blood Glucose; Body Composition; Diabetes Mellitus, Type 2; Diet; Female; Humans; Insulin Resistance; Leptin; Middle Aged; Oxidation-Reduction; Oxygen Consumption; Patient Compliance; Physical Conditioning, Human

The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health.. A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior.. The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04).. The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin.

Topics: Bacteria; Black or African American; Chronic Disease; Cost of Illness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Humans; Leptin; Male; Metformin; Opioid-Related Disorders; Oxytocin

Patients with type 2 diabetes mellitus (T2DM) have been known to be suffering from coenzyme Q10 (CoQ10) deficiency which results in some complications in them. The purpose of this clinical trial study was to evaluate the effects of CoQ10 supplementation on serum values of adiponectin (A), leptin (L), 8-isoprostane, malondialdehyde (MDA), the A/L ratio in women with T2DM. Sixty-eight women with T2DM were enrolled in the current study and were randomly divided into drug (n = 34) and placebo (n = 34) groups who were consuming 100 mg CoQ10 and 100 mg cellulose acetate per day for 12 weeks, respectively. Measurements were performed at the beginning and after the intervention. Serum values of adiponectin (p = .001) and the A/L ratio (p = .001) were increased while values of leptin (p = .041), MDA (p = .023), 8-isoprostane (p = .004) were decreased significantly in drug group after intervention. This study had shown that CoQ10 supplementation in women with T2DM was effective in elevation of adiponectin and the A/L ratio and reduction of leptin, MDA and 8-isoprostane which could result in improving insulin resistance and modulating oxidative stress situation.. 摘要 患有2型糖尿病（T2DM）的患者伴有辅酶Q10（CoQ10）缺乏, 这将导致一系列并发症。该临床试验研究的目的是评估补充CoQ10对2型糖尿病（T2DM）女性患者的脂联素（A）, 瘦素（L）, 8-异前列烷, 丙二醛（MDA）, A/L比值的影响。本研究纳入了68名T2DM女性, 随机分为药物组（n = 34）和安慰剂组（n = 34）, 每天服用100mg辅酶Q10和100mg醋酸纤维素, 共12周。在开始时和干预后对观察指标进行测量。干预后药物组患者的脂联素（p = .001）和A/L比（p = .001）的血清值增加, 瘦素（p = .041）, MDA（p = .023）, 8-异前列烷（p = .004）显著下降。本研究表明补充CoQ10对T2DM女性有效, 可提高脂联素和A/L比值, 减少瘦素, MDA和8-异前列烷, 从而改善胰岛素抵抗, 调节氧化应激状态。.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Dietary Supplements; Dinoprost; Double-Blind Method; Female; Humans; Leptin; Malondialdehyde; Middle Aged; Ubiquinone; Vitamins

Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved.. In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses.. Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens.. Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day.

Topics: Adult; Aged; Body Weight; Caloric Restriction; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin Resistance; Leptin; Male; Meals; Middle Aged; Pancreatic Polypeptide; Peptide YY; Time Factors; Treatment Outcome

Despite numerous studies on cardioprotective effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs), there is limited evidence for n-3 PUFA-mediated effects, especially at its higher dose, on cardiovascular risk in patients with type 2 diabetes (DM2) and established atherosclerosis.. To investigate the effect of daily treatment with a higher dose (2 g) of n-3 PUFAs on platelet function, coagulation parameters, fibrin clot properties, markers of systemic inflammation and metabolic status, in patients with atherosclerotic vascular disease and DM2 who receive optimal medical therapy.. We conducted a prospective, double-blind, placebo-controlled, randomized, double-center study, in which thrombin generation (plasma thrombogenic potential from automated thrombogram), fibrin clot properties (plasma fibrin clot permeability; lysis time), platelet aggregation (light transmission aggregometry with adenosine diphosphate and arachidonic acid used as agonists), HbA1c, insulin level, lipid profiles, leptin and adiponectin levels, as well as markers of systemic inflammation (i.e., hsCRP, IL-6, TNF-α, ICAM-1, VCAM-1, and myeloperoxidase) were determined at baseline and at 3 months after treatment with 2 g/day of n-3 PUFAs (n = 36) or placebo (n = 38). Moreover, we assessed serum fatty acids of the phospholipid fraction by gas chromatography both at baseline and at the end of the study.. Majority of patients were treated with optimal medical therapy and achieved recommended treatment targets. Despite higher serum levels of eicosapentaenoic acid (EPA) (by 204%; p < 0.001) and docosahexaenoic acid (DHA) (by 62%; p < 0.0001) in n-3 PUFA group at the end of treatment no changes in platelet aggregation, thrombin generation, fibrin clot properties or markers of systemic inflammation were observed. No intergroup differences in the insulin, HbA1c and lipid levels were found at the end of the study. There was no change in adiponectin and leptin in interventional group, however leptin increased in control group (p = 0.01), therefore after study period leptin levels were lower in the interventional group (p = 0.01). Additionally, resolvin D1 did not differ between interventional and control group.. In conclusion, our study demonstrated that in patients with long-standing, well-controlled DM2 and atherosclerotic disease the treatment with a high dose of n-3 PUFAs (namely, 1 g/day of EPA and 1 g/day of DHA for 3 months) does not improve coagulation, metabolic, and inflammatory status when measured with the specified tests. The study was registered in ClinicalTrials.gov; identifier: NCT02178501. Registration date: April 12, 2014.

Topics: Adiponectin; Aged; Atherosclerosis; Biomarkers; Blood Coagulation; Blood Platelets; Diabetes Mellitus, Type 2; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Female; Glycated Hemoglobin; Humans; Inflammation; Inflammation Mediators; Insulin; Leptin; Lipids; Male; Middle Aged; Platelet Aggregation; Poland; Prospective Studies; Thrombin; Time Factors; Treatment Outcome

Men with type 2 diabetes mellitus (T2D) often have lowered testosterone levels and an increased risk of cardiovascular disease (CVD). Ectopic fat increases the risk of CVD, whereas subcutaneous gluteofemoral fat protects against CVD and has a beneficial adipokine-secreting profile.. Testosterone replacement therapy (TRT) may reduce the content of ectopic fat and improve the adipokine profile in men with T2D.. A randomized, double-blinded, placebo-controlled study in 39 men aged 50-70 years with T2D and bioavailable testosterone levels <7.3 nmol/L. Patients were randomized to TRT (. TFA (. The effects of TRT on cardiovascular risk markers were ambiguous. We observed potentially harmful changes in cardiovascular risk parameters, markedly reduced subcutaneous fat and unchanged ectopic fat during TRT and a reduction in adiponectin levels. On the other hand, the decrease in leptin and leptin:adiponectin ratio assessments could reflect an amelioration of the cardiovascular risk profile linked to hyperleptinaemia in ageing men with T2D.

Topics: Adiponectin; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Hormone Replacement Therapy; Humans; Leptin; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Testosterone

The aim of the present study is to quantitatively assess the expression of selected regulatory molecules, such as leptin, leptin receptor, and adiponectin in the blood of obese patients with type 2 diabetes both before treatment and after six months of pharmacological therapy with the long-lasting insulin analogue, insulin detemir. A significant decrease in the analysed regulatory molecules, i.e., leptin receptor and adiponectin, was found in blood plasma of the patients with untreated type 2 diabetes. These changes were accompanied by an increase in plasma leptin concentrations. Insulin treatment resulted in the normalization of plasma leptin receptor and adiponectin concentrations. The circulating leptin level did not change following anti-diabetic therapy with insulin detemir. Gender was a significant factor modifying the circulating level of all the analysed regulatory active compounds. Bioinformatic analysis was performed using Matlab with the Signal Processing Toolbox. The conducted discriminant analysis revealed that the leptin receptor, Δw(19), and adiponectin, Δw(21), were the parameters undergoing the most significant quantitative changes during the six-month therapy with insulin detemir. The conducted examinations indicated the contribution of adipocytokines-the biologically-active mediators of systemic metabolism, such as leptin and adiponectin in the pathomechanism of disorders being the basis for obesity which leads to development of insulin resistance, which, in turn, results in the occurrence of type 2 diabetes.

Topics: Adiponectin; Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Insulin Detemir; Leptin; Male; Middle Aged; Obesity; Receptors, Leptin; Sex Factors

Unimolecular dual incretins derived from hybridized glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) sequences have demonstrated synergistic reduction of adiposity in animal models and reductions of hyperglycemia in short-duration human trials. Here, we extend the characterization of NNC0090-2746 (also known as RG7697), a fatty-acylated dual agonist possessing in vitro balanced GIPR and GLP-1R agonism. In this 12-week, randomized, placebo-controlled, double-blind phase 2a trial, patients with type 2 diabetes inadequately controlled with metformin received 1.8 mg of NNC0090-2746 or placebo subcutaneously once daily. Liraglutide 1.8 mg (Victoza), starting with 2-week dose escalation, was administered subcutaneously once daily as an open-label reference arm. Measurements were collected at regular intervals after randomization. NNC0090-2746 significantly improved glycemic control and reduced body weight compared with placebo. Total cholesterol, alone among a range of lipid parameters, and leptin were both significantly reduced compared with placebo. Treatment with NNC0090-2746 was generally safe and well tolerated.

Topics: Adult; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Leptin; Liraglutide; Male; Middle Aged

Emerging evidence suggests that helminths might confer protection against the development of type 2 diabetes. We aimed to assess the role of adipokines in mediating the effect of helminths on insulin resistance. Serum samples were obtained from a randomized-controlled trial of anthelmintic treatment in an area endemic for soil-transmitted helminths (STH), Flores Island, Indonesia. In STH-infected subjects, anthelmintic treatment significantly increased the ratio of leptin to adiponectin (treatment effect factor (95% confidence interval (CI)), P-value for interaction: 1.20 (1.06-1.35), P=0.010), which largely stemmed from a significant reduction in adiponectin (0.91 (0.85-0.98), P=0.020) and a trend for an increase in leptin level (1.10 (1.00-1.21), P=0.119). No significant effect on resistin level was observed. This increase in leptin to adiponectin ratio seemed to contribute to the observed effect of deworming on increased insulin resistance (IR) as adjustment for leptin to adiponectin ratio attenuated the effect on IR from 1.07 (1.01-1.14, P=0.023) to 1.05 (0.99-1.11, P=0.075). Anthelmintic treatment in STH-infected subjects increases leptin to adiponectin ratio which may in small part contribute to the modest increase in IR. Further studies will be needed to assess the effect of the changes in adipokine levels on the host immune response and metabolism.

Topics: Adiponectin; Adult; Albendazole; Anthelmintics; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Helminthiasis; Humans; Indonesia; Insulin Resistance; Leptin; Male; Middle Aged; Placebos

The purpose of this study is to compare the effect of diabetes control induced by Roux-en-Y gastrojejunostomy(RY) vs Billroth-I reconstruction(BI) after distal gastrectomy in patients with early gastric cancer(EGC) and type 2 diabetes(T2DM). Forty EGC patients with T2DM, aged 20-80 years, who were expected to undergo curative distal gastrectomy were randomized 1:1 to RY(n = 20) or BI(n = 20). Diabetes medication status, biochemical and hormonal data including blood glucose, HbA1c, insulin, C-peptide, HOMA-IR, ghrelin, leptin, GLP-1, PYY, and GIP were evaluated for 12 months after surgery. Although pre- and postoperative 12-month fasting and postprandial glucose levels did not show a significant difference, HbA1c, C-peptide, and HOMA-IR levels were significantly improved at 12 months after surgery in both BI and RY groups. Sixty percent of RY patients and 20% of BI patients decreased their medication satisfying FBS<126 mg/dL and HbA1c<6.5% and 5% of BI patients stopped their medication satisfying the criteria of FBS<126 mg/dL and HbA1c<6.0%. The improvement patterns were more sustainable with less fluctuation in RY than in BI. On hormonal analysis, ghrelin and leptin levels were decreased and PYY and GIP levels were increased at 12 months after surgery in both groups without significant difference according to the reconstruction type and diabetic improvement status except ghrelin. In gastric cancer surgery, RY reconstruction showed better and more durable diabetes control compared to BI during the first year after surgery. Gastric cancer surgery led to decreased ghrelin and leptin and increased PYY and GIP, which might have a role in improving insulin resistance and glucose homeostasis.

Topics: Aged; Diabetes Mellitus, Type 2; Duodenum; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Male; Middle Aged; Peptide YY; Prospective Studies; Stomach; Stomach Neoplasms; Treatment Outcome

Curcumin is a naturally occurring polyphenol derived from tumeric that has been reported to have anti-inflammatory properties with effects on adipokine and ghrelin levels. Adiponectin, leptin and ghrelin modulate energy homeostasis but each has modulatory effects on inflammatory cytokines and the immune system. Therefore, this analysis was performed to investigate the effect of curcumin on adiponectin, leptin and ghrelin.. A double blind randomised control trial comparing curcumin 1000mg with 10mg of piperine daily to placebo over a 12 week period. 118 patients with type 2 diabetes were recruited out of which 50 control and 50 active subjects completed the trial. Adiponectin, leptin, ghrelin and tumor necrosis factor-α (TNF-α) were measured at baseline and 12 weeks.. Between group comparison of the magnitude of changes showed serum levels of leptin (p<0.001), TNF-α (p<0.001) and leptin:adiponectin ratio (p<0.001) to be significantly reduced while serum adiponectin levels were elevated in the curcuminoids versus placebo group (p=0.032). Changes in serum ghrelin levels did not differ between the study groups (p=0.135).. Curcumin supplementation increased adiponectin, whilst the the leptin:adiponectin ratio (a measure of atherosclerosis) and leptin levels were decreased independent of weight change and reflected a decrease in the inflammatory TNF-α levels.

Topics: Adipokines; Adiponectin; Adult; Alkaloids; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Curcumin; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha

Dietary calorie restriction and exercise promote weight loss and may have additive effects for improving insulin sensitivity, independent of weight loss. It is not known if these effects are attributable to changes in circulating cytokines. We evaluated the hypothesis that modest, matched weight loss induced by calorie restriction and exercise have additive effects on circulating cytokines and these changes correlate with improvements in insulin sensitivity. Overweight and sedentary women and men (n = 52, 45-65 years) were randomized to undergo 7 % weight loss by using 3-6 months of calorie restriction, exercise, or a combination of both calorie restriction and exercise. Concentrations of cytokines and hormones were measured in fasting and oral glucose tolerance test blood samples. Insulin sensitivity was estimated based on oral glucose tolerance test for glucose and insulin. With all groups combined, fasting leptin (p < 0.0001) and high molecular weight adiponectin (p = 0.04) decreased and pentraxin-3 increased (p < 0.0001), in a manner that correlated with improvements in insulin sensitivity (all p ≤ 0.0002). These changes, combined with decreases in glucose-dependent insulinotropic polypeptide from the oral glucose tolerance test, explained 63 % of the variance (p < 0.0001) in insulin sensitivity improvements. Exercise and calorie restriction had additive effects on leptin, with a similar trend for high molecular weight adiponectin. Monocyte chemoattractant protein-1 and C-reactive protein concentrations did not change. Calorie restriction and exercise had opposite effects on soluble tumor necrosis factor receptor-1. Modest weight loss in overweight adults decreases serum leptin and high molecular weight adiponectin, and increases pentraxin-3 concentrations in a manner that correlates with increased insulin sensitivity. Exercise has additive effects to those induced by calorie restriction for reductions in leptin and possibly adiponectin. These changes may contribute to the additive effects of calorie restriction and exercise for improving insulin sensitivity.

Topics: Adiponectin; Aged; Biomarkers; Body Mass Index; C-Reactive Protein; Caloric Restriction; Combined Modality Therapy; Cytokines; Diabetes Mellitus, Type 2; Exercise; Female; Follow-Up Studies; Gastric Inhibitory Polypeptide; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Missouri; Overweight; Peptide Fragments; Risk; Serum Amyloid P-Component; Weight Loss

Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type 2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide (

Topics: Adiponectin; Adipose Tissue; Aged; Diabetes Mellitus, Type 2; Extracellular Matrix; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Inflammation; Leptin; Liraglutide; Male; Middle Aged; Obesity

One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH.. A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks.. Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all).. Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.

Topics: Adult; Body Composition; C-Reactive Protein; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Hormone Replacement Therapy; Humans; Hypogonadism; Inflammation; Insulin; Insulin Resistance; Interleukin-1beta; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Subcutaneous Fat; Testosterone; Tumor Necrosis Factor-alpha

Obesity induces insulin resistance (IR), the key etiologic defect of type 2 diabetes mellitus (T2DM). Therefore, an incidence of obesity-induced diabetes is expected to decrease if obesity is controlled. Although Metformin is currently one of the main treatment options for T2DM in obese patients, resulting in an average of 5% weight loss, adequate weight control in all patients cannot be achieved with Metformin alone. Thus, additional therapies with a weight loss effect, such as acupuncture, may improve the effectiveness of Metformin.Subjective:We designed this randomized clinical trial (RCT) to compare the effects of Metformin monotherapy with that of Metformin and acupuncture combined therapy on weight loss and insulin sensitivity among overweight/obese T2DM patients, to understand whether acupuncture plus Metformin is a better approach than Metformin only on treating diabetes. To understand whether acupuncture can be an insulin sensitizer and, if so, its therapeutic mechanism.. Our results show that Metformin and acupuncture combined therapy significantly improves body weight, body mass index (BMI), fasting blood sugar (FBS), fasting insulin (FINS), homeostasis model assessment (HOMA) index, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, adiponectin, glucagon-like peptide-1 (GLP-1), resistin, serotonin, free fatty acids (FFAs), triglyceride (TG), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc) and ceramides.. Consequently, Metformin and acupuncture combined therapy is more effective than Metformin only, proving that acupuncture is an insulin sensitizer and is able to improve insulin sensitivity possibly by reducing body weight and inflammation, while improving lipid metabolism and adipokines. As a result, electro-acupuncture (EA) might be useful in controlling the ongoing epidemics in obesity and T2DM.

Topics: Acupuncture Therapy; Adiponectin; Adult; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Metformin; Obesity; Resistin; Serotonin; Triglycerides; Tumor Necrosis Factor-alpha; Weight Loss

To compare the effects of the basal insulin analogues glargine and detemir on endothelial function and adipocytokine levels in people with Type 2 diabetes.. We studied 32 people with Type 2 diabetes whose blood glucose control was unsatisfactory while receiving only oral hypoglycaemic drugs. Participants were randomized to either insulin glargine or detemir for 24 weeks and then crossed over to the other treatment without a washout period. Flow-mediated vasodilatation, adipocytokine levels (plasminogen activator inhibitor-1 and leptin/adiponectin ratio), and fasting ghrelin levels were monitored.. These results suggest that the effect on endothelial function and adipocytokine profiles may differ between glargine and detemir in people with diabetes (Trial registration ID: UMIN000004973).

Topics: Adipokines; Adiponectin; Adult; Aged; Ankle Brachial Index; C-Reactive Protein; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Ghrelin; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Leptin; Male; Middle Aged; Obesity; Plasminogen Activator Inhibitor 1; Vasodilation; Young Adult

The study was conducted to evaluate the impact of laparoscopic sleeve gastrectomy (LSG) on type 2 diabetes mellitus (T2DM) in patients with a body mass index (BMI) of 30.0-35.0 kg/m. Twenty obese patients with T2DM and with a BMI of 30.0-35.0 kg/m. The average duration of follow-up was 17.6 months, and 10 patients had completed 2 years of follow-up. After 2 years, the average BMI decreased from 33.4 ± 1.2 to 26.7 ± 1.8 kg/m. This prospective study confirms the positive impact of LSG on diabetic status of non-morbidly obese patients. The possible mechanisms include the rise in post-prandial GLP-1 level induced by accelerated gastric emptying, leading to an increase in insulin secretion. LSG also leads to decreased ghrelin and leptin levels which may have a role in improving glucose homeostasis after surgery.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Emptying; Ghrelin; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Laparoscopy; Leptin; Male; Middle Aged; Obesity; Treatment Outcome; Young Adult

We have previously shown that a Palaeolithic diet consisting of the typical food groups that our ancestors ate during the Palaeolithic era, improves cardiovascular disease risk factors and glucose control compared to the currently recommended diabetes diet in patients with type 2 diabetes. To elucidate the mechanisms behind these effects, we evaluated fasting plasma concentrations of glucagon, insulin, incretins, ghrelin, C-peptide and adipokines from the same study.. In a randomised, open-label, cross-over study, 13 patients with type 2 diabetes were randomly assigned to eat a Palaeolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, or a diabetes diet designed in accordance with current diabetes dietary guidelines during two consecutive 3-month periods. The patients were recruited from primary health-care units and included three women and 10 men [age (mean ± SD) 64 ± 6 years; BMI 30 ± 7 kg/m(2); diabetes duration 8 ± 5 years; glycated haemoglobin 6.6 ± 0.6 % (57.3 ± 6 mmol/mol)] with unaltered diabetes treatment and stable body weight for 3 months prior to the start of the study. Outcome variables included fasting plasma concentrations of leptin, adiponectin, adipsin, visfatin, resistin, glucagon, insulin, C-peptide, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and ghrelin. Dietary intake was evaluated by use of 4-day weighed food records.. Seven participants started with the Palaeolithic diet and six with the diabetes diet. The Palaeolithic diet resulted in a large effect size (Cohen's d = -1.26) at lowering fasting plasma leptin levels compared to the diabetes diet [mean difference (95 % CI), -2.3 (-5.1 to 0.4) ng/ml, p = 0.023]. No statistically significant differences between the diets for the other variables, analysed in this study, were observed.. Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C-peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet.. ClinicalTrials.gov NCT00435240.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Humans; Insulin; Leptin; Male; Middle Aged

Acute and chronic hyperthermic treatments in diabetic animal models repeatedly improve insulin sensitivity and glycemic control. Therefore, the purpose of this study was to test the hypothesis that an acute 1h bout of hyperthermic treatment improves glucose, insulin, and leptin responses to an oral glucose challenge (OGTT) in obese type 2 diabetics and healthy humans. Nine obese (45±7.1% fat mass) type 2 diabetics (T2DM: 50.1±12y, 7.5±1.8% HbA1c) absent of insulin therapy and nine similar aged (41.1±13.7y) healthy non-obese controls (HC: 33.4±7.8% fat mass, P<0.01; 5.3±0.4% HbA1c, P<0.01) participated. Using a randomized design, subjects underwent either a whole body passive hyperthermia treatment via head-out hot water immersion (1h resting in 39.4±0.4°C water) that increased internal temperature above baseline by ∆1.6±0.4°C or a control resting condition. Twenty-four hours post treatments, a 75g OGTT was administered to evaluate changes in plasma glucose, insulin, C-peptide, and leptin concentrations. Hyperthermia itself did not alter area under the curve for plasma glucose, insulin, or C-peptide during the OGTT in either group. Fasting absolute and normalized (kg·fat mass) plasma leptin was significantly increased (P<0.01) only after the hyperthermic exposure by 17% in T2DM and 24% in HC groups (P<0.001) when compared to the control condition. These data indicate that an acute hyperthermic treatment does not improve glucose tolerance 24h post treatment in moderate metabolic controlled obese T2DM or HC individuals.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hyperthermia, Induced; Insulin; Leptin; Male; Middle Aged; Obesity

GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics.. Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues.. By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA.. We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.

Topics: Attention; Brain; Cross-Over Studies; Cues; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Functional Neuroimaging; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Hypoglycemic Agents; Image Processing, Computer-Assisted; Leptin; Liraglutide; Magnetic Resonance Imaging; Male; Middle Aged; Peptide YY; Reward

Obese subjects have elevated leptin levels, which have been associated with increased risk of cardiovascular events. Because leptin has direct cellular effects on various tissues, we tested the hypothesis that leptin levels are associated with cardiac structure or function in patients with coronary artery disease (CAD).. The study population consisted of 1 601 CAD patients, of whom 42% had type 2 diabetes mellitus. Plasma leptin was measured in fasted state and an echocardiography performed. Leptin levels were not related to LV dimensions or LV ejection fraction (NS for all), but higher leptin levels were associated with elevated E/E' (9.43 vs. 11.94 in the lowest and the highest leptin quartile, respectively; p=0.018 for trend). Correspondingly, a decreasing trend was observed in E/A (1.15 vs. 1.06; p=0.037). These associations were independent of obesity and other relevant confounding variables.. We conclude that elevated plasma leptin levels are associated with impaired left ventricular diastolic function in patients with CAD independently of obesity and other confounding variables. Leptin may be one of the mechanistic links explaining the development of congestive heart failure in obese subjects.

Topics: Aged; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diastole; Echocardiography; Female; Heart Failure; Humans; Leptin; Male; Middle Aged; Obesity; Risk Factors; Ventricular Dysfunction, Left

Weight loss interventions such as Roux-en-Y gastric bypass (RYGB) and very low calorie diets (VLCD) lead to improvement of glucose metabolism in obese individuals with type-2 diabetes. Weight loss can also positively influence the unfavorable inflammatory profile associated with obesity. However, a direct comparison of the effect of VLCD and RYGB on systemic inflammation is lacking.. Systemic inflammation was investigated in age- and BMI-matched morbidly obese T2DM women by determining the number and activation- or memory status of peripheral blood leukocytes by flow cytometry, in addition to measuring circulating levels of cytokines and CRP. Systemic inflammation was assessed one month before and three months after RYGB (n=15) or VLCD (n=12). An age matched group of lean women (n=12) was studied as control group.. Three months after the intervention, CRP and leptin levels were reduced whereas adiponectin levels were increased both by RYGB and VLCD. TNF-α levels were increased by RYGB, but reduced by VLCD. IL-2 and IL-6 levels were reduced and IL-4 levels were increased by VLCD but not affected by RYGB. The number of activated peripheral cytotoxic T (CD8+CD25+) and B (CD19+CD38+) cells was significantly higher after RYGB than after VLCD.. In conclusion, RYGB and VLCD have differential effects on the activation status of peripheral leukocytes and levels of cytokines in obese women with T2DM, despite comparable weight loss three months after the intervention. VLCD seems to have more favorable effects on the inflammatory profile as compared to RYGB.

Topics: Adiponectin; Adult; Blood Glucose; C-Reactive Protein; Caloric Restriction; Cytokines; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Inflammation; Insulin; Leptin; Lymphocyte Count; Middle Aged; Obesity, Morbid; Treatment Outcome; Weight Loss

Metformin, α-glucosidase inhibitors (α-GIs), and dipeptidyl peptidase 4 inhibitors (DPP-4Is) reduce hyperglycemia without excessive insulin secretion, and enhance postprandial plasma concentration of glucagon-like peptide-1 (GLP-1) in type-2 diabetes mellitus (T2DM) patients. We assessed add-on therapeutic effects of DPP-4I anagliptin in Japanese T2DM patients treated with metformin, an α-GI miglitol, or both drugs on postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of the appetite-suppressing hormone leptin. Forty-two Japanese T2DM patients with inadequately controlled disease (HbA1c: 6.5%-8.0%) treated with metformin (n=14), miglitol (n=14) or a combination of the two drugs (n=14) received additional treatment with anagliptin (100mg, p.o., b.i.d.) for 52 weeks. We assessed glycemic control, postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of leptin in those patients. Add-on therapy with anagliptin for 52 weeks improved glycemic control and increased the area under the curve of biologically active GLP-1 concentration without altering obesity indicators. Total GIP concentration at 52 weeks was reduced by add-on therapy in groups treated with miglitol compared with those treated with metformin. Add-on therapy reduced leptin concentrations. Add-on therapy with anagliptin in Japanese T2DM patients treated with metformin and miglitol for 52 weeks improved glycemic control and enhanced postprandial concentrations of active GLP-1/total GIP, and reduce the leptin concentration.

Topics: 1-Deoxynojirimycin; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Leptin; Male; Metformin; Middle Aged; Pyrimidines; Treatment Outcome

This study assessed the effect of a 12-week sports-based exercise intervention on glucose regulation, anthropometry and inflammatory markers associated with the prevalence of type 2 diabetes mellitus (T2DM) in Indigenous Australian men.. Twenty-six inactive Indigenous Australian men (48.6±6.6 years) were randomized into exercise (n=16) or control (n=10)conditions.. Training included ∼2-3 days/week for 12 weeks of sports and gym exercises in a group environment, whilst control participants maintained normal activity and dietary patterns. Pre- and post-intervention testing included: anthropometry, peak aerobic capacity, fasting blood chemistry of inflammatory cytokines, adiponectin, leptin, cholesterol, glucose, insulin and C-peptide. An oral glucose tolerance test measured glucose, insulin and C-peptide 30, 60, 90 and 120min post 75g glucose ingestion.. The exercise condition decreased insulin area under the curve (25±22%), increased estimated insulin sensitivity (35±62%) and decreased insulin resistance (9±35%; p<0.05), compared with control (p>0.05). The exercise condition decreased in body mass index, waist circumference and waist to hip ratio (p<0.05), compared to control (p>0.05). Leptin decreased in the exercise group, with no changes for adiponectin (p>0.05) or inflammatory markers (p>0.05) in either condition. Aerobic fitness variables showed significant increases in peak oxygen consumption for the exercise condition compared to no change in control (p>0.05).. Findings indicate positive clinical outcomes in metabolic, anthropometric and aerobic fitness variables. This study provides evidence for sport and group-based activities leading to improved clinical risk factors associated with T2DM development in clinically obese Indigenous Australian men.

Topics: Adiponectin; Adult; Australia; Body Mass Index; Cytokines; Diabetes Mellitus, Type 2; Exercise; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Native Hawaiian or Other Pacific Islander; Oxygen Consumption; Physical Conditioning, Human; Risk Factors; Sports; Waist Circumference; Waist-Hip Ratio; Young Adult

Obesity is a major risk factor for arterial hypertension, coronary artery disease, dyslipidemias, and type 2 diabetes. Spa therapy has long been used for treating obesity and its comorbidities. Enlargement of adipose tissue has been linked to a dysregulation of adipokine secretion and adipose tissue inflammation. Adipokines are currently investigated as potential drug targets in these conditions. Our primary aim was to assess the clinical efficacy of a 3-week program of diet combined with spa therapy in obese patients with and without type 2 diabetes. The secondary aim was to examine whether this combined program influences the response of serum levels of leptin, adiponectin, visfatin, and high-sensitivity C-reactive protein. Fifty obese males were enrolled and 21 of these featured a type 2 diabetes. During the 3-week period of the study, the patients were on a 1,000-kcal diet and were involved in mineral bath and total body's mud-pack applications (15 procedures). Patients were assessed at baseline and at the end of the therapy for clinical and biochemical parameters (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glycemia, and adipokines). We showed that a 3-week program of spa therapy in obese patients induced significant decrease of body weight, body mass index, triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, glycemia, and serum levels of leptin and high-sensitivity C-reactive protein. So, a cycle of mud-bath therapy associated with a controlled diet may be a promising treatment for obesity and type 2 diabetes decreasing body weight and many risk factors for atherosclerosis and metabolic syndrome.

Topics: Adiponectin; Adult; Aged; Balneology; C-Reactive Protein; Cytokines; Diabetes Mellitus, Type 2; Diet; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Pilot Projects; Treatment Outcome

The aim of the present study was to examine the effects of consumption of desserts with low glycemic index (GI) and low glycemic load (GL), as part of a balanced hypo-caloric diet, on anthropometric and biochemical parameters in patients with type 2 diabetes mellitus (T2DM).. A total of 61 subjects with T2DM were randomly assigned to the intervention (n = 30) or to the control group (n = 31). Both groups followed the same hypo-caloric (-500 kcal) diet for 12 weeks. Consumption of four portions of low-GI/low-GL desserts/week was included in the diet in the intervention group while one portion of a favorite usual sweet/week was allowed to be consumed in the control group.. Thirty subjects in the control and 28 subjects in the intervention group completed the trial. Body weight, body mass index, and waist circumference were reduced significantly in both groups. Arterial blood pressure, fasting blood glucose, glycosylated hemoglobin, insulin, and γ-GT were reduced significantly only in the intervention group; however, there were no significant differences between the two groups at endpoint. C-reactive protein was reduced in the intervention, and HDL cholesterol was also reduced in the control group; the reductions were significantly different at the end of the trial. No significant changes were observed in the other plasma lipids, uric acid, leptin, adiponectin, and interleukin-6 in either study group.. Consumption of desserts with low GI/GL in a balanced hypo-caloric diet has a positive impact on anthropometric and metabolic parameters of patients with T2DM.

Topics: Adiponectin; Adult; Aged; Biomarkers; Body Mass Index; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Energy Intake; Female; Glycated Hemoglobin; Glycemic Index; Glycemic Load; Humans; Interleukin-6; Leptin; Male; Middle Aged; Prospective Studies; Triglycerides; Waist Circumference

The aim of this study is to investigate the protein and gene expression of leptin and visfatin in gingival tissue from patients with chronic periodontitis (CP), patients with CP and type 2 diabetes mellitus (T2DM), and healthy individuals.. The study includes 50 individuals: 10 healthy individuals, 20 patients with CP, and 20 patients with CP and T2DM. Plaque index, gingival index, probing depth, and clinical attachment loss were measured, and gingival biopsies were obtained. Leptin and visfatin protein expression in gingival tissues was determined using enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was measured via real-time polymerase chain reaction.. The highest leptin mRNA and protein expression was observed in the control group and was significantly (P ≤0.05) different from the CP and CP+T2DM groups. Gingival tissues from patients with CP and T2DM had a significant increase in visfatin and a decrease in leptin gene and protein expression (P <0.05) compared with both controls and patients with CP.. Expression of leptin and visfatin in the gingival tissues suggests a possible role for these adipokines in the pathogenesis of CP and T2DM.

Topics: Adult; Biopsy; Blood Glucose; Chronic Periodontitis; Cytokines; Dental Plaque Index; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Gingiva; Glycated Hemoglobin; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Real-Time Polymerase Chain Reaction

Recent evidence suggests that omega-3 polyunsaturated fatty acids [n-3 PUFAs: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], improve insulin sensitivity in humans. In a double-blind, placebo-controlled, randomized, crossover study, we investigated the effects of EPA/DHA on paraoxonase-1 activity as well as fasting and postprandial levels of circulating adiponectin and leptin in 34 subjects with type 2 diabetes mellitus who received daily for 6 weeks either 2 g purified EPA/DHA or olive oil (placebo), separated by a 6 weeks washout. At the end of each treatment, measurements were performed in fasting state and 2, 4, and 6 h following a standardized high-fat meal (600 kcal). No significant differences in fasting and postprandial circulating adiponectin, leptin, and paraoxonase-1 activity were seen between n-3 PUFAs and placebo. Our data do not support an insulin sensitizing effect of n-3 PUFAs by means of influencing circulating adipocytokines in this population. Clinical Trial Register Number: NCT00328536.

Topics: Adiponectin; Adult; Aged; Diabetes Mellitus, Type 2; Fatty Acids, Omega-3; Humans; Leptin; Middle Aged

The aim of this study was to assess the effects of single oral bolus of 300,000 IU Vitamin D3 on serum levels and on bone and metabolic parameters in diabetic patients. This study is a Phase IV, randomized, double-blind, placebo-controlled, monocenter clinical trial. Thirty patients, 60 years or older, with type 2 diabetes mellitus, and diabetic foot complications, were enrolled and monitored for 24 weeks: 14 were treated with Vitamin D3 and 16 with placebo. Parameters including glucose, adiponectin, leptin, osteoprotegerin (OPG), 25-hydroxyvitamin D [25(OH)D], beta-CrossLaps, osteocalcin, bone-specific isoenzyme of alkaline phosphatase, tumor necrosis factor-α and parathyroid hormone were measured at screening and baseline and 12 and 24 weeks after treatment. Analysis of covariance was used to compare treatment groups. Analysis of the data detected a significant increase in 25(OH)D serum levels both at 12 and 24 weeks with respect to baseline values only in the treated patients. Significant variations with respect to baseline values were noted in OPG (P = 0.0085) and in leptin (P = 0.0442) levels: these were lower in the placebo group at week 24 but higher in the treated group. Vitamin D3 supplementation significantly increased serum leptin and OPG levels. Further, large-scale clinical trials are warranted to confirm these results.

Topics: Aged; Aged, 80 and over; Blood Glucose; Cholecalciferol; Diabetes Mellitus, Type 2; Female; Humans; Italy; Leptin; Male; Middle Aged; Osteoprotegerin

Although benefits have been attributed to the Mediterranean diet, its effect on glycaemic control has not been totally elucidated. The aim of this work was to compare the effect of two Mediterranean diets versus a low-fat diet on several parameters and indices related to glycaemic control in type 2 diabetic subjects.. A multicentric parallel trial was conducted on 191 participants (77 men and 114 women) of the PREDIMED study in order to compare three dietary interventions: two Mediterranean diets supplemented with virgin olive oil (n=67; body mass index (BMI)=29.4±2.9) or mixed nuts (n=74; BMI=30.1±3.1) and a low-fat diet (n=50; BMI=29.8±2.8). There were no drop-outs. Changes in body weight and waist circumference were determined. Insulin resistance was measured by HOMA-IR index, adiponectin/leptin and adiponectin/HOMA-R ratios after 1 year of follow-up.. Increased values of adiponectin/leptin ratio (P=0.043, P=0.001 and P<0.001 for low-fat, olive oil and nut diets, respectively) and adiponectin/HOMA-IR ratio (P=0.061, P=0.027 and P=0.069 for low-fat, olive oil and nut diets, respectively) and decreased values of waist circumference (P=0.003, P=0.001 and P=0.001 for low-fat, olive oil and nut diets, respectively) were observed in the three groups. In both Mediterranean diet groups, but not in the low-fat diet group, this was associated with a significant reduction in body weight (P=0.347, P=0.003 and P=0.021 for low-fat, olive oil and nut diets, respectively).. Mediterranean diets supplemented with virgin olive oil or nuts reduced total body weight and improved glucose metabolism to the same extent as the usually recommended low-fat diet.

Topics: Adipokines; Adiponectin; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Diet, Mediterranean; Dietary Fats; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Nuts; Obesity; Olive Oil; Plant Oils; Waist Circumference; Weight Loss

Longevity is commonly associated with good health and with delayed onset of age-related diseases with usually benign course. Leptin (LEP) significantly affects metabolism and numerous functions of the organism. To find out if extreme longevity and its phenotype are associated with genetic variants of leptin and leptin receptor (LEPR) genes, we analysed the frequencies of the -2548 G/A and +19 G/A LEP, as well as the K109R, Q223R, and K656N LEPR polymorphisms in centenarians and in control groups.. The frequencies of the LEP and LEPR polymorphisms were tested by restriction fragment length polymorphism in 128 centenarians, 414 young controls (Y), 226 myocardial infarction (MI) patients, and 190 type 2 diabetes mellitus (DM2) patients.. The GG genotype of the -2548 G/A LEP polymorphism was significantly more common in centenarians than in the Y, MI and DM2 groups (p = 0.048, p = 0.003, p = 0.049, respectively). In addition, the AA genotype of the K109R LEPR polymorphism was significantly less frequent in centenarians than in the Y, MI, and DM2 groups (p = 0.026, p = 0.013, and p = 0.001, respectively).. We suggest that the leptin pathway plays a role in the regulation of longevity, possibly by modulating the risk of development of MI and of DM2.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Longevity; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Receptors, Leptin; Young Adult

Diabetic Nephropathy (DN) is one of the main complications of diabetes mellitus, mostly ending to end-stage renal disease. Leptin and C-reactive protein (CRP), as inflammatory markers implicated in the progression of DN, increase in diabetes mellitus, while transferrin and albumin, as members of anti-oxidant defense mechanism, are found to decline.. In a controlled clinical trial, 65 patients with type 2 DN were assigned to receive lovastatin or placebo, for 3 months, to assess statins' impact on serum levels of leptin, CRP, transferrin, albumin, and lipid profile.. Serum levels of CRP (3.52 +/- 4.16 mg/dL to 2.84 +/- 3.06 mg/dL, P = .02), leptin (10.78 +/- 8.30 mg/dL to 7.80 +/- 5.41 mg/dL, P = .006), low-density lipoprotein cholesterol (116.16 +/- 46.54 mg/dL to 85.46 +/- 29.22 mg/dL, P = .001), and total cholesterol (199.00 +/- 43.33 mg/dL to 164.67 +/- 35.19 mg/dL, P = .001) were lowered after lovastatin therapy. Mean serum level of high-density lipoprotein cholesterol increased (40.00 mg/dL to 42.80 mg/dL, P = .005) after the treatment. Lovastatin had no significant effect on albumin and transferrin. Placebo did not change any of the parameters after 3 months.. The effect of statins on the inflammatory markers involved in the development of DN is a new approach to evidence supporting the pleiotropic effect of this drug group.

Topics: Adult; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Leptin; Lovastatin; Male; Middle Aged

Identification of novel biomarkers of diabetes risk help to understand mechanisms of pathogenesis and improve risk prediction. Our objectives were to examine the relationships between adipokines, biomarkers of inflammation and endothelial function and development of type 2 diabetes; and to assess the relevance of including these biomarkers in type 2 diabetes prediction risk models.. 1345 subjects from the SU.VI.MAX study, who were free of diabetes at baseline and who completed 13 years of follow-up were included in the present analyses. Odds ratios (OR) with 95% confidence intervals (95% CI) of incident type 2 diabetes associated with a 1-SD increase in adiponectin, leptin, C-reactive protein (CRP), soluble intracellular adhesion modecule-1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), E-selectin and monocyte chemoattractant protein-1 (MCP-1) were estimated. Predicitive performances of models including biomarkers were assessed with area under the receiver operating curves (AUC) and integrated discrimination improvement (IDI) statistics.. 82 subjects developed type 2 diabetes during follow-up. The risk of developing type 2 diabetes increased with increasing concentrations of leptin (2.04 (1.28;3.26)), sICAM-1 (1.39 (1.08;1.78)) and sVCAM-1 (1.29 (1.01;1.64)). Type 2 diabetes associations with leptin remained significant after adjusting for a combination of biomarkers. Models adjusted for novel biomarkers had improved performance compared to models adjusted for classical risk factors as assessed by IDI, but not by AUC.. Adipokines, biomarkers of inflammation and endothelial function were significantly associated to onset of type 2 diabetes. However their inclusion in predictive scores is not supported by the present study.

Topics: Adipokines; Adiponectin; Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Chemokine CCL2; Diabetes Mellitus, Type 2; Double-Blind Method; E-Selectin; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Inflammation; Leptin; Male; Middle Aged; Odds Ratio; Risk Factors

Obesity, insulin resistance, and aging are closely associated and adipokines seem to have a crucial role in their pathophysiology. We aim to study the relationship between aging and chemerin, adiponectin, and leptin levels in type 2 diabetes mellitus (T2DM). Age correlated positively with chemerin and leptin and inversely with adiponectin. Body mass index (BMI) correlated positively with leptin (in males) and chemerin and inversely with adiponectin. The patients with ≥ 65 years (n = 34) showed significantly higher leptin and chemerin and lower adiponectin levels than middle-aged (38-64 years) patients (n = 39) and controls (n = 20). After statistical adjustment for length of disease, there was a loss of significance, between T2DM groups, for adiponectin and, in female, for leptin. In the older group, BMI correlated with adiponectin and with leptin, but not with chemerin. Adiponectin and leptin levels in elderly T2DM patients seem to be closely linked to obesity and to length of the disease. In elderly T2DM patients, chemerin concentrations are increased and seem to be independent of length of disease and BMI, suggesting that adipocyte dysfunction is enhanced with aging. The understanding of the glucose homeostasis impairment in the elderly is mandatory in order to achieve ways to improve their quality of life and longevity.

Topics: Adiponectin; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Body Mass Index; Chemokines; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Time Factors

To explore the clinical efficacy and mechanism of acupuncture and tapping therapy in the treatment of type 2 diabetes of yin deficiency pattern combined with stasis in the patients.. One hundred and twelve patients were treated with acupuncture, followed by tapping method. The reinforcing method with lifting, thrusting and rotating needle technique was used at Taixi (KI 3), Shenmen (HT 7), Taibai (SP 3), Taiyuan (LU 9), Sanyinjiao (SP 6) and Zusanli (ST 36); and the even-needling technique was used at Taichong (LR 3), Hegu (LI 4), Xuehai (SP 10) and Fenglong (ST 40). The needles were remained for 30 min. After needle removal, the tapping method with plum-blossom needle was applied to Geshu (BL 17), Yishu (EX-B 3), Ganshu (BL 18), Shenshu (BL 23) and Pishu (BL 20), once every two days. The treatment of 3 months was required. The changes were observed before and after treatment in the relevant indices of fat-islet axis such as fasting plasma glucose (FPG), fasting leptin (FLP), fasting insulin (FINS), insulin sensitivity index (ISI), insulin resistance (Homa IR), insulin secretion index (Homa-beta) and the indices of obesity and blood lipids in the patients.. After treatment, the total effective rate was 84.8% (95/112), in which the efficacy on the stasis predominated syndrome was better than that of yin deficiency predominated syndrome [92.9% (52/56) vs 76.8% (43/56), P < 0.05]. Before treatment, FPG, FLP, FINS, Homa-IR, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), body mass, body mass index (BMI), fat percentage (F%) and obesity degree in the patients were higher obviously than those in the normal group (all P < 0.01); high-density lipoprotein cholesterol (HDL-C) and ISI were lower than those in the normal group (both P < 0.01). After treatment, FPG, FLP, FINS, Homa-IR, TC, TG, LDL-C, body mass, BMI, F% and obesity degree were all reduced obviously as compared with those before treatment (all P < 0.01). ISI and HDL-C were increased apparently (both P < 0.01). The efficacy on mild obesity was superior to that on moderate and severe obesity, and the efficacy in the young patients was better than that in the elderly, the efficacy in the males was better than that in the females, but the differences were not significant (all P > 0.05). The efficacy in the cases with 10 years duration of sickness was superior to those with over 10 years duration of sickness (P < 0. 01).. Acupuncture and tapping therapy achieves the significant efficacy on type 2 diabetes of yin deficiency pattern combined with stasis and its effect mechanism is related to the positive regulation of glucose, lipid metabolism and fat-islet axis.

Topics: Acupuncture Points; Acupuncture Therapy; Adult; Aged; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Leptin; Male; Middle Aged; Treatment Outcome; Triglycerides; Yin Deficiency

Multiple epidemiological studies have shown that low testosterone levels are associated with and predict the future development of type 2 diabetes mellitus and the metabolic syndrome. The aim of our study was to show the influence of testosterone replacement therapy on obesity, HbA1c level, hypertension and dyslipidemia in patients with diabetes mellitus and androgen deficiency.. One hundred and twenty-five male patients with diabetes mellitus were screened; 85 subjects aged 41 to 65 years, with BMI from 27.0 to 48.0 kg/m(2), were randomized in a placebo-controlled study. They also underwent a routine physical examination and selected by free testosterone examination. We divided patients into two groups: 1) treatment group, where we used diet, physical activity, patient's antidiabetic therapy and testosterone replacement therapy; 2) placebo group, where we used diet, physical activity, patient's antidiabetic therapy and placebo.. After 6 months of treatment we repeated the diagnostic assessments: lipid profile was improved in both groups but in first group it was clinically significant. Free testosterone level increased in all groups, but in group I was clinically significant. HbA1c decreased in both groups, but in group I we obtained the best result. Leptin level after treatment was approximately the same in both groups. Also, blood pressure was reduced in both groups but results were similar.. Our study demonstrated that it is possible to break this metabolic vicious circle by raising testosterone levels in diabetic men with androgen deficiency. Re-instituting physiological levels of testosterone, as the study has shown, has an important role in reducing the prevalence of diabetic complications.

Topics: Adult; Aged; Blood Pressure; Diabetes Mellitus, Type 2; Hormone Replacement Therapy; Humans; Hypertension; Leptin; Male; Middle Aged; Obesity; Testosterone

The visceral fat is linked to insulin resistance, the metabolic syndrome, type 2 diabetes and an increased cardiovascular risk, but it is not clear whether it has a causative role.. Surgical resection of this fat depot is a research model to address this issue. Twenty premenopausal women with metabolic syndrome and grade III obesity were randomized to undergo Roux-en-Y gastric bypass (RYGBP) either alone or combined with omentectomy. Insulin sensitivity (IS; euglycemic-hyperinsulinemic clamp), acute insulin response to glucose (AIR; intravenous glucose tolerance test), disposition index (DI = AIR × IS measured by clamp), lipid profile, adipokine profile (leptin, adiponectin, resistin, visfatin, interleukin-6, TNF-α, MCP-1), ultra-sensitive C-reactive protein (CRP), body composition, and abdominal fat echography were assessed prior to surgery and 1, 6, and 12 months post-surgery.. Omentectomy was associated with greater weight loss at all time points. IS improved similarly in both groups. Omentectomy was associated to lower CRP after 12 months, but it did not influence adipokines and other metabolic parameters. Among non-diabetic subjects, omentectomy was associated with a preservation of baseline AIR after 12 months (as opposed to deterioration in the control group) and a greater DI after 6 and 12 months.. Although omentectomy did not enhance the effect of RYGBP on insulin sensitivity and adipokines, it was associated with a preservation of insulin secretion, a greater weight loss, and lower CRP.

Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Body Composition; C-Reactive Protein; Cardiovascular Diseases; Chemokine CCL2; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucose Tolerance Test; Humans; Inflammation; Insulin Resistance; Insulin-Secreting Cells; Interleukin-6; Intra-Abdominal Fat; Leptin; Metabolic Syndrome; Nicotinamide Phosphoribosyltransferase; Obesity; Premenopause; Prospective Studies; Resistin; Risk Factors; Tumor Necrosis Factor-alpha; Weight Loss; Young Adult

Resistin and the proinflammatory cytokines, such as TNF- α , IL-6, and IL-1 β , produced by adipocytes, and macrophages, are considered to be important modulators of chronic inflammation contributing to the development of obesity and atherosclerosis. Human monocyte-enriched mononuclear cells, from ten healthy individuals, were exposed to high concentrations of insulin, leptin, and glucose (alone or in combination) for 24 hours in vitro. Resistin, TNF- α , IL-6, and IL-1 β production was examined and compared to that in untreated cells. High insulin and leptin concentrations significantly upregulated resistin and the cytokines. The subsequent addition of high glucose significantly upregulated resistin and TNF- α mRNA and protein secretion, while it did not have any effect on IL-6 or IL-1 β production. By comparison, exposure to dexamethasone reduced TNF- α , IL-6, and IL-1 β production, while at this time point it increased resistin protein secretion. These data suggest that the expression of resistin, TNF- α , IL-6, and IL-1 β from human mononuclear cells, might be enhanced by the hyperinsulinemia and hyperleptinemia and possibly by the hyperglycemia in metabolic diseases as obesity, type 2 diabetes, and atherosclerosis. Therefore, the above increased production may contribute to detrimental effects of their increased adipocyte-derived circulating levels on systemic inflammation, insulin sensitivity, and endothelial function of these patients.

Topics: Adult; Anti-Inflammatory Agents; Atherosclerosis; Cells, Cultured; Cytokines; Dexamethasone; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Glucose; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Inflammation Mediators; Insulin; Leptin; Leukocytes, Mononuclear; Male; Obesity; Resistin; RNA, Messenger; Sweetening Agents

The correlation between total testosterone levels, exercise capacity, and metabolic and echocardiographic parameters was studied in 1097 male subjects with coronary artery disease (CAD) and different stages of glucose tolerance.. Testosterone level was the lowest among diabetics as compared to prediabetics or controls (P < 0.001). Total and abdominal adiposity were the highest in the subjects with the lowest testosterone. Independent of adiposity, fasting glucose, insulin, and leptin were higher (P < 0.03 to < 0.001) among diabetic and control groups in the lowest, and HbA1c values (P < 0.001) higher among diabetics in the lowest, than in the highest testosterone tertile. Controls and prediabetic subjects with the lowest testosterone levels had the lowest HDL-cholesterol levels, and controls also the highest triglycerides. An association between low testosterone level and low maximal exercise capacity was observed in diabetics (P < 0.001) and controls (P < 0.03). Independent of adiposity and metabolic parameters, low testosterone levels were associated with the highest septal wall thickness (P < 0.03) among diabetics.. A negative correlation between low testosterone and dysmetabolic features was observed. Independent of metabolic status, low plasma testosterone seems to be an indicator of impaired maximal exercise capacity and cardiac hypertrophy among CAD patients with type II diabetes.

Topics: Analysis of Variance; Blood Glucose; Body Mass Index; Cholesterol, HDL; Coronary Artery Disease; Diabetes Mellitus, Type 2; Echocardiography, Doppler; Exercise Tolerance; Glycated Hemoglobin; Heart Septum; Humans; Hypertrophy; Insulin; Leptin; Male; Prediabetic State; Testosterone; Triglycerides; Waist Circumference

Vitamin D supplementation has the potential to alleviate the cardiovascular damage in diabetic patients. The present study was designed to evaluate long term impact of high doses of vitamin D on arterial properties, glucose homeostasis, adiponectin and leptin in patients with type 2 diabetes mellitus.. In randomized, placebo-controlled study 47 diabetic patients were assigned into two groups: Group 1 received oral daily supplementation with vitamin D at a dose of 1000 U/day for 12 months. Group 2 received matching placebo capsules. Blood sampling for metabolic parameters, including fasting glucose, lipid profile, HbA1C, insulin, hs-CRP, 25 OH Vit D, adiponectin and leptin was performed at baseline and at the end of the study. Insulin resistance was assessed by homeostasis model assessment (HOMA-IR). Central aortic augmentation index (AI) was evaluated using SphygmoCor.. The two groups were similar at baseline in terms of hemodynamic parameters. After 12 months, AI decreased significantly during the treatment period in patients received vitamin D (p < 0.0001) and did not change in placebo group. Glucose homeostasis parameters, leptin as well as leptin adiponectin ratio did not change in both groups. 25 OH Vit D level significantly increased (p = 0.022) and circulating adiponectin marginally increased (p = 0.065) during 12 month treatment period in active treatment and did not change in placebo group.. High doses of vitamin D supplementation in diabetic patients was associated with significant decrease in AI during one year treatment. This beneficial vascular effect was not associated with improvement in glucose homeostasis parameters.

Topics: Adiponectin; Administration, Oral; Aged; Arteries; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Female; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Vitamin D

C reactive protein (CRP) is an inflammatory marker believed to be of value in the early prediction of type 2 diabetes (T2DM). Recent studies have shown a positive correlation between leptin and CRP levels. Here, we aimed to study the correlation between leptin and CRP in patients with T2DM. We also studied the effect of metformin therapy on the CRP-leptin correlation in patients with newly diagnosed diabetes. We performed a follow-up study on three groups of participants defined as 1: patients with newly diagnosed T2DM, 2: patients with long-standing T2DM, and 3: healthy controls. Patients with newly diagnosed diabetes were followed for three months after the initiation of metformin therapy. The homeostatic model assessment of insulin resistance (HOMA-IR) decreased, while leptin levels (15.9 ± 1.6 versus 21.4 ± 2.5, p<0.01) increased after metformin therapy. Leptin levels correlated significantly with CRP in healthy controls (r = 0.48; p<0.01); patients with newly diagnosed diabetes before (r = 0.35; p<0.05), and after (r = 0.55, p<0.001) metformin therapy, while there was no significant correlation between leptin and CRP in patients with long-standing diabetes (r = 0.15; p = 0.55). After multiple adjustments for potential confounders, leptin was the best predictor of CRP in controls (β coefficient = 0.433, p<0.01), and patients with newly diagnosed T2DM who received metformin (β coefficient = 0.584, p<0.01). Statin treatment did not have any significant effect on the results. This is the first report demonstrating the restorative role of metformin on the leptin-CRP correlation in patients with newly diagnosed diabetes.

Topics: C-Reactive Protein; Case-Control Studies; Demography; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Leptin; Linear Models; Metformin; Middle Aged

Obesity and weight loss influence thyroid hormone physiology. The effects of weight loss by calorie restriction vs Roux-en-Y gastric bypass (RYGB) in obese subjects have not been studied in parallel. We hypothesized that differences in transient systemic inflammation and catabolic state between the intervention types could lead to differential effects on thyroid hormone physiology.. We recruited 12 lean and 27 obese females with normal fasting glucose (normal glucose tolerant (NGT)) and 27 obese females with type 2 diabetes mellitus (T2DM) for this study. Weight loss was achieved by restrictive treatment (gastric banding or high-protein-low-calorie diet) or by RYGB. Fasting serum leptin, TSH, triiodothyronine (T₃), reverse T₃ (rT₃), and free thyroxine (fT₄) concentrations were measured at baseline and 3 weeks and 3 months after the start of the interventions.. Obesity was associated with higher TSH, T₃, and rT₃ levels and normal fT₄ levels in all the subjects when compared with the controls. After 3 weeks, calorie restriction and RYGB induced a decline in TSH levels and a rise in rT₃ and fT₄ levels. The increase in rT₃ levels correlated with serum interleukin 8 (IL8) and IL6 levels. After 3 months, fT₄ and rT₃ levels returned to baseline levels, whereas TSH and T₃ levels were persistently decreased when compared with baseline levels. No differences in the effects on thyroid hormone parameters between the interventions or between NGT and T2DM subjects were observed at any time point.. In summary, weight loss directly influences thyroid hormone regulation, independently of the weight loss strategy used. The effects may be explained by a combination of decreased leptin levels and transient changes in peripheral thyroid hormone metabolism.

Topics: Adult; Body Mass Index; Caloric Restriction; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Gastric Bypass; Humans; Leptin; Middle Aged; Obesity; Obesity, Morbid; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Weight Loss

Hypovitaminosis D has been associated with an increased prevalence of Type 2 diabetes mellitus (DMT2) and metabolic syndrome manifestations. The purpose of this study was to examine the association between 25-hydroxy-vitamin D (25-OH-VitD) levels and indices of insulin resistance (IR), including adipocytokines, in a Saudi population with or without DMT2.. A total of 266 subjects (153 DMT2 and 113 healthy controls) aged 26-80 yr were randomly selected from the existing Biomarkers Screening in Riyadh Program (RIYADH Cohort). Subjects were assessed clinically, anthropometry was performed, morning blood chemistries, including fasting glucose (FG), triglycerides, total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol were obtained. Homeostasis model assessment of IR (HOMA-IR) was calculated, and serum 25-OH-VitD, leptin, adiponectin, resistin, insulin, high sensitivity CRP (hsCRP), and tumor necrosis factor α concentrations were measured using specific assays.. In DMT2 subjects, negative correlations between 25-OH-vitD and body mass index (BMI), FG, insulin, HOMA-IR, cholesterol, LDL-C, and hsCRP were observed, while a positive correlation between 25-OH-VitD and adiponectin was detected. The later remained significant after controlling for BMI. Interestingly, only weak and nonsignificant associations between 25-OH-VitD and metabolic parameters were observed in the control group, whereas, when the entire population was examined, negative correlations were evident primarily between 25-OH-VitD and FG, HOMA-IR, total cholesterol, LDL-C. These associations remained significant after controlling for BMI.. These results suggest that hypovitaminosis D associations with metabolic disturbances are accentuated in DMT2. The BMIindependent positive correlation between 25-OH-VitD and adiponectin suggests a potential role for this adipocytokine as a link between 25-OH-VitD and IR in patients with DMT2.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Prognosis; Vitamin D; Vitamin D Deficiency; Young Adult

Epidemiological and clinical studies suggest that low-glycemic index diets could protect against weight gain. However, the relationship between these diets and adipokines or inflammatory markers is unclear. In the present study we examine how the dietary glycemic index (GI) and dietary glycemic load (GL) are associated with several adipokines and related metabolic risk markers of obesity and diabetes in a cross-sectional and longitudinal manner.. 511 elderly community-dwelling men and women at high cardiovascular risk were recruited for the PREDIMED trial. Dietary data were collected at baseline and after 1 year of follow-up. The GI and GL were calculated. Plasma leptin, adiponectin and other metabolic risk markers were measured at baseline and after 1 year. At baseline, subjects in the highest quartiles of GI showed significantly higher levels of TNF and IL-6 than those in the lowest quartiles. Dietary GI index was negatively related to plasma leptin and adiponectin levels. After 1 year of follow-up, subjects with a higher increase in dietary GI or GL showed a greater reduction in leptin and adiponectin plasma levels. There was no association between GI or GL and the other metabolic markers measured.. Our results suggest that the consumption of high-GI or high-GL diets may modulate plasma concentrations of leptin and adiponectin, both adipostatic molecules implicated in energy balance and cardiometabolic risk.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet, Mediterranean; Dietary Carbohydrates; Female; Follow-Up Studies; Glycemic Index; Humans; Interleukin-6; Leptin; Logistic Models; Longitudinal Studies; Male; Middle Aged; Nutrition Assessment; Obesity; Resistin; Risk Factors; Spain; Tumor Necrosis Factor-alpha

The effects of metformin and pioglitazone on ghrelin, a physiologic regulator of appetite and food intake, have not been clearly established. In a randomized clinical trial, we randomly assigned 60 type 2 diabetic patients to either metformin (Group A; n=30) or pioglitazone (Group B; n=30) treatment groups. The groups were similar in their baseline characteristics. A standard fasting 75 g oral glucose tolerance test was performed at time zero before starting metformin or pioglitazone, and 3 months later. After 3 months of treatment, pioglitazone, but not metformin, was significantly associated with weight gain. Both groups experienced a significant reduction in fasting plasma glucose (p<0.01), hemoglobin A1c (p<0.01 in Group A and p<0.05 in Group B), and insulin resistance (p<0.01). The effect of metformin on preprandial ghrelin and its response to glucose challenge was not significant, while the pioglitazone group had a significant reduction in preprandial ghrelin levels after treatment (p<0.05). The effect of pioglitazone on ghrelin was independent of changes in body weight, body mass index, glucose control, insulin resistance, and plasma insulin. In conclusion, treatment with pioglitazone is associated with a decrease in preprandial ghrelin levels and therefore, the weight gain and increased food intake related to pioglitazone use cannot be explained by its effects on ghrelin. The effect of pioglitazone on ghrelin is independent of changes in body weight, body mass index, plasma insulin, insulin resistance, or glucose control.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Leptin; Male; Metformin; Middle Aged; Pioglitazone; Thiazolidinediones

To assess the effects of two commonly used oral hypoglycemic medications metformin and pioglitazone on serum concentrations of omentin and leptin in patients with newly diagnosed type 2 diabetes.. In a clinical trial setting (NCT01593371), patients were randomly allocated to either metformin 1000mg daily (n=41), or pioglitazone 30mg daily (n=50). Serum concentrations of omentin and leptin were measured at baseline and after 12weeks. Patients' weight, waist circumference, blood pressure, fasting plasma glucose, fasting insulin, HbA1c, highly sensitive C-reactive protein, and serum lipids were also measured at the two visits.. Baseline concentrations of omentin and leptin were not different between the two arms of the trial. After three months, metformin decreased both omentin and leptin concentrations in women, and leptin concentrations only in men. On the other hand, pioglitazone reduced both adipokines only in women, but not men. Univariate and multivariate ANCOVA models revealed that both interventions are equally effective in reducing omentin concentration (p=0.497 for women and 0.344 for men in multivariate models controlling for the effects of confounding variables). Similarly, neither medication was more effective in reducing leptin concentrations after three months (p=0.822 for women and 0.441 for men in multivariate models).. Metformin and pioglitazone at pharmacologic doses are equally effective in alteration of serum omentin and leptin concentrations in patients with diabetes, albeit sex differences in response to medications exist. Implication of these findings on long term management and complication prevention of diabetes needs to be elucidated.

Topics: Adult; Aged; Blood Glucose; Cytokines; Diabetes Mellitus, Type 2; Female; GPI-Linked Proteins; Humans; Hypoglycemic Agents; Lectins; Leptin; Male; Metformin; Middle Aged; Pioglitazone; Thiazolidinediones

Low birth weight (LBW) is associated with an increased risk of insulin resistance and downregulation of oxidative phosphorylation (OXPHOS) genes when exposed to a metabolic challenge of high-fat overfeeding (HFO). To elaborate further on the differential effects of HFO in LBW subjects, we measured in vivo mitochondrial function, insulin secretion, hepatic glucose production, and plasma levels of key regulatory hormones before and after 5 days of HFO in 20 young LBW and 26 normal-birth-weight (NBW) men. The LBW subjects developed peripheral insulin resistance after HFO due to impaired endogenous glucose storage (9.42 ± 4.19 vs. 5.91 ± 4.42 mg·kg FFM(-1)·min(-1), P = 0.01). Resting muscle phosphorcreatine and total ATP in muscle increased significantly after HFO in LBW subjects only, whereas additional measurements of mitochondrial function remained unaffected. Despite similar plasma FFA levels, LBW subjects displayed increased fat oxidation during insulin infusion compared with normal-birth-weight (NBW) subjects after HFO (0.37 ± 0.35 vs. 0.17 ± 0.33 mg·kg FFM(-1)·min(-1), P = 0.02). In contrast to NBW subjects, the plasma leptin levels of LBW subjects did not increase, and the plasma gastric inhibitory polypeptide (GIP) as well as pancreatic polypeptide (PP) levels increased less in LBW compared with NBW subjects during HFO. In conclusion, HFO unmasks dissociation between insulin resistance and mitochondrial dysfunction in LBW subjects, suggesting that insulin resistance may be a cause, rather than an effect, of impaired muscle OXPHOS gene expression and mitochondrial dysfunction. Reduced increments in response to HFO of fasting plasma leptin, PP, and GIP levels may contribute to insulin resistance, lower satiety, and impaired insulin secretion in LBW subjects.

Topics: Adenosine Triphosphate; Adipokines; Adult; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Dietary Fats; Gastric Inhibitory Polypeptide; Glucose; Humans; Infant, Low Birth Weight; Infant, Newborn; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mitochondria, Muscle; Muscle, Skeletal; Pancreatic Polypeptide; Phosphocreatine; Protein Precursors; Registries; Young Adult

We evaluated the long-term effects of rosuvastatin and simvastatin on insulin sensitivity and secretion in patients with well-controlled type 2 diabetes.. After a 3 weeks run-in, 27 eligible patients were randomly assigned to receive either rosuvastatin 20 mg daily (Group 1) or simvastatin 20 mg daily (Group 2) for 6 months; thereafter they were switched to the other treatment for additional 6 months. Patients were recruited among individuals attending the outpatient service of the Diabetology Unit of the "Policlinico Tor Vergata" University Hospital, Rome, Italy. Serum lipids, glucose and insulin, glycated hemoglobin, C-reactive protein, TNF-α, leptin, adiponectin, insulin sensitivity by euglycemic-hyperinsulinemic clamp, β-cells function by HOMA-β were assessed at months 0, 6 and 12. Additionally, endothelial function was assessed by use of the brachial artery reactivity technique.. Besides marked reduction in lipid levels, glycated hemoglobin significantly increased from baseline after 12 months in both Group 1 (+0.8 ± 0.2%, p < 0.001) and Group 2 (+0.9 ± 0.3%; p < 0.001). Similar trends were observed for fasting glucose in both groups. No changes in insulin sensitivity were detected throughout the study, whereas HOMA-β significantly decreased from baseline after 12 months in both Group 1 (-21.9%, p < 0.01) and Group 2 (-38.9%; p < 0.001). In addition, both treatments similarly decreased C-reactive protein and leptin, as well as improved endothelial function. No changes in anthropometric measures were observed.. In well-controlled type 2 diabetic patients both rosuvastatin and simvastatin significantly impaired glycemic control and insulin secretion, without affecting insulin sensitivity.

Topics: Adiponectin; Biomarkers; Blood Glucose; Brachial Artery; C-Reactive Protein; Chi-Square Distribution; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Fluorobenzenes; Glucose Clamp Technique; Glycated Hemoglobin; Homeostasis; Hospitals, University; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Lipids; Male; Middle Aged; Pyrimidines; Rome; Rosuvastatin Calcium; Simvastatin; Single-Blind Method; Sulfonamides; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Daughters of diabetes patients have lower insulin sensitivity than women with no diabetes family history, but increase insulin sensitivity to a greater extent with exercise training. This study aimed to determine whether differences in circulating concentrations of adiponectin and leptin, and adipose tissue expression of their genes and receptors played a role. Women offspring of patients with type 2 diabetes mellitus (n = 34; age, 35.6 ± 7.0 years; body mass index, 28.1 ± 5.1 kg/m²) and matched controls with no diabetes family history (n = 36; age, 33.6 ± 6.1 years; body mass index, 27.3 ± 4.7 kg/m²) participated. Blood and abdominal subcutaneous adipose tissue samples were obtained at baseline and after a controlled 7-week endurance-type exercise intervention (sessions were performed at 65%-80% of maximum heart rate). At baseline, no significant differences were observed between groups in circulating leptin or adiponectin concentrations, or expression of their genes or receptors. In response to exercise, plasma leptin decreased more in offspring than controls (-32.2% vs -7.3%, P = .005 for interaction); and the long isoform of the leptin receptor messenger RNA (mRNA) increased significantly only in the offspring (+39.4%, P = .026 vs +7.7%, P = .892). Leptin mRNA decreased similarly in both groups (-24.7% vs -25.0%, P < .05 for both). Furthermore, changes in plasma leptin (r = -0.432, P < .001) and leptin mRNA (r = -0.298, P = .019) correlated significantly with changes in insulin sensitivity. Plasma adiponectin decreased similarly in both groups (-12.1% vs -15.2%, P < .01 for both), but no significant changes were observed in adiponectin-related gene expression. This work shows that exercise training has differing effects on leptin-related variables between women with and without a diabetes family history and suggests that these molecular differences may contribute to the differential effects of exercise training on insulin sensitivity between these 2 groups.

Topics: Abdominal Fat; Adiponectin; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Exercise; Family; Female; Gene Expression; Humans; Insulin; Insulin Resistance; Leptin; Physical Endurance; Receptors, Adiponectin; Receptors, Leptin

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus L-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA(1c), fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus L-carnitine compared with sibutramine alone. Sibutramine plus L-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.

Topics: Aged; Appetite Depressants; Blood Glucose; Body Weight; C-Reactive Protein; Carnitine; Cholesterol; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Tumor Necrosis Factor-alpha; Vitamin B Complex

The efficacy of sibutramine has been demonstrated in randomized trials in obese/overweight patients including those with type 2 diabetes mellitus (T2DM). Our objective was to evaluate the effects of 1-year treatment with sibutramine compared to placebo on body weight, glycaemic control, lipid profile, and inflammatory parameters in type 2 diabetic patients.. Two hundred and forty-six patients with uncontrolled T2DM [glycated haemoglobin (HbA(1c) ) > 8·0%] in therapy with different oral hypoglycaemic agents or insulin were randomized to take 10 mg of sibutramine or placebo for 12 months. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c) , fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), leptin, tumour necrosis factor-α (TNF-α), adiponectin (ADN), vaspin, high sensitivity C-reactive protein (Hs-CRP).. We observed a decrease of body weight after 9 and 12 months in the group treated with sibutramine, but not in the control group. Regarding glycaemic and lipid profile, although there are differences seen over time within each of the groups, we did not obtain any significant differences between the two groups. Both placebo and sibutramine gave a similar improvement of HOMA-IR, leptin, TNF-α, ADN, and Hs-CRP. No vaspin variations were observed in either group.. Sibutramine resulted in a decrease in body weight at 9 months and at 12 months that was not observed with placebo. Although there were differences seen over time within each of the groups, there were no significant differences between groups for any other parameter that we measured.

Topics: Adiponectin; Appetite Depressants; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Comorbidity; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Placebos; Randomized Controlled Trials as Topic; Thiazolidinediones; Time Factors

To evaluate the effects of 1-year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and inflammatory parameters in obese type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated the following parameters at baseline and after 3, 6, 9, and 12 months: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c) ), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), adiponectin (ADN), leptin, tumor necrosis factor-α (TNF-α), vaspin, and high-sensitivity C-reactive protein (Hs-CRP). We observed a better decrease in body weight, glycemic profile, HOMA-IR, LDL-C, and ADN and a faster improvement in FPI, TC, Tg, leptin, TNF-α, Hs-CRP with orlistat plus L-carnitine compared to orlistat alone. We also recorded an improvement in vaspin with orlistat plus l-carnitine not reached with orlistat alone. Orlistat plus L-carnitine gave a better improvement in body weight, glycemic and lipid profile compared to orlistat alone; furthermore, a faster and better improvement in inflammatory parameters was observed with orlistat plus L-carnitine compared to orlistat alone.

Topics: Adiponectin; Anti-Inflammatory Agents; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Carnitine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Lactones; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Obesity; Orlistat; Thiazolidinediones; Time Factors

Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers.. An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m², total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks.. Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p<0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p<0.001 vs. -32.9%, p<0.01) and increases in HDL-C (+18.0%, p<0.001 vs. +11.7%, p<0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p<0.01; non-HDL-C, -17.3%, p<0.01; apolipoprotein B, -15.1%, p<0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p<0.05) and metabolic markers (γ-GTP, -38.9%, p<0.01; adiponectin, +15.4%, p<0.05; urine 8-OHdG/Cre, -9.5%, p<0.05).. Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adipokines; Adiponectin; Adult; Aged; Bezafibrate; Body Mass Index; Cholesterol; Cholesterol, HDL; Cross-Over Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Fenofibrate; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Peroxisome Proliferator-Activated Receptors; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases; Time Factors; Triglycerides

Leptin therapy improves insulin sensitivity in people with leptin deficiency, but it is not known whether it improves insulin action in people who are not leptin deficient. The purpose of the current study was to determine whether leptin treatment has weight loss-independent effects on insulin action in obese subjects with type 2 diabetes.. We conducted a randomized, placebo-controlled trial in obese subjects (BMI: 35.4 ± 0.6 kg/m(2); mean ± SE) with newly diagnosed type 2 diabetes. Subjects were randomized to treatment with placebo (saline), low-dose (30 mg/day), or high-dose (80 mg/day) recombinant methionyl human (r-Met hu) leptin for 14 days. Multiorgan insulin sensitivity before and after treatment was evaluated by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions to measure glucose, glycerol, and fatty acid kinetics.. Low-dose and high-dose leptin treatment resulted in a threefold (P < 0.01) and 150-fold (P < 0.001) increase in basal plasma leptin concentrations, respectively. However, neither low-dose nor high-dose therapy had an effect on insulin-mediated suppression of glucose, glycerol, or palmitate rates of appearance into plasma compared with placebo. In addition, leptin treatment did not increase insulin-mediated stimulation of glucose disposal compared with placebo (14.3 ± 3.1, 18.4 ± 3.6, 16.7 ± 2.4 vs. 17.5 ± 2.5, 20.7 ± 3.0, 19.1 ± 3.3 μmol/kg body wt/min before vs. after treatment in the placebo, low-dose, and high-dose leptin groups, respectively).. r-Met hu leptin does not have weight loss-independent, clinically important effects on insulin sensitivity in obese people with type 2 diabetes.

Topics: Blood Glucose; Body Composition; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Glycerol; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Palmitic Acid; Placebos

Patients with type 2 diabetes (T2DM) have a high restenosis rate after percutaneous coronary intervention (PCI). This study investigated whether markers of inflammation and the adipo-insular axis associated with T2DM and poor metabolic control were able to predict restenosis after PCI in T2DM patients.. The predictive value of traditional and non-traditional risk markers, including IL-1β, IL-6, TNF-α, hsCRP, interferon gamma, leptin, IGF-I, insulin, proinsulin and NT-proBNP, was investigated in 82 patients with T2DM. A re-angiography 6 months after the index percutaneous coronary intervention (PCI) revealed that 43% of the patients had a restenosis. In a multiple regression analysis, the only independent predictors of restenosis were fasting glucose before the PCI and previous myocardial infarction (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.07-1.92; p = 0.015 and OR 8.00, 95% CI 2.49-25.67; p ≤ 0.001, respectively). None of the other markers remained as significant predictors.. Fasting glucose prior to the PCI was an independent predictor of restenosis in patients with T2DM while analyses of a variety of markers related to inflammation and the adipo-insular axis did not add any further information.

Topics: Aged; Angioplasty, Balloon, Coronary; Biomarkers; Blood Glucose; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Cytokines; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin-Like Growth Factor I; Leptin; Logistic Models; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Odds Ratio; Peptide Fragments; Proinsulin; Prospective Studies; Risk Assessment; Risk Factors; Sweden; Time Factors; Treatment Outcome

Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes.. We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo-controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.. In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA(1c) marginally (8.01 ± 0.93-7.96 ± 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ∼50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling.. In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA(1c) marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes.

Topics: Adipocytes; Adult; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Mellitus, Type 2; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Obesity; Phosphorylation; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

To study the relationship between serum leptin and insulin resistance, and to analyze the effect of acupuncture on serum leptin level in patients with type-II diabetes mellitus (DM).. A total of 80 type-II DM patients were randomized into acupuncture and medication groups. Acupuncture was applied to Yishu (EX), Feishu (BL13), Pishu (BL 20), etc. according to syndrome identification. The treatment was given once every other day for 12 weeks. For patients in the medication group, Glibenclamide (2.5-7.5 mg/time, 1-2 times/d according to blood sugar level) was given for 12 weeks. Fasting blood glucose (FBG), fasting insulin (FINS) and fasting leptin (FLP) were detected by using glucose oxidase method, radioimmunoassay and ELISA, respectively. Insulin sensitivity index (ISI) and homeostasis model assessment-insulin resistance (HOMA-IR) were calculated.. In comparison with pre-treatment, FBG levels and HOMA-IR in both acupuncture and medication groups, and FINS and FLP levels in the acupuncture group were decreased significantly (P < 0.01), while ISI in both acupuncture and medication groups, and FINS level in the medication group were increased remarkably after the treatment (P < 0.01). Comparison between two groups showed that after the treatment, FINS and FLP levels, and HOMA-IR of the acupuncture group were considerably lower than those of the medication group (P < 0.01), while ISI of the acupuncture group was significantly higher than that of the medication group (P < 0.01).. Acupuncture therapy is effective in lowering FLP level, which may contribute to its clinical effect in improving type-II DM.

Topics: Acupuncture Therapy; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged

Leptin has lipid peroxidation properties in healthy individuals. Here we aimed to study the correlation between serum-oxidized low-density lipoprotein (ox-LDL) and leptin levels in patients with type 2 diabetes. We also studied the effect of metformin therapy on the correlation between serum ox-LDL and leptin levels in patients with newly diagnosed diabetes.. We performed a cross-sectional study on two groups of patients with type 2 diabetes stratified according to (1) patients with newly diagnosed diabetes and (2) patients with long-standing diabetes plus healthy controls. Patients with newly diagnosed diabetes were followed for 3 months after the initiation of metformin therapy.. Patients with type 2 diabetes had a higher serum ox-LDL, ox-LDL/LDL ratio, waist circumference, fasting blood sugars (FBSs), hemoglobin A1C (HbA1C), triglyceride, homeostatic model assessment of insulin resistance (HOMA-IR) and a lower serum leptin levels than controls. Serum ox-LDL, ox-LDL/LDL ratio (0.08 (0.08-0.12) vs. 0.06 (0.05-0.08), P<0.001) and HOMA-IR (3.26±0.23 vs. 2.93±0.32; P<0.01) were decreased when serum leptin levels (15.9±1.6 vs. 21.4±2.5, P<0.01) were increased after 3 months of metformin therapy. This remained significant after multiple adjustments for age, body mass index, FBS, HbA1c, and HOMA-IR. Leptin was significantly correlated with ox-LDL/LDL ratio in controls (r=0.78, P<0.01), and in patients with newly diagnosed diabetes (r=0.4, P<0.05), after metformin therapy. There were not any correlation between leptin and ox-LDL/LDL ratio in patients with long-standing diabetes and patients with newly diagnosed diabetes before treatment.. Metformin restores the positive correlation between serum ox-LDL and leptin levels in patients with type 2 diabetes.

Topics: Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Lipoproteins, LDL; Male; Metformin; Middle Aged; Oxidative Stress

Adiponectin and leptin are adipocytokines associated with insulin resistance. The objective of this study was to evaluate the performance of the adiponectin-leptin ratio as a measure of insulin resistance in comparison with other surrogate measures of insulin resistance based on fasting insulin and glucose levels [homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), fasting glucose/insulin ratio] and with measures based on fasting insulin and triglyceride levels (McAuley index) in Caucasian patients with Type 2 diabetes (T2D).. In 70 patients included in DEMAND (delapril and manidipine for nephroprotection in diabetes) study, fasting samples of plasma insulin and adiponectin were determined by a radioimmunoassay, whereas plasma leptin was determined by an enzyme-linked immunosorbent assay. Insulin resistance estimates were derived by the established equations and compared with the direct measurement of insulin resistance obtained with the euglycemic hyperinsulinemic clamp. Insulin resistance estimates and the clamp derived sensitivity index were compared by correlation analysis.. The adiponectin-leptin ratio correlated best with the clamp derived sensitivity index (r=0.553, p<0.001) compared to other surrogate measures of insulin resistance. In multiple linear regression models including different surrogate measures of insulin resistance as independent predictors of the sensitivity index, the model with the adiponectin-leptin ratio accounted for the highest variability of the sensitivity index (r2=0.336, p<0.001).. The adiponectin-leptin ratio is associated with insulin resistance, measured with the euglycemic hyperinsulinemic clamp, in Caucasians with T2D. The association with clamp derived sensitivity index is even stronger than that of HOMA, QUICKI, fasting glucose/insulin ratio or McAuley index and is independent of body mass index or glycemic control. The adiponectin-leptin ratio promises to become a new laboratory marker of insulin resistance in T2D.

Topics: Adiponectin; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Leptin; Male; Sensitivity and Specificity

Topics: Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Diet; Fasting; Female; Humans; Leptin; Male; Middle Aged; Yoga

The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding.. We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH- respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp).. Body weight was increased compared with baseline at 3 and 28 days in both groups (p < 0.001), FH+ individuals having gained significantly more weight than FH- individuals at 28 days (3.4 +/- 1.6 vs 2.2 +/- 1.4 kg, p < 0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH- for insulin at +3 and +28 days (p < 0.01) and C-peptide at +28 days (p < 0.05). Fasting glucose also increased at both time points, but without a significant group effect (p = 0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8 +/- 17.7 to 50.3 +/- 15.6 micromol min(-1) [kg fat-free mass](-1), p = 0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p < 0.001) and to a greater extent in FH+ than in FH- (p = 0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p < 0.001).. Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy individuals. However, individuals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy individuals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding.. ClinicalTrials.gov NCT00562393. The study was funded by the National Health and Medical Research Council (NHMRC), Australia (no. #427639).

Topics: Adult; Analysis of Variance; Australia; Body Composition; C-Peptide; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Genetic Predisposition to Disease; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Overnutrition; Risk Factors; Sedentary Behavior; Weight Gain

Insulin resistance ameliorates after bariatric surgery, yet there is still a need for data on the acute effect of Roux-en-Y gastric bypass (RYGBP) on insulin sensitivity.. The objective of the study was to describe the acute effect of RYGBP on insulin sensitivity, measured by both the euglycemic-hyperinsulinemic clamp and homeostasis model assessment insulin resistance index (HOMA-IR).. Evaluations were conducted before and 1 month after RYGBP at State University of Campinas (São Paulo, Brazil).. Patients included 19 premenopausal women with metabolic syndrome aged 35.3 (6.7) yr, body mass index 45.50 (3.74) kg/m2 [mean (sd)]. Six had mild type 2 diabetes, seven impaired glucose tolerance, and six normal glucose tolerance.. The volunteers underwent RYGBP either alone or combined with omentectomy. Euglycemic-hyperinsulinemic clamp, HOMA-IR, nonesterified fatty acids, leptin, ultrasensitive C-reactive protein, adiponectin, and IL-6 were assessed at baseline and 4.5 (0.9) wk postoperatively.. Fasting glucose decreased [99.2 (13.1) to 83.6 (8.1) mg/dl, P<0.01] along with a reduction in fasting insulin [30.4 (17.0) to 11.4 (6.3) mU/liter, P<0.01]. M value did not improve postoperatively [25.82 (6.30) to 22.02 (6.05) micromol/kgFFM.min] despite of a decrease in body weight [114.8 (14.5) to 102.3 (14.5) kg, P<0.001]. This finding was discordant to the observation of an improvement in HOMA-IR [3.85 (2.10) to 1.42 (0.76), P<0.01]. Nonesterified fatty acids increased. Leptin and C-reactive protein decreased. IL-6 and adiponectin remained unchanged.. A month after RYGBP, fasting glucose metabolism improves independent of a change in peripheral insulin sensitivity.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Female; Gastric Bypass; Glucose Clamp Technique; Humans; Insulin Resistance; Interleukin-6; Leptin; Metabolic Syndrome; Obesity, Morbid; Statistics, Nonparametric; Treatment Outcome

To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients.. Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-alpha, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR).. Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-alpha, and a faster decrease of leptin and HS-CRP in the orlistat group compared with the control group. We also recorded a significant reduction of body weight and BMI with orlistat, but not with placebo. A faster improvement of glycemic profile and FPI was obtained with orlistat compared with the controls. Also, there was a significant reduction of lipid profile with orlistat, not reached with placebo.. Orlistat was more effective than placebo in ameliorating inflammatory parameters such as ADN and TNF-alpha, and anthropometric parameters.

Topics: Adiponectin; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin Resistance; Italy; Lactones; Leptin; Lipids; Male; Middle Aged; Obesity; Orlistat; Placebo Effect; Serpins; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Waist Circumference

Insulin resistance is a major feature of type 2 diabetes mellitus, obesity and nonalcoholic fatty liver disease (NAFLD). Several studies pointed out the possible role of increased leptin in NAFLD in humans. The aim of this study is to determine the effect of metformin on plasma leptin levels in obese patients with type 2 diabetes mellitus and NAFLD compared with lifestyle interventions. Thirty-four obese patients with newly diagnosed type 2 diabetes mellitus were prospectively followed for 6 months. All patients had ultrasonographic evidence of NAFLD at baseline. The patients were randomized into two groups: group 1 (n = 15) followed lifestyle changes only and group 2 (n = 19) received metformin (1,700 mg/day). At the end of treatment, BMI, WHR, HbA1c, fasting glucose, leptin, HOMA-IR, alanine aminotransferase values decreased in both groups. No significant difference in the end-points was observed between two groups. Only in group 2, LDL decreased and HDL increased significantly. Liver echogenity decreased significantly at the end of study in both groups. The percentage of patients who no longer had evidence of NAFLD was not significantly different between the groups (20% of patients on lifestyle intervention vs. 16% of patients on metformin). The data demonstrate that, metformin and lifestyle interventions equally affected the plasma leptin levels, BMI and degree of NAFLD in obese patients with type 2 diabetes mellitus. In addition, the effects of metformin on the variables were not found to be mediated by leptin.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Exercise; Fatty Liver; Female; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Life Style; Lipoproteins; Liver Function Tests; Male; Metformin; Middle Aged; Obesity; Triglycerides

Effects of glucomannan as a supplementary treatment in type 2 diabetes mellitus were investigated by measuring ghrelin, leptin and insulin responses to OGTT. Glucomannan enhanced prandial ghrelin reduction when given before glucose load and impeded the rise of fasting ghrelin after 4-week supplement. Ghrelin-induced feeding may be attenuated by glucomannan.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dietary Supplements; Fasting; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Mannans; Placebos; Postprandial Period; Time Factors

Adipocytokines represent a molecular link between metabolic factors and vascular function. The purpose of our study was to investigate the relationship between adiponectin, leptin and renal function parameters in patients with glomerular filtration rate (GFR) above 90 ml/min/m(2) and type 2 diabetes.. In 52 patients, plasma (P-) and urinary (U-) adiponectin and leptin were determined by radioimmunoassay and ELISA, respectively. Kidney function was assessed with GFR (plasma iohexol clearance) and albuminuria (radioimmunoassay).. The patients were aged 58+/-8 years and had a mean BMI value of 31.2+/-5.2 kg/m(2). Our measurements yielded the following values, expressed as median (25th percentile, 75th percentile): P-adiponectin 11.0 (7.1, 14.5) microg/ml, P-leptin 20.7 (9.6, 35.9)ng/ml, U-adiponectin 0.8 (0.3, 1.2) microg/mg creatinine, and U-leptin 1.0 (0.4, 1.9) microg/mg creatinine. Albuminuria correlated with P-adiponectin (R=-0.31, p=0.03), and GFR correlated with U-leptin (R=-0.32, p=0.04).. Adiponectin and leptin are associated with parameters of renal function already at the stage of apparently normal kidney function in type 2 diabetes. The exact mechanisms of the adipocyte-vasculature axis still remain to be elucidated.

Topics: Adipocytes; Adiponectin; Aged; Albuminuria; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Kidney; Leptin; Male; Middle Aged; Prospective Studies

To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY3-36 (PYY3-36), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY3-36 levels.. The increased PYY3-36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery.. Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10).. : PYY3-36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 +/- 34.4 pg/mL vs. 39.9 +/- 21.1 pg/mL; P < 0.05). PYY3-36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 +/- 20.5 pg/mL-132.7 +/- 49.7 pg/mL; P < 0.001; AUC0-180: 51.5 +/- 23.3 pg/mL x min-91.1 +/- 32.2 pg/mL x min P < 0.001), but not after diet (peak: 85.5 +/- 51.9 pg/mL-84.8 +/- 41.13 pg/mL; P = NS; AUC0-180: 68.3 +/- 38.5 pg/mL x min-61.1 +/- 42.2 pg/mL.min P = NS). Fasting ghrelin levels increased after diet (425 +/- 91 pg/mL-519 +/- 105 pg/mL; P < 0.05), but did not change after GBP (506 +/- 121 pg/mL-482 +/- 196 pg/mL; P = NS).. Diabetes status seems to be a determinant of PYY3-36 levels. GBP, but not diet-induced weight loss, resulted in markedly increased glucose-stimulated PYY3-36 levels. The increase in stimulated PYY3-36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY3-36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss.

Topics: Adult; Body Mass Index; Caloric Restriction; Cohort Studies; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Ghrelin; Humans; Leptin; Middle Aged; Obesity, Morbid; Peptide Fragments; Peptide YY; Weight Loss

Leptin modulates satiety and increases in obesity and type 2 diabetes mellitus in parallel with leptin resistance. Postprandial leptin regulation has been previously postulated to depend on meal composition, but data are controversial. The hypothesis of our study was that in people with type 2 diabetes mellitus, a postprandial leptin regulation exists that can be regulated not only by meal composition but also by the cooking method. In 20 inpatients with type 2 diabetes (mean age: 55.9 years), the acute effects of 2 meals, a high-heat-processed meal HHPM or a low-heat-processed meal LHPM, on leptin levels were studied on 2 different days in a randomized, crossover design. Both test meals had similar ingredients and differed only in the cooking method used. Parameters were measured after an overnight fast and at 2, 4, and 6 h postprandially. The HHPM induced a marked decrease in leptin levels, from 8 717+/-2 079 pg/ml at baseline to 6 788+/-1 598 pg/ml at 2 h postprandially (-1 929 pg/ml, -22%*), an effect significantly reduced by the LHPM, where values were 8 563+/-1 900 pg/ml at baseline and 7 425+/-1 591 pg/ml at 2 h postprandially (-1 138 pg/ml, -13%* (double dagger)) (*p<0.05 vs. baseline, (double dagger)p<0.05 vs. HHPM). Parameters of oxidative stress and blood AGEs increased only following the HHPM, while postprandial glucose, triglycerides, and insulin excursions were similar between meals. Postprandial leptin decreases following a HHPM meal in people with T2DM, an effect reduced by the cooking method.

Topics: Blood Glucose; Cooking; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Diet, Diabetic; Female; Glycation End Products, Advanced; Humans; Leptin; Lipids; Male; Middle Aged; Postprandial Period; Pyruvaldehyde

Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes.. Twenty-one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA-IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([DeltaI5/DeltaG5]/HOMA-IR).. Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 +/- 29.5 vs. 644.9 +/- 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 +/- 0.5 vs. 17.6 +/- 3.9 1/mmol(2), P < 0.001). One month following BPD, in both groups BW was reduced (by approximately 11%), but all subjects were still severely obese; HOMA-IR and leptin decreased significanlty, while high-molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non-diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 +/- 29.5 to 273.8 +/- 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia.. BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.

Topics: Adiponectin; Adult; Biliopancreatic Diversion; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Fasting; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Obesity; Weight Loss

In addition to lipid lowering, further pleotropic effects of statins have been postulated. We aimed to study if the various pleotropic effects are due indirectly to the modulation of adipocytokines.. We studied the effect of atorvastatin on insulin sensitivity and the plasma adiponectin and leptin concentrations. Our randomized open labeled study had 29 hyperlipidemic Type 2 diabetic patients (14 females, 15 males, mean age 60.0+/-2.2 yr). They were randomized into three 12-week atorvastatin intervention types. Each day patients were given either 10 mg (no.=10), 20 mg (no.=10) or 40 mg (no.=9). Evaluations were performed before and after intervention.. All baseline characteristics were statistically identical in the 3 groups. Drop in total cholesterol, LDL-cholesterol, and triglyceride levels were measured at the end. With 10 mg the drop was 30%, 37%, and 30%. The 20 mg group was 43%, 54%, and 34%. The 40 mg group was 42%, 51%, and 27%. Groups had no significant change of body mass index, HDLcholesterol, and glycated hemoglobin levels. Also, levels of insulin, adiponectin, leptin, homeostasis model assessment index (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) stayed the same. Pooled parameters of all 29 patients showed no difference in levels of insulin, adiponectin, leptin, HOMA, and QUICKI before and after treatment.. Atorvstatin does not affect insulin sensitivity and the adiponectin or leptin levels in hyperlipidemic Type 2 diabetes.

Topics: Adiponectin; Aged; Anticholesteremic Agents; Atorvastatin; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Heptanoic Acids; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Male; Middle Aged; Pyrroles

Few studies have directly compared rosiglitazone and metformin effects on adipocytokines. The aim was to observe the possible effects of rosiglitazone and metformin on glycemic control, insulin sensitivity, plasma leptin (pL), adiponectin (ADN), tumor necrosis factor-alpha (TNF-alpha), and resistin (R) in overweight and obese diabetic patients intolerant to metformin.. Six hundred and ninety-four consecutive overweight and obese type 2 diabetic patients were evaluated and 56 patients were intolerant to metformin at maximum dosage. We added rosiglitazone to metformin in these intolerant patients (RM) and we compared them with 61 patients treated with metformin (M) in a single-blind placebo-controlled trial. We evaluated body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), pL, ADN, TNF-alpha, and R at baseline and after 3 and 6 months. Furthermore, we calculated insulin resistance index (HOMA-index) using FPG and FPI.. Glycated hemoglobin, FPG, FPI, and HOMA-index results were lower than baseline values in RM and M groups. Glycated hemoglobin and HOMA-index values were significantly lower in RM group compared to M group at 6 months. Plasma leptin, ADN, TNF-alpha, and R were significantly improved in RM group compared to M group at 6 months.. No BMI change was observed, probably because rosiglitazone was added to metformin, that could mitigate the body increase of rosiglitazone. Rosiglitazone improved glycemic control and insulin resistance-correlated parameters when added to intolerant metformin patients. These data suggest that rosiglitazone may be the drug of choice for the treatment of overweight and obese type 2 diabetic patients.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Italy; Leptin; Male; Metformin; Middle Aged; Obesity; Overweight; Resistin; Rosiglitazone; Single-Blind Method; Thiazolidinediones; Tumor Necrosis Factor-alpha

Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on arterial stiffness is less clear. The aim of the present study was to assess the differential effect of pioglitazone or rosiglitazone on arterial stiffness and plasma levels of adiponectin and leptin in patients with type 2 diabetes mellitus.. Thirty-five type 2 diabetic subjects were randomly assigned to receive pioglitazone (30 mg/day; n = 14), rosiglitazone (4 mg/day; n = 11), or placebo (medical nutrition therapy; n = 10) for 12 weeks. Changes in plasma glucose, glycosylated hemoglobin, insulin resistance (HOMA-IR), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, adiponectin, and leptin were evaluated at baseline and after 12 weeks. In parallel, large arterial compliance (C1) and small arterial compliance (C2) were measured at baseline and at the end of treatment period.. At 12 weeks, the rosiglitazone (P = 0.026) and pioglitazone (P = 0.004) groups had a significant increase from baseline in adiponectin that was not seen in the medical nutrition therapy group. No significant changes in plasma leptin and in C1 and C2 elasticity indexes were observed over the entire study period in any of the treatment groups.. In this study of patients with type 2 diabetes, treatment with TZDs was associated with a significant improvement in adiponectin levels, although no significant effects were seen on leptin levels and arterial elasticity.

Topics: Adiponectin; Arteries; Blood Glucose; Body Mass Index; Capillary Resistance; Diabetes Mellitus, Type 2; Elasticity; Female; Glycemic Index; Humans; Hypoglycemic Agents; Leptin; Lipids; Male; Middle Aged; Pioglitazone; Placebos; Rosiglitazone; Thiazolidinediones

Adipose tissue contributes to plasma levels of lipid transfer proteins and is also the major source of plasma adipokines. We hypothesized that plasma cholesteryl ester transfer protein (CETP) mass, phospholipid transfer protein (PLTP) activity and cholesteryl ester transfer (CET, a measure of CETP action) are determined by adipokine levels. In this study, relationships of plasma CETP mass, PLTP activity and CET with leptin, resistin and adiponectin were analyzed in type 2 diabetic patients and control subjects. Plasma PLTP activity (P<0.001), CET (P<0.001), leptin (P=0.003), resistin (P<0.001), high sensitive C-reactive protein (P=0.005), and insulin resistance (HOMA(ir)) (P<0.001) were higher, whereas HDL cholesterol (P<0.001) and plasma adiponectin (P<0.001) were lower in 83 type 2 diabetic patients (32 females) than in 83 sex-matched control subjects. Multiple linear regression analysis demonstrated that in diabetic patients plasma leptin levels were related to plasma CETP mass (P=0.018) and PLTP activity (P<0.001), but not to the other adipokines measured. Plasma CET was inversely correlated with adiponectin in univariate analysis, but this association disappeared in multivariate models that included plasma lipids and CETP. In conclusion, both plasma CETP mass and PLTP activity are associated with plasma leptin in type 2 diabetes. The elevated CET in these patients is not independently related to any of the measured plasma adipokines.

Topics: Blood Proteins; Cholesterol Ester Transfer Proteins; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Lipids; Male; Middle Aged; Multivariate Analysis; Phospholipid Transfer Proteins

Telmisartan, a new angiotensin II type 1 receptor blocker (ARB), was recently reported to stimulate PPARgamma, and stronger effects of Telmisartan on insulin sensitivity has been expected than the class effect of ARB. In the present study, we examined the effects of Telmisartan on insulin sensitivity and adipokine levels in hypertensive and type 2 diabetic patients. Outpatients with both hypertension and type 2 diabetes mellitus (n=36; male 23, female 13), received 20-40mg Telmisartan orally once daily for 6 months. Physical examinations and blood or urine tests were performed before and 3 or 6 months after starting Telmisartan treatment. Results were statistically compared using Wilcoxon analysis. Telmisartan treatment for 3 or 6 months reduced systolic and diastolic blood pressure and urinary albumin excretion. Fasting plasma glucose, HbA1c, total and HDL-cholesterol, triglyceride, body weight, BMI and waist length were not changed. Fasting IRI and HOMA-IR were significantly decreased after Telmisartan treatment, suggesting the improved insulin sensitivity. Total and high molecular adiponectin were not changed. Interestingly, serum leptin was significantly increased by 3 months Telmisartan treatment, suggesting a possible involvement of leptin in improved insulin sensitivity. In conclusion, Telmisartan improved insulin resistance with increased serum leptin level in hypertensive and type 2 diabetic patients.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Female; Humans; Hypertension; Hypoglycemic Agents; Leptin; Lipids; Male; Middle Aged; Telmisartan

Serum testosterone levels are known to inversely correlate with insulin sensitivity and obesity in men. Furthermore, there is evidence to suggest that testosterone replacement therapy reduces insulin resistance and visceral adiposity in type 2 diabetic men. Adipocytokines are hormones secreted by adipose tissue and contribute to insulin resistance. We examined the effects of testosterone replacement treatment on various adipocytokines and C-reactive protein (CRP) in type 2 diabetic men.. Double-blinded placebo-controlled crossover study in 20 hypogonadal type 2 diabetic men. Patients were treated with testosterone (sustanon 200 mg) or placebo intramuscularly every 2 weeks for 3 months in random order followed by a washout period of 1 month before the alternate treatment phase.. Leptin, adiponectin, resistin, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and CRP levels were measured before and after each treatment phase. Body mass index (BMI) and waist circumference were also recorded.. At baseline, leptin levels significantly correlated with BMI and waist circumference. There was a significant inverse correlation between baseline IL-6 and total testosterone (r=-0.68; P=0.002) and bioavailable testosterone levels (r=-0.73; P=0.007). CRP levels also correlated significantly with total testosterone levels (r=-0.59; P=0.01). Testosterone treatment reduced leptin (-7141.9 +/- 1461.8 pg/ml; P=0.0001) and adiponectin levels (-2075.8 +/- 852.3 ng/ml; P=0.02). There was a significant reduction in waist circumference. No significant effects of testosterone therapy on resistin, TNF-alpha, IL-6 or CRP levels were observed.. Testosterone replacement treatment decreases leptin and adiponectin levels in type 2 diabetic men. Moreover, low levels of testosterone in men are associated with pro-inflammatory profile, though testosterone treatment over 3 months had no effect on inflammatory markers.

Topics: Adiponectin; Aged; Body Composition; C-Reactive Protein; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Hormone Replacement Therapy; Humans; Hypogonadism; Interleukin-6; Leptin; Male; Middle Aged; Peptide Hormones; Resistin; Statistics, Nonparametric; Testosterone; Tumor Necrosis Factor-alpha

We investigated whether circulating adipokine concentrations can be altered by lifestyle intervention according to general recommendations in subjects at risk for diabetes as well as the potential of leptin, adiponectin, and resistin as biomarkers for lifestyle-induced improvements in glucose metabolism and insulin resistance.. In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 men and women with impaired glucose tolerance (IGT) were randomized to either a combined diet-and-exercise intervention or a control program. At baseline and after 1 year, an oral glucose tolerance test, an exercise test, and anthropometric measurements were performed. After 1 year, complete data of 103 subjects (50 intervention and 53 control subjects) were obtained.. Lifestyle intervention reduced plasma leptin concentrations (-14.2%) in IGT subjects but did not alter plasma adiponectin (-0.3%) or resistin (-6.5%) concentrations despite marked improvements in glucose tolerance and insulin resistance.. Changes in leptin concentration were related to improvements in insulin sensitivity independent of changes in body composition.

Topics: Adipokines; Adiponectin; Biomarkers; Body Size; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise; Female; Glucose Intolerance; Humans; Leptin; Life Style; Male; Reference Values; Resistin

Adipocytokines are involved in the development of insulin resistance and endothelial dysfunction in diabetic patients. However, the relationship between these factors remains unclear. We observed a chronological change in circulating adipocytokines and blood pressure levels with administration of oral hypoglycaemic agents in Type 2 diabetic (T2DM) subjects.. Thirty poorly controlled T2DM subjects (aged 60.1 +/- 1.5 years, 11 males and 19 females) were randomized into two groups: voglibose (initial dose 0.6 mg/day, increased to 0.9 mg/day) and pioglitazone (initial dose 15 mg/day, increased to 30 mg/day).. Both treatment groups showed a similar improvement in glycaemic control. In pioglitazone-treated patients, circulating adiponectin levels were significantly increased from 4 weeks after the start of treatment, and until the end of the study at 12 weeks. Plasma tumour necrosis factor-alpha (TNF-alpha) levels were significantly decreased only at 12 weeks. In contrast, no significant changes in plasma adiponectin or TNF-alpha levels were observed in voglibose-treated patients. Plasma PAI-1 and leptin levels were not significantly changed at 12 weeks in either treatment group. Pioglitazone significantly decreased systolic and diastolic blood pressure levels at 12 weeks, but voglibose had no effect.. In summary, pioglitazone caused an immediate increase in circulating adiponectin levels, followed by a reduction of TNF-alpha. The observed increase in circulating adiponectin could be related to decreases in both systolic and diastolic blood pressure.

Topics: Adiponectin; Administration, Oral; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Inositol; Leptin; Male; Middle Aged; Pioglitazone; Plasminogen Activator Inhibitor 1; Thiazolidinediones; Tumor Necrosis Factor-alpha

Adiponutrin is a newly described white adipose tissue (WAT)-derived protein whose function and regulation remain widely unclear in humans though it is suggested to be related to insulin sensitivity. Recently, we found that adiponutrin expression is reduced in type 2 diabetic subjects in basal and insulin-stimulated states. To examine adiponutrin regulation by the insulin pathway in relation to other WAT-related proteins with well-known relation to insulin signaling and action, we examined in healthy young men (1) the association of adiponutrin with p85alpha PI3K and HKII, leptin, adiponectin, and acylation-stimulating protein (ASP) and (2) the regulation of adiponutrin and WAT-derived proteins by 3-h hyperinsulinemic euglycemic clamp (HIEG). At baseline (N = 20), adiponutrin expressions were positively correlated with those of p85alpha PI3K (R = 0.54, P = 0.017), HKII (R = 0.58, P = 0.010), and serum leptin (R = 0.51, P = 0.036), but not with any other parameter measured including insulin sensitivity. Hyperinsulinemia (N = 10, +2365% above baseline) significantly increased the expression of adiponutrin (+770%, P = 0.002), p85alpha PI3K (+150%, P = 0.033), HKII (+147%, P = 0.007), and serum leptin (+11%, P = 0.031), while it decreased serum adiponectin (-15%, P = 0.001). In the insulin-stimulated state, adiponutrin mRNA expression levels correlated with basal p85alpha PI3K (R = 0.76, P = 0.018) and HKII (R = 0.86, P = 0.003) expression levels, with percentage increase in insulin (R = 0.73, P = 0.040), and with insulin-stimulated state HKII (R = 0.82, P = 0.007), leptin (R = 0.84, P = 0.005), and adiponectin (R = 0.85, P = 0.004) mRNA levels. In healthy young men, adiponutrin expression is upregulated [corrected] by hyperinsulinemia and is related to basal and/or insulin-stimulated p85alpha PI3K, HKII, adiponectin, and leptin expression levels. We hypothesize that insulin-mediated regulation of adiponutrin expression is under the PI3K pathway. The relevance of the present findings to reduced adiponutrin expression in type 2 diabetes is discussed.

Topics: Adiponectin; Adipose Tissue, White; Adult; Blood Glucose; Complement C3; Diabetes Mellitus, Type 2; Gene Expression Regulation; Glucose; Hexokinase; Humans; Insulin; Insulin Resistance; Leptin; Male; Membrane Proteins; Phosphatidylinositol 3-Kinases

In this investigation shown the influence of traditional hypocaloric diet on concentration of leptin level and leptin receptor in type 2 diabetic patients. Our results show that diet therapy improves metabolic control, and as a result of a diet were normoglucaemia and decrease of leptin and leptin receptor level in type 2 diabetic patients.

Topics: Blood Glucose; C-Reactive Protein; Caloric Restriction; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Diet, Diabetic; Humans; Leptin; Receptors, Cell Surface; Receptors, Leptin

To specify changes in clinicolaboratory parameters in reduction of obesity in patients with diabetes mellitus type 2 (DM-2).. Antropometry, densitometry of fat tissue (FT) were made and parameters of fat and carbohydrate metabolism (lipidogram, glycated hemoglobin, immunoreactive insulin), FT secretory activity (leptin, adiponectin, TNF-alpha) were studied in 75 obese DM-2 patients. After the above primary examination all the patients were randomized into 2 groups: group 1 (n = 55) received xenical (120 mg 3 times a day) and kept moderate hypocaloric diet; group 2 (n = 20) received only the above diet therapy. Active treatment lasted 24 weeks.. In addition to symptoms of metabolic syndrome (MS) the patients were found to have secretory disturbances of FT activity: elevation of leptin and TNF-alpha levels, subnormal adiponectin. These alterations directly correlated with body mass, FT mass gain, increase in waist circumference. Hyperleptinemia, hyperinsulinemia and hypoadiponectinemia were considered as markers of insulin resistance (IR) and related conditions. Xenical promoted a significant weight loss resulting in a positive trend in the parameters of adipokines, fat and carbohydrate metabolism, in reduction of IR.. Xenical is beneficial for patients with DM-2 and obesity because it improves metabolic processes.

Topics: Adiponectin; Adipose Tissue; Anthropometry; Anti-Obesity Agents; Biomarkers; Body Weight; Caloric Restriction; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lactones; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Orlistat; Tumor Necrosis Factor-alpha

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56+/-5, treated with telmisartan; and 45 males and 48 females, aged 55+/-4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-alpha (TNF-alpha), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbAlc and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-alpha and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid contr

Topics: Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Biphenyl Compounds; Blood Glucose; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Irbesartan; Leptin; Lipids; Male; Middle Aged; Rosiglitazone; Telmisartan; Tetrazoles; Thiazolidinediones; Tumor Necrosis Factor-alpha

Weight gain during treatment with psychotropic drugs is frequently observed and is assumed to be responsible for non-compliance and for an elevated risk to develop a number of somatic co-morbidities including cardiovascular disorders and type 2 diabetes. Absence of weight inducing effects is therefore a major objective for the development of new compounds. Recently, R121919, the first corticotropin releasing hormone receptor 1 (CRH1R) antagonist, was tested in major depression. Clinical efficacy, safety, and tolerability of this compound could be demonstrated. Since CRH is discussed to be involved in the regulation of appetite and weight, directly and via interaction with leptin, CRH1R antagonists are suspected to influence body weight. Effects of 30 days of treatment with the CRH1R antagonist R121919 on weight and leptin levels in 20 patients suffering from major depression were investigated. No significant weight changes during treatment with R121919 were observed. Furthermore, noeffects on plasma leptin concentrations were found. We conclude that treatment with the CRH1R antagonist R121919 does not affect weight or plasma leptin concentrations in patients with major depression. Together with previous findings indicating safety, tolerability, and clinical efficacy CRH1R antagonists are highly promising as a new treatment option in depression.

Topics: Adult; Depressive Disorder, Major; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Pyrimidines; Receptors, Corticotropin-Releasing Hormone; Receptors, Leptin; Risk Factors; Weight Gain

Topics: Adiponectin; Anti-Inflammatory Agents, Non-Steroidal; Atorvastatin; C-Reactive Protein; Cytokines; Diabetes Mellitus, Type 2; Female; Heptanoic Acids; Hormones, Ectopic; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Placebos; Pyrroles; Resistin

The role of resistin in human biology remains uncertain. We measured serum resistin levels in Japanese patients with (n=111) and without (n=98) type 2 diabetes mellitus and investigated the significance of this hormone in the pathophysiology of diabetes. The levels of serum adiponectin and leptin were also measured. Resistin levels were increased significantly in patients with type 2 diabetes compared with non-diabetic subjects (24.7+/-2.6 vs. 15.0+/-1.2 ng/ml, p=0.0013). However, there was no correlation in either patient group between serum resistin levels and markers of insulin resistance, obesity or hyperlipidaemia. These results were in direct contrast to the data of leptin or adiponectin, both of which were closely related to these clinical markers of diabetes. Multivariate regression analysis on the combined data of the two groups demonstrated that the presence of diabetes and HDL cholesterol levels were significant predictors of serum resistin levels (diabetes: beta=0.159, p=0.035; HDL: beta=-0.172, p=0.039). No correlation was observed between C-reactive protein and resistin adjusted for BMI. Taken together, these findings demonstrate that serum resistin levels are increased in patients with type 2 diabetes, but this increase is not linked to markers of insulin resistance or adiposity. Further studies are necessary to elucidate the significance of serum resistin concentration in human pathophysiology.

Topics: Adiponectin; Aged; Biomarkers; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Patient Selection; Reference Values; Resistin

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.9 +/- 0.6%; BMI, 31.9 +/- 1.5 kg/m(2)). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-(3)H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 +/- 0.1 vs. P- = 1.7 +/- 0.3 mg. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). min(-1); P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.

Topics: Adiponectin; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Drug Synergism; Female; Gene Expression; Humans; Hypoglycemic Agents; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Muscle, Skeletal; Pioglitazone; Proteins; Thiazolidinediones

Leptin plays an important role in the regulation of body weight and is known to circulate in both free and bound forms. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. Clinical studies have shown that soluble leptin receptor (sOB-R) levels are lower in obese individuals. In the present study, we measured the serum sOB-R level in 419 healthy Japanese subjects (198 men and 221 women, aged 30 to 65 years, body mass index [BMI] 21.7 +/- 2.6 [SD] kg/m2) and in 150 type 2 diabetic patients (96 men and 54 women, BMI 24.3 +/- 3.8 kg/m2). We investigated the relationships between serum sOB-R level and BMI, blood pressure, homeostasis model assessment-insulin resistance index (HOMA-IR), serum leptin and adiponectin levels, lipid profile, and leptin receptor (LEPR) gene Lys109Arg and Gln223Arg polymorphisms. Serum leptin and sOB-R levels were measured by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum sOB-R level in men was significantly higher than that in women. The serum sOB-R level was negatively correlated with BMI, fasting insulin, HOMA-IR, and serum leptin level and positively correlated with high-density lipoprotein (HDL)-cholesterol and serum adiponectin levels. The correlations between serum sOB-R level and fasting insulin, HOMA-IR, serum leptin, adiponectin, and HDL-cholesterol levels were significant even after adjustment for age, sex, and BMI in healthy subjects. There was no association between serum sOB-R level and the LEPR polymorphisms examined. These findings suggest that the serum sOB-R level is negatively correlated with HOMA-IR and serum leptin level and positively correlated with HDL-cholesterol level and serum adiponectin level, independent of age, sex, and BMI, in the Japanese population.

Topics: Adiponectin; Adult; Aged; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; DNA Probes; Enzyme-Linked Immunosorbent Assay; Female; Homeostasis; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Japan; Leptin; Lipids; Male; Middle Aged; Polymorphism, Genetic; Population; Proteins; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction

We examined the effect of pioglitazone (PIO) on circulating adipocytokine levels to elucidate the mechanisms by which thiazolidinediones improve insulin resistance in type 2 diabetes mellitus (T2DM). Twenty-three subjects with T2DM (age 54 +/- 2 yr, body mass index 29 +/- 1 kg/m(2)) were randomly assigned to receive placebo (n = 11) or PIO, 45 mg/d (n = 12), for 4 months. Before and after treatment, subjects received a 75-g oral glucose tolerance test (OGTT); euglycemic insulin clamp (40 mU/m(2).min) with 3-(3)H-glucose; determination of fat mass ((3)H(2)O); and measurement of fasting glucose, free fatty acids (FFAs), leptin, adiponectin, and TNFalpha concentrations. After 4 months of PIO, fasting plasma glucose concentration (Delta = -2.7 mol/liter), mean plasma glucose during OGTT (Delta = -3.8 mol/liter), and hemoglobin A(1c) (Delta = 1.7%) decreased (P < 0.05 vs. placebo) without change in fasting or post-OGTT plasma insulin levels. Fasting FFAs (Delta = 168 micromol/liter) and TNFalpha (Delta = 0.7 pg/ml) concentrations decreased (P < 0.05 vs. placebo), whereas adiponectin (Delta = 8.7 microg/ml) increased (P < 0.01 vs. placebo). Despite the increase in body fat mass (Delta = 3.4 kg) after PIO, plasma leptin concentration did not change significantly. No changes in plasma glucose, FFAs, or adipocytokine levels were observed in placebo-treated subjects. During the insulin clamp, endogenous (hepatic) glucose production decreased (Delta = -2.67 micromol/fat-free mass.min, P < 0.05 vs. placebo), whereas metabolic clearance rate of glucose (MCR) increased (Delta = 0.58 ml/fat-free mass.min, P < 0.05 vs. placebo) after PIO. In all subjects, before and after PIO, the decrease in plasma FFA concentration was correlated with the changes in both endogenous (hepatic) glucose production (r = 0.47, P < 0.05) and MCR (r = -0.41, P < 0.05), whereas the increase in plasma adiponectin concentration was correlated with the change in endogenous (hepatic) glucose production (r = -0.70, P < 0.01) and MCR (r = 0.49, P < 0.05). These results suggest that the direct effects of PIO on adipose tissue to decrease plasma FFA levels and increase plasma adiponectin contribute to the improvements in hepatic and peripheral insulin sensitivity and glucose tolerance in patients with T2DM.

Topics: Adiponectin; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Clearance Rate; Middle Aged; Pioglitazone; Proteins; Sex Factors; Thiazolidinediones; Tumor Necrosis Factor-alpha

The metabolic and hormonal impact of rapid dietary changes in type 2 diabetes has not been clarified. The objective of this study was to test whether a short-term, low-fat diet affected metabolic control, insulin sensitivity, lipids and adipocyte hormones in patients with type 2 diabetes with hypertriacylglycerolaemia. Nineteen outpatient subjects (10 M, 9 F) with type 2 diabetes and triacylglycerols >2.2 mmol/L at screening were included in the study. Dietary intake was assessed by weighing during two periods of 3-day baseline diet followed by a 3-day low-fat dietary intervention. The two periods of baseline diet did not differ with respect to relevant variables during intervention. Subjects were advised to increase fibre-rich and low-fat foods and to decrease intake of visible fat in an isoenergetic manner. The percentage of energy from fat was reduced from 39 to 22 (p < 0.0001), median values. Daytime blood glucose did not change and fasting insulin and fasting glucose to insulin ratios were unaffected. Total cholesterol decreased from 6.3 to 6.2 mmol/L (p < 0.005), high-density lipoprotein cholesterol from 1.13 to 1.10 mmol/L (p < 0.048) and the ratio of n-6 to n-3 fatty acids in phospholipids from 2.5 to 1.9 (p < 0.003). Concentrations of leptin decreased from 12.1 to 9.9 ng/mL (p < 0.005) and adiponectin increased from 8.6 to 10.5 microg/mL (p < 0.024). The effect on leptin was confined to women. A low-fat diet intervention for 3 days in insulin-resistant type 2 diabetes affects lipid, adiponectin and leptin levels but fails to improve insulin sensitivity and metabolic control.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Female; Humans; Hypertriglyceridemia; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Male; Middle Aged; Norway

The metabolic effects of a biguanide, metformin, on glycemic control and eating behavior were investigated in 16 type 2 diabetic subjects with mental retardation who were habitual overeaters and had difficulty in controlling their appetites. The subjects (n = 16) received metformin (750 mg/day) for 6 months and body weight, body mass index (BMI) were measured monthly. They had repetitive metabolic and hormonal studies. Their eating behavior was analyzed by questionnaires given by their guardians before and after treatment. Metformin treatment significantly reduced their body weights (p < 0.01), body mass index (BMI) (p < 0.01), the levels of HbA1c (p < 0.001), fasting blood glucose (FBG) (p < 0.05), serum insulin (p < 0.05), C-peptide (p < 0.01), triglyceride (p < 0.01), and total cholesterol (p < 0.05). Insulin resistance index (FBG (mg/dl) x serum insulin levels ( micro U/ml) x 1/405) was significantly reduced after 1-month treatment. The serum leptin levels were significantly decreased after 4 month's treatment and thereafter (p < 0.05). Analysis of the questionnaires before and after treatment showed that the daily intake of regular and additional foods significantly decreased after treatment (p < 0.01 and p < 0.001, respectively) with improvements of eating behavior. We conclude that metformin may have beneficial effects not only to control glycemia but also to correct eating behavior in obese type 2 diabetic patients with the difficulty in controlling their appetites. The improvement was related to the reduction of insulin resistance and serum leptin levels.

Topics: Adult; Blood Glucose; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 2; Energy Intake; Feeding Behavior; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Intellectual Disability; Leptin; Male; Metformin; Obesity; Surveys and Questionnaires; Treatment Outcome; Triglycerides

To learn more about the factors that regulate adipokines in diabetes, we examined fasting plasma concentrations of adiponectin and C-reactive protein (CRP) in well-characterized groups of age-matched individuals classified as: (1) type 2 diabetes; (2) impaired fasting glucose or mild diabetes (IFG/mild DM); (3) obese, matched for body mass index (BMI); and (4) non-obese. Diabetic subjects were also studied on no phamacologic treatment, after 3 months randomization to metformin or glyburide, and after 3 months crossover to the opposite drug. CRP decreased and adiponectin increased progressively between subjects in groups 1 through 4. CRP was significantly associated with percent (r = 0.45) and total (r = 0.50) fat, insulin sensitivity as S(I) (r = -0.39) or homeostasis model assessment of insulin resistance [HOMA (IR)] (r = -0.36), and hemoglobin A(1c) (HbA(1c)) (r = 0.41). The relationship of CRP to percent fat appeared to be logarithmic and log CRP varied with percent fat independent of gender. Adiponectin concentration was significantly associated with insulin sensitivity as S(I) (r = 0.55) or HOMA (IR) (r = -0.46). Adiponectin concentrations were higher among women overall (all groups included) but not in women classified as type 2 diabetes. Although mean adiponectin was higher in subjects classified as non-obese compared to obese, adiponectin, in sharp contrast to leptin (previously reported data) and to CRP, varied markedly when expressed as a function of adiposity. Multiple regression models confirmed the strong relationship of adiponectin to insulin sensitivity, as well as the relationships of CRP to adiposity and insulin sensitivity. Glyburide treatment of diabetes decreased CRP and did so even though body weight increased. We conclude that both CRP and adiponectin correlate strongly to S(I). CRP, in contrast to adiponectin, is far more dependent on adiposity. The relationship between CRP (like leptin) and gender depends on how CRP is expressed relative to adiposity. Our data raise the possibility that gender differences in adiponectin may be lost in diabetes. Finally, pharmacologic treatment of diabetes may modulate CRP independent of adiposity.

Topics: Adiponectin; Blood Glucose; Body Composition; C-Reactive Protein; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Linear Models; Lipids; Male; Metformin; Middle Aged; Obesity; Sex Factors

Isomers of conjugated linoleic acid (CLA) are found in beef, lamb and dairy products. Diets containing CLA reduce adipose mass in various depots of experimental animals. In addition, CLA delays the onset of diabetes in the ZDF rat model for obesity-linked type 2 diabetes mellitus. We hypothesize that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes mellitus. In this double-blind study, subjects with type 2 diabetes mellitus were randomized into one of two groups receiving either a supplement containing mixed CLA isomers (CLA-mix; 8.0 g daily, 76% pure CLA; n = 12) or a supplement containing safflower oil (placebo; 8.0 g daily safflower oil, n = 9) for 8 wk. The isomers of CLA in the CLA-mix supplement were primarily c9t11-CLA ( approximately 37%) and t10c12-CLA ( approximately 39%) in free fatty acid form. Plasma levels of CLA were inversely associated with body weight (P < 0.05) and serum leptin levels (P < 0.05). When levels of plasma t10c12-CLA isomer were correlated with changes in body weight or serum leptin, t10c12-CLA, but not c9t11-CLA, was inversely associated with body weights (P < 0.05) and serum leptin (P < 0.02). These findings strongly suggest that the t10c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in subjects with type 2 diabetes. Future studies are needed to determine a causal relationship, if any, of t10c12-CLA or c9t11-CLA to modulate body weight and composition in subjects with type 2 diabetes. Furthermore, determining the ability of CLA isomers to influence glucose and lipid metabolism as well as markers of insulin sensitivity is imperative to understanding the role of CLA to aid in the management of type 2 diabetes and other related conditions of insulin resistance.

Topics: Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Humans; Leptin; Linoleic Acid; Obesity; Randomized Controlled Trials as Topic

Pioglitazone is considered to reduce insulin resistance. This study was conducted to evaluate the efficacy, safety and clinical profile of pioglitazone in patients whose type 2 diabetes were poorly controlled with alpha-glucosidase inhibitor alone or alpha-glucosidase in combination with sulfonylurea.. Twenty patients with type 2 diabetes were treated with pioglitazone (30 mg q.d.) orally for 16 weeks.. There were significant reductions in HbA1C, FPG and postprandial plasma glucose at week 16. As adverse events, oedema, hypoglycaemia-like reaction, increases in LDH, CPK, etc. were noted. There was no significant change in TNF-alpha. Leptin levels increased significantly at week 16 and were still increasing 4 weeks after the treatment. Per cent body fat was almost constant throughout the study period. When efficacy was classified by demographic variables, pioglitazone was found to be more effective in the subjects who had a higher postprandial 2-h plasma glucose level, leptin level or per cent body fat value.. Pioglitazone was considered to be effective when used in patients whose type 2 diabetes were poorly controlled with alpha-glucosidase inhibitor alone or alpha-glucosidase in combination with sulfonylurea.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Pioglitazone; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Treatment Failure; Treatment Outcome

To better understand the relations among leptin, insulin, and body fat during the metabolic progression to diabetes and during drug monotherapy, metabolic parameters were examined in subjects classified as 1) type 2 diabetes; 2) impaired fasting glucose or mild diabetes mellitus; 3) nondiabetic, matched for body mass index (BMI); and 4) nonobese, nondiabetic. Diabetic subjects were also studied during no pharmacological treatment, after 3 months of randomization to metformin or glyburide, and after 3 months of cross-over to the opposite drug. Log leptin correlated more with percent body fat (slope, 0.042; confidence interval, 0.036-0.047; r(2) = 0.826; P < 0.0001) than with total fat mass, percent truncal or nontruncal fat, or BMI. When normalized to percent fat, leptin did not differ by gender. Leptin normalized to percent fat was 35% less in untreated diabetes than that in BMI-matched controls (P < 0.001). Leptin normalized to percent fat was increased by 25% (P < 0.01) as a result of glyburide therapy compared with pretreatment values, but was unchanged by therapy with metformin. Across a spectrum of subjects with diabetes, impaired fasting glucose/mild diabetes, or BMI-matched nondiabetic controls, normalized leptin significantly correlated with glucose-induced insulin release, but not with insulin sensitivity. Our data suggest that plasma leptin is reduced in untreated type 2 diabetes probably as a consequence of reduced insulin secretion and that circulating leptin concentrations are differentially affected by monodrug therapy.

Topics: Adipose Tissue; Body Composition; Body Mass Index; Cholesterol, HDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Leptin; Male; Metformin; Middle Aged

The thiazolidinedione (TZD) class of antidiabetic drugs has been shown to inhibit the formation of bone-resorbing osteoclasts in vitro and to decrease bone resorption markers in vivo. These drugs also inhibit the expression of leptin in adipocytes. Less leptin can be associated with higher bone mass, based on analyses of mice deficient in leptin action. Effects of 1-year treatment with troglitazone, a member of the TZDs, on bone mineral density (BMD) and bone metabolism were examined in 25 Japanese type 2 diabetic patients. Glucose metabolism was improved, whereas body mass index and percent body fat did not change throughout the study. The percent change of BMD was negatively correlated with that of serum leptin, whereas it was not associated with changes of bone metabolic markers, type I collagen N-telopeptide (NTx), bone alkaline phosphatase (ALP), body mass index, or HbA1c. Serum leptin decreased in 68% of subjects (responders) after 1-month treatment and was consistently lower than the basal level throughout the treatment. Percent changes of BMD were significantly higher in the responders than in the nonresponders and in nondiabetic subjects at 6 and 12 months. NTx and bone ALP decreased at 1 month but increased thereafter in either group of patients. Thus, it is suggested that the decrease in serum leptin with no reduction in body fat mass by troglitazone is associated with preventing bone loss in type 2 diabetic patients. Hence, TZDs may have an advantage for diabetic patients who have risk factors for osteoporosis.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Bone Density; Chromans; Collagen; Collagen Type I; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Leptin; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Peptides; Prospective Studies; Thiazolidinediones; Troglitazone

This study set out to define relationships between changes in plasma leptin and changes in body weight, plasma insulin and blood glucose control during a 12-month crossover study of once-daily Ultratard or twice-daily Insulatard insulin.. Fasting plasma leptin and insulin were measured during a multicentre cross-over study involving 60 subjects with type 2 diabetes (fasting glucose > 8 mM). After a 2-month run-in, there were two 6-month periods of treatment with Insulatard or Ultratard insulin.. Mean plasma leptin increased significantly in both groups after insulin therapy was instigated (12.8 +/- 8.1 to 22.9 +/- 13.1 ng/ml in the Insulatard group; 12.1 +/- 7.2 to 19.2 +/- 12.3 ng/ml in the Ultratard group). Weight also increased significantly in both groups (82.4 +/- 14.3 kg to 88.8 +/- 14.3 kg and 82.2 +/- 15.3 kg to 85.3 +/- 15.2 kg respectively). The increase in plasma leptin correlated well with the increase in weight (R = 0.416, p = 0.001), and this correlation continued after the crossover point. Plasma leptin correlated with BMI throughout the study (R = 0.540, p = 0.000).. The sustained rise in body weight despite a substantial increase in plasma leptin suggests that either resistance to the hypothalamic action of leptin develops when insulin therapy is begun in type 2 diabetes, or that resetting of the set point for body weight occurs such that a larger body mass is tolerated for a given level of plasma leptin.

Topics: Body Mass Index; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Insulin; Insulin, Isophane; Insulin, Long-Acting; Insulin, Regular, Human; Isophane Insulin, Human; Leptin; Male; Middle Aged

Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients.. A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n = 70) and the untreated control group (n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone.. The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA(1c) levels and increased plasma adiponectin concentrations relative to the control group (P < 0.01). It also significantly decreased CRP and PWV (P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing <1% of reduction in HbA(1c) (n = 30) and responders showing >1% of reduction (n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism.. This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect.

Topics: Adiponectin; Arteriosclerosis; Blood Pressure; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycolipids; Humans; Hyperglycemia; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Japan; Leptin; Male; Middle Aged; Pioglitazone; Proteins; Thiazolidinediones

Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting.. Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only DeltaAUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up.. We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.

Topics: Area Under Curve; Blood Glucose; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Disease; Coronary Restenosis; Diabetes Mellitus, Type 2; Endothelium, Vascular; Follow-Up Studies; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Nitric Oxide; Predictive Value of Tests; Regression Analysis; Stents; Vascular Patency

Resistin is a novel adipocyte-secreted hormone proposed to link obesity with diabetes. Studies in mice have revealed conflicting data however, and the physiological role of circulating resistin in humans remains unknown. We conducted cross-sectional studies in 123 middle-aged women and 120 healthy young subjects and found that serum resistin levels did not correlate with markers of adiposity, including body mass index, waist-to-hip ratio, or fat mass, or insulin resistance assessed by homeostasis model, lipid profile, or serum leptin levels; but females had higher resistin levels than males (P < 0.02). We also found no difference in serum resistin levels between lean healthy and obese insulin-resistant nondiabetic and type 2 diabetic adolescents. Finally, to evaluate the effect of food deprivation and/or leptin administration on resistin levels, we performed interventional studies that revealed no significant difference in resistin levels after 48 h of fasting and/or leptin administration at either physiological or pharmacological doses. We conclude that circulating resistin is unlikely to play a major role in insulin resistance or energy homeostasis in humans.

Topics: Adolescent; Adult; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Energy Intake; Fasting; Female; Homeostasis; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Resistin

We investigated the effect of an intensive training program on fasting leptin and adiponectin levels.. Sixteen middle-aged men with type 2 diabetes were randomly assigned to either a training or control group. The training program consisted of 8 weeks of supervised endurance exercise (75% VO(2peak), 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO(2peak) separated by 3 min exercises at 50% VO(2peak)) once a week, on an ergocycle.. Training decreased abdominal fat by 44%, increased mid-thigh muscle cross-sectional area by 24%, and improved insulin sensitivity by 58% without significant change in body weight. Compared with controls, no significant variation in leptin or adiponectin levels was observed. However, in the trained group, change in adiponectin correlated with change in body weight (Spearman rank correlation, r(s):-0.76, P=0.03) but not with insulin sensitivity or abdominal adiposity variations.. An 8 week intensive training program inducing a marked reduction in abdominal fat and increase in insulin sensitivity does not affect adiponectin and leptin levels in men with type 2 diabetes.

Topics: Abdomen; Adiponectin; Adipose Tissue; Adult; Diabetes Mellitus, Type 2; Exercise; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Physical Endurance; Proteins; Weight Loss

This study evaluated the efficacy of adding pioglitazone 30 mg to the therapy of patients with type 2 diabetes mellitus whose glycaemic control was poor on an alpha-glucosidase inhibitor (alpha-GI) alone or in combination with a sulphonylurea (SU). The patients (n = 20) had a HbA(1c) level between 7.0 and 12.0% and the fasting plasma glucose was 7.8 mmol/l or higher. They were treated with 30 mg pioglitazone once daily for 16 weeks. The decrease in HbA(1c) at week 16 of treatment was 0.8% (7.8% at baseline dropping to 7.1% at week 16; p < or = 0.01). An increase in leptin was observed 4 weeks after starting the post-study period (p < or = 0.05). Tumour necrosis factor-alpha (TNF-alpha) and body fat percentage did not show any significant alterations. Correlations between the decrease in HbA1c at week 16 and characteristic variables of patients were examined. A correlation with leptin (p = -0.5632, p < or = 0.05) levels was found. Five patients experienced adverse drug reactions, such as oedema, hypoglycaemia and increased creatine phosphokinase (CK), all of which were mild in severity. The addition of pioglitazone in diabetics whose glycaemic control was poor on a alpha-GI alone or with a alpha-GI and SU combination resulted in a significant decrease in HbA1c, and the treatment was well-tolerated. Our findings also suggest that leptin levels could be useful for assessing responders to pioglitazone.

Topics: Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Leptin; Male; Middle Aged; Pioglitazone; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; Tumor Necrosis Factor-alpha

Low-glycemic index diets are associated with a wide range of benefits when followed on a chronic basis. The chronic effects, however, of the substitution of 1 meal per day are not well known in diabetic subjects. Therefore, we aimed to evaluate whether the chronic use of a low-glycemic index breakfast (low-GIB) rich in low-GI carbohydrates and a modest amount of soluble fibers could have an effect on lipemia at a subsequent lunch, and improve glucose and lipid metabolism in men with type 2 diabetes. A total of 13 men with type 2 diabetes were randomly allocated in a double-blind cross-over design to a 4-week daily intake of a low-GI versus a high-GI breakfast separated by a 15-day washout interval. The low-GI breakfast was composed of whole grain bread and muesli containing 3 g beta-glucan from oats. Low-GIB induced lower postprandial plasma glucose peaks than the high-GIB at the beginning (baseline, P <.001) and after the 4-week intake (P <.001). The incremental area under the plasma glucose curve was also lower (P <.001, P <.01, baseline, and 4 weeks, respectively). There was no effect on fasting plasma glucose, insulin, fructosamine, or glycosylated hemoglobin (HbA(1c)). Fasting plasma cholesterol, as well as the incremental area under the cholesterol curve, were lower (P <.03, P <.02) after the 4-week low-GIB period than after the high-GIB period. Apolipoprotein B (apo B) was also decreased by the 4-week low-GIB. There was no effect of the low-GI breakfast on triacylglycerol excursions or glucose and insulin responses at the second meal. The high-GIB, however, tended to decrease the amount of mRNA of leptin in abdominal adipose tissue, but had no effect on peroxisome proliferator-activated receptor gamma (PPARgamma) and cholesterylester transfer protein (CETP) mRNA amounts. In conclusion, the intake of a low-GI breakfast containing a modest amount (3 g) of beta-glucan for 4 weeks allowed good glycemic control and induced low plasma cholesterol levels in men with type 2 diabetes. The decrease in plasma cholesterol associated with low-GI breakfast intake may reduce the risk of developing cardiovascular complications in subjects with type 2 diabetes.

Topics: Adipose Tissue; Adult; Aged; Apolipoproteins B; Blood Glucose; Carrier Proteins; Cholesterol; Cholesterol Ester Transfer Proteins; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fiber; Double-Blind Method; Fructosamine; Glucose; Glycated Hemoglobin; Glycoproteins; Humans; Insulin; Leptin; Lipid Metabolism; Male; Middle Aged; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Transcription Factors; Triglycerides

The prevalence of type 2 diabetes in American adolescents has increased markedly during the past generation. Although the factors that contribute to the development of type 2 diabetes are complex and not wholly elucidated, the triad of severe obesity, hyperinsulinemia, and a family history of type 2 diabetes places a child at an increased risk for development of the disease. Current approaches to the prevention of type 2 diabetes, including dietary counseling and exercise, have had limited success. We reasoned that drugs that increase glucose tolerance in diabetic patients might prove useful in preventing the progression to glucose intolerance in high-risk patients. To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index (BMI), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.. The study population consisted of 29 white and black adolescents aged 12 to 19 years. All had BMIs exceeding 30 kg/m(2). Criteria for enrollment included: 1) a fasting insulin concentration exceeding 15 microU/mL; and 2) at least 1 first- or second-degree relative with type 2 diabetes. All patients had fasting plasma glucose concentrations <110 mg% and hemoglobin A1c concentrations

Topics: Adolescent; Blood Glucose; Body Mass Index; Body Weight; Child; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Family; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Obesity; Pilot Projects

Troglitazone is effective in approximately 50% in patients with type 2 diabetes (NIDDM). In this study, we investigated the relations between serum leptin levels and clinical efficacy of troglitazone. Forty-five type 2 diabetic patients (23 men and 22 women) from our outpatient clinic were treated with troglitazone 400 mg daily for 12 weeks. Fasting plasma glucose (FPG), HbA1c, body weight, serum insulin and leptin concentrations were measured before and after troglitazone treatment. After 12 weeks of troglitazone treatment, FPG (before versus after, 179+/-33 vs. 138+/-26 mg/dl, mean+/-SD), HbA1c (7.8+/-1.3 vs. 6.9+/-1.0%), IRI (8.3+/-4.3 vs. 6.3+/-3.4 microU/ml) and HOMA-R index (homeostasis model assessment of insulin resistance) (3.8+/-2.4 vs. 2.2+/-1.3) decreased significantly, while body mass index (BMI) slightly increased (26.3+/-3.5 vs. 26.6+/- 3.6 kg/m(2)), and serum leptin remained unchanged (8.5+/-7.2 vs. 9.1+/-8.7 ng/ml). Reduction in FPG (DeltaFPG) after troglitazone treatment were correlated with reduction in HOMA-R (DeltaHOMA-R) (r=0.721, P<0.0001). DeltaFPG was correlated with serum leptin (r=0.441, P<0.01), HOMA-R (r=0.460, P<0.01) and FPG (r=-0.781, P<0.0001) at baseline, but not with BMI and serum IRI at baseline. Furthermore, serum leptin at baseline was significantly correlated with DeltaHOMA-R (r=0.634, P<0.01). Leptin concentration before treatment therefore, can be used as an predictor for clinical efficacy of troglitazone in patients with type 2 diabetes.

Topics: Biomarkers; Blood Glucose; Chromans; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Models, Biological; Predictive Value of Tests; Regression Analysis; Thiazoles; Thiazolidinediones; Time Factors; Troglitazone

Acylation-stimulating protein is an adipocyte-derived protein that has recently been suggested to play an important role in the regulation of triglyceride storage. To date, little information has been reported with regard to fasting acylation-stimulating protein levels and its relation to metabolic control, leptin, and/or lipids in subjects with diabetes mellitus. We therefore evaluated fasting acylation-stimulating protein, leptin, and lipid levels before and 4 months after improving glycemic control with sulfonylurea treatment in a group of poorly controlled obese women with type 2 diabetes and in age- and body mass index-matched nondiabetic obese women. Fasting plasma acylation-stimulating protein (49.67 +/- 19.73 vs. 48.49 +/- 20.70 nmol/liter) and leptin concentrations (33.7 +/- 23.2 vs. 26.2 +/- 10.6 ng/ml) were not significantly different between the groups. Improvement of glycemic control produced parallel falls in fasting blood glucose and hemoglobin A1c. Plasma leptin concentrations were also significantly reduced (33.69 +/- 23.2 vs. 22.73 +/- 11.26 ng/ml; P = 0.036), whereas fasting acylation-stimulating protein concentrations were significantly increased after treatment (48.49 +/- 20.70 vs. 72,82 +/- 29,72 nmol/liter; P = 0.004). Nevertheless, lipids and apolipoprotein B did not significantly improve. We could not find any correlation between elevated acylation-stimulating protein levels and changes in body mass index, glucose, insulin, hemoglobin A1c, leptin, or lipid levels. Similarly, the decrement in circulating leptin levels observed after treatment did not correlate with changes in the levels of glucose, insulin, hemoglobin A1c, or any lipid parameters. We conclude that improved glycemic control increases fasting acylation-stimulating protein and decreases leptin concentrations, but not corrects critical lipid abnormalities in type 2 obese diabetic subjects. Moreover, altered plasma acylation-stimulating protein levels are not associated with changes in body mass index or lipid, leptin, insulin, or glucose levels. Thus, our findings suggest that improved glycemic control or insulin resistance is not responsible for abnormal fatty acid trapping, and failure of lipids to improve after treatment in our patients is consistent with the acylation-stimulating protein resistance concept.

Topics: Apolipoprotein A-I; Apolipoproteins B; Biomarkers; Blood Glucose; Blood Pressure; Blood Proteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Complement C3a; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Middle Aged; Obesity; Sulfonylurea Compounds; Triglycerides

The role of leptin in human pathophysiology elicits considerable interest in view of its potential role as a treatment tool for obesity and other insulin resistant states, like type 2 diabetes mellitus (T2DM). Leptin has been extensively studied in obese humans, and much less so in other pathologic conditions. Leptin level has been reported to correlate with percent body fat mass (%FM), fasting serum insulin (FPI), insulin sensitivity and blood pressure. The aim of this study was to compare the leptin concentration, and its relationship with some anthropometric and biochemical parameters related to insulin resistance in 140 moderately obese type 2 diabetics (T2DM) and 160 age and weight matched non-diabetic controls in order to get a better insight into the possible role of leptin in the metabolic abnormalities of diabetes. The leptin levels were lower in the diabetic population only when both sexes were combined (p < 0.05) and were higher in the females of both groups. Among the nondiabetics, the leptin levels appeared to be related to BMI, %FM, HDL and FPI, while this was not the case in the diabetics. After correction for BMI, leptin appeared to be correlated with the FPI levels only in the non-diabetic females. When plasma leptin was included in a multiple linear regression model with plasma leptin as a dependent variable, BMI, W:Hr and FPI levels were significantly related to leptin in the non diabetic population, while no relationship reached the level of statistical significance among the diabetics, with the exception of the borderline value for the FPI (p = .052). In conclusion, leptin levels were independent of any of the parameters examined in our diabetic population, possibly due to the progressive loss of the normal mechanisms of leptin regulation with advancing disease. Conclusive data can only be obtained from the longitudinal study of a cohort of newly diagnosed diabetic subjects.

Topics: Aged; Body Composition; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Sex Characteristics

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, 16-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% +/- 1.6%, total cholesterol (TC) by 12% +/- 1.1%, plasma glucose (PG) from 151.3 +/- 3.5 to 128.6 +/- 3.4 mg/dL, and hemoglobin A1c (HbA1c) from 7.2% +/- 0.1% to 6.9% +/- 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% +/- 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-alpha) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be improved by bezafibrate treatment in DM2.

Topics: Bezafibrate; Blood Glucose; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypolipidemic Agents; Leptin; Male; Middle Aged; Triglycerides; Tumor Necrosis Factor-alpha

Leptin levels have been shown previously to be associated with anthropometric parameters such as the body mass index (BMI), total body fat, and subcutaneous fat. Since apolipoprotein E (apoE) polymorphism is known to be a genetic marker affecting the relationship between certain anthropometric and metabolic parameters, we evaluated whether the leptin level and/or associations between the leptin level and body composition in non-insulin-dependent diabetic patients could be determined by apoE polymorphism. In 171 type 2 diabetic patients (105 male and 66 female), body composition (BMI, waist to hip ratio [WHR], fat mass, and visceral fat) was measured and fasting blood samples were obtained to determine the apoE genotype, leptin, glucose, and insulin levels, and the lipid profile. The mean leptin level for the whole group was 11.7 +/- 9.3 ng/mL, with a significant difference (P < .001) between men (7.1 +/- 4.9 ng/mL) and women (19.0 +/- 10.1 ng/mL). No difference was found for leptin levels or anthropometric variables between the 3 different apoE genotypes (E3/E3 homozygotes, E2 carriers, and E4 carriers). Only low-density lipoprotein (LDL) cholesterol was significantly different between the 3 apoE subgroups. The correlations of leptin with anthropometric variables, especially visceral fat, tended to be different between the 3 apoE groups, but this was not independent and no effect was found after controlling for the other parameters in the model. A multiple regression model containing gender, subcutaneous fat, fasting glucose, triglycerides, and high-density lipoprotein (HDL) cholesterol explained 81% of the variance in leptin levels. We conclude that apoE polymorphism has no effect on the leptin level or its associations with other anthropometric and metabolic parameters.

Topics: Apolipoproteins E; Body Composition; Body Mass Index; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Leptin; Lipid Metabolism; Lipids; Male; Middle Aged; Polymorphism, Genetic; Regression Analysis

The aim of this study was to investigate the potential role of adipose cytokines in the obesity-associated insulin resistance. To that end, we compared: 1) serum concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), and leptin in eight healthy lean control females and in android obese female without (n = 14) and with (n = 7) type 2 diabetes; and 2) the levels of these cytokines both in serum and in sc adipose tissue in the 14 obese nondiabetic women before and after 3 weeks of a very low-calorie diet (VLCD). As compared with lean controls, obese nondiabetic and diabetic patients were more insulin resistant and presented increased values for leptin, IL-6, TNFalpha, and C-reactive protein. In the whole group, IL-6 values were more closely related to the parameters evaluating insulin resistance than leptin or TNFalpha values. VLCD resulted in weight loss and decreased body fat mass (approximately 3 kg). Insulin sensitivity was improved with no significant change in both serum and adipose tissue TNFalpha levels. In contrast, VLCD induced significant decreases in IL-6 and leptin levels in both adipose tissue and serum. These results suggest that, as for leptin, circulating IL-6 concentrations reflect, at least in part, adipose tissue production. The reduced production and serum concentrations after weight loss could play a role in the improved sensitivity to insulin observed in these patients.

Topics: Adipose Tissue; Adult; Aged; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Humans; Interleukin-6; Leptin; Middle Aged; Obesity; Tumor Necrosis Factor-alpha; Weight Loss

The effect of 3 days of intensive treatment with acipimox, an antilipolytic nicotinic acid derivative, on plasma leptin levels was studied in eight patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, cross-over study. Acipimox reduced plasma free fatty acids (FFA) markedly and lowered plasma triglycerides, glucose and insulin. Plasma leptin levels were elevated in all eight patients during 3 days of acipimox treatment (mean increase+/-s.e.: 2.38+/-0.57ng/ml, P<0.005) and the 24h mean effect of acipimox on leptin levels increased during the experimental period (P<0.03). The effect on plasma insulin and glucose resembled a mirror image of the effect on plasma leptin during 3 days of treatment. The suggestion that leptin mediates insulin resistance and may be involved in the development of the diabetic syndrome cannot be supported by the present results. It has been reported that FFA stimulates leptin secretion. Surprisingly, despite a markedly reduced FFA level, leptin concentration increased in the present study. We suggest that a primary acipimox effect is to increase leptin secretion, and that this prevails over the reduced FFA stimulus.

Topics: Area Under Curve; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Female; Humans; Hypolipidemic Agents; Insulin; Leptin; Male; Middle Aged; Niacin; Pyrazines; Triglycerides

To identify variables associated with leptin change in subjects with type 2 diabetes after 3 weeks and 20 weeks of weight loss.. Subjects with type 2 diabetes treated with diet or sulfonylureas (n = 54) were enrolled in a 20-week behavioral weight control program. Sulfonylureas were stopped > or =2 weeks before study entry. Seven subjects who restarted sulfonylureas after week 3 had their data analyzed separately after this point.. Leptin, fasting plasma glucose, and insulin levels were measured at baseline and at 3, 10, and 20 weeks. After 3 weeks, subjects lost 2.7+/-2.0 kg (p<0.001), and had significant decreases in leptin (5.2+/-7.0 ng/mL, p<0.001), fasting plasma glucose (1.8+/-1.8 mmol/L, p<0.001), and insulin (23+/-60 pmol/L, p<0.03). Between week 3 and week 20, subjects lost an additional 6.3+/-4.4 kg (p<0.001), but had no further changes in leptin. The primary determinants of leptin change at all time-points were weight loss and initial leptin level. Changes in insulin were not related to changes in leptin after controlling for the effects of weight loss. At week 20, more recent weight loss (week 10 to week 20) was as strong a predictor of overall change in leptin as overall weight loss (baseline to 20 week). Subjects who restarted sulfonylureas had an increase in both leptin levels (+1.9+/-9.0 ng/mL, p<0.05) and insulin levels (+23+/-65 pmol/L, p<0.05), despite significant overall weight loss (-7.4+/-4.0 kg, p<0.01). Initial changes in leptin (0 weeks to 3 weeks) did not affect subsequent ability to lose weight.. Both short- and long-term changes in weight had an effect on leptin changes in individuals with type 2 diabetes. Although physiological insulin changes did not independently influence changes in leptin concentration with weight loss, increases in insulin levels with sulfonylurea therapy were associated with increases in leptin levels despite weight loss.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diet, Reducing; Energy Intake; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Proteins; Sex Characteristics; Sulfonylurea Compounds; Weight Loss

The aim of the study was to examine the effects of weight reduction by exercise and diet on metabolic control in obese subjects with insulin resistance, particularly investigating if changes in serum leptin concentrations were directly associated with improvements in metabolic control. Twenty obese men (48 +/- 8 yr; body mass index 32. 1 +/- 3.9 kg/m(2)) with previously diagnosed type II diabetes mellitus were assigned to a 4-wk intervention program of exercise (2, 200 kcal/wk) and diet (1,000 kcal/day; 50% carbohydrates, 25% protein, 25% fat; polyunsaturated-to-saturated fatty acid ratio 1.0). Intervention induced significant reductions in body weight and serum leptin levels, and improvements in lipoprotein profile and glucose control. Reductions in leptin levels were directly associated with reductions in serum triglycerides and cholesterol, a finding that was independent of improvements in glucose control. These data show that serum leptin concentrations can be reduced with caloric restriction and exercise in male patients with type II diabetes, and they suggest a direct relationship between leptin and lipoprotein metabolism that is not solely due to weight reduction.

Topics: Adult; Blood Glucose; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise Therapy; Humans; Leptin; Lipids; Lipoproteins; Longitudinal Studies; Male; Middle Aged; Obesity; Prospective Studies; Proteins; Triglycerides; Weight Loss

Topics: Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Syndrome

To investigate the effect of physical training on leptin levels in elderly, obese patients with type 2 diabetes mellitus.. Twenty men and 38 women with type 2 diabetes mellitus with a body mass index (BMI) of > 25 kg/m2 participated in a prospective randomized study. Patients were either on oral glucose lowering drugs (n = 39) or insulin therapy (n = 19). Physical training consisted of a guided, standardized, 6-week training programme performed in the hospital on a cyclo ergometer followed by a 6-week period of guided training at home and ended in a 12-week period of training at home without supervision. Clinical data and laboratory samples including fasting insulin and leptin levels and maximal aerobic capacity were assessed at the start of the study and at 6 and 26 weeks thereafter.. Physical training resulted in significantly positive changes in maximal aerobic capacity (VO2max) and maximum work load. No effects of physical training on serum leptin levels and insulin concentrations were detected. Leptin levels were strongly correlated with body mass index (r = 0.63), body fat content (r = 0.61), and fasting insulin concentrations (r = 0.38). Women had threefold higher leptin levels than men. No differences in leptin levels between patients on insulin therapy and patients on oral glucose lowering drugs were found.. No effect of physical training on leptin levels was detectable in elderly, obese type 2 diabetes mellitus patients.

Topics: Aged; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Obesity; Oxygen Consumption; Physical Education and Training; Prospective Studies; Sex Characteristics

Leptin, a hormone produced by adipose tissue, is potentially involved in the regulation of adiposity. The effects of insulin and body fat distribution on human plasma leptin have not yet been clearly defined. The present study investigated the relationships between plasma leptin and total and regional body fat parameters measured by anthropometry and bienergetic absorptiometry associated or not with computed tomography, taking glucose metabolism into account. A cohort of 51 obese Caucasian women (23 with normal glucose tolerance, 11 with impaired glucose tolerance, and 17 with Type 2 diabetes) was analysed. All non-diabetic subjects had an oral glucose tolerance test together with plasma glucose and insulin measurements. Moreover, a subgroup of 7 diabetic subjects with failure to oral antidiabetic treatment was submitted to about 12 days of intensive subcutaneous insulin therapy. Plasma leptin was essentially dependent on total body fat mass (r = 0.83, p < 0.0001, for the whole population), but not related to adipose tissue distribution. An independent correlation between leptin adjusted on body fat mass and fasting insulinaemia (R = 0.72, p < 0.02) or C-peptide (R = 0.62, p < 0.03) was found significant only in the diabetic group. Insulin treatment was associated with a moderate and transient increase of plasma leptin. The relative variations of plasma leptin levels were strongly negatively correlated with those of free fatty acids. The present data confirm that plasma leptin is not dependent on body fat distribution and suggest an indirect effect of insulin on leptin secretion in clinical conditions.

Topics: Adipose Tissue; Adult; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Leptin; Linear Models; Middle Aged; Obesity; Proteins; White People

Troglitazone, which improves peripheral insulin resistance of experimental diabetic animals and diabetic patients, affects ob gene expression in the adipose tissue of rodents. The present study was undertaken to examine a hypothesis that clinical administration of troglitazone may reduce circulating leptin levels and affect eating behavior in NIDDM patients.. Troglitazone was administered at a dosage of 200 mg twice daily for 12 weeks in 20 poorly controlled NIDDM patients. Chronological changes in glycemic control, serum lipids, immunoreactive leptin (IRL) levels, and BMI were measured. Body fat weight was also assessed by bioelectric impedance.. Troglitazone significantly decreased fasting plasma glucose, serum immunoreactive insulin, and HbA1c levels. Serum levels of IRL and triglyceride were significantly reduced by troglitazone administered for 4, 8, and 12 weeks. Troglitazone administration significantly increased the BMI in NIDDM patients, and two-thirds of the patients complained of increased hunger after the start of troglitazone administration.. Troglitazone significantly reduces circulating leptin levels at clinical doses. It may affect the eating behavior of poorly controlled NIDDM patients through the improvement of glycemic control and/or the reduction of circulating leptin.

Topics: Blood Glucose; Body Mass Index; Chromans; Diabetes Mellitus, Type 2; Energy Intake; Feeding Behavior; Glycated Hemoglobin; Humans; Hunger; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Leptin; Lipids; Middle Aged; Proteins; Thiazoles; Thiazolidinediones; Troglitazone

Leptin, the product of ob gene is secreted by adipose tissue. It is believed that leptin plays an important role in energy balance. The secretion of leptin by adipose tissue is influenced by insulin. The aim of the present study was the estimation of plasma leptin concentrations in patients with type 2 diabetes mellitus. The study was carried out in 21 diabetic obese patients (BMI > 27.5), 8 diabetic patients with BMI < 27.5, 24 obese patients with normal glucose tolerance (BMI > 27.5) and 10 patients from the control group (BMI < 27.5). The mean leptin concentration in obese diabetic patients was 22.5 + 6.5 ng/ml and was not significantly different from that in obese patients without diabetes (24.1 + 10.3 ng/ml) but differed markedly in comparison to the normal weight diabetic patients (7.9 + 4.3 ng/ml, p < 0.01). Plasma leptin concentration correlated significantly and positively with BMI and fasting insulin in all studied groups. There was no significant correlation between leptin and glycated hemoglobin, total cholesterol and triglycerides. We conclude that serum leptin concentrations in patients with type 2 diabetes depends mainly on the amount of body fat.

Topics: Adipose Tissue; Adult; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 2; Energy Metabolism; Hemoglobins; Humans; Leptin; Middle Aged; Obesity; Proteins; Triglycerides

The aim of this study was to determine whether serum leptin concentrations are reduced in response to short-term energy restriction in centrally obese individuals with impaired glucose tolerance or non-insulin-dependent diabetes mellitus. Twenty African Americans [16 females and 4 males, 44 +/- 7 y (x +/- SD), 107.2 +/- 23.8 kg, 39 +/- 7% body fat] consumed a 7-d energy-restricted diet (4.03 +/- 0.72 MJ/d) of whole foods. Oral-glucose-tolerance tests (OGTTs) were performed before and immediately after the diet to assess changes in serum leptin, glucose, and insulin concentrations. Baseline leptin concentration correlated significantly with percentage body fat (r = 0.80), body mass index (r = 0.72), fat mass (4 = 0.64), waist-height ratio (r = 0.6), body weight (r = 0.59, all P < 0.01), waist circumference (r = 0.49), and basal insulin concentration (r = 0.48, both P < 0.05). Seven days of energy restriction resulted in significant reductions (P < 0.005) in leptin (-6.1 +/- 8.4 micrograms/L), basal glucose (-0.9 +/- 0.8 mmol/L), OGTT glucose area under the curve (-158 +/- 164 mmol/L), and basal insulin concentration (-34 +/- 69 pmol/L, P < 0.05). In addition, there was a trend for a reduction in OGTT insulin area under the curve (-15,567 +/- 3,658 pmol/L, P = 0.05), and a tendency for basal insulin and leptin to change together (r = 0.41, P = 0.07). Despite the weight loss of 3.1 +/- 1.3 kg (P < 0.0001), the loss of fat mass was calculated to be only -1.0 +/- 0.1 kg. These results suggest that negative energy balance or improved insulin action was responsible for the changes in leptin, glucose, and insulin concentrations. In summary, short-term energy restriction effectively reduced serum leptin concentrations and improved glucose tolerance and insulin action in obese individuals with impaired or diabetic glucose tolerance.

Topics: Adult; Area Under Curve; Black People; Blood Glucose; Diabetes Mellitus, Type 2; Energy Intake; Female; Glucose Intolerance; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Proteins; Weight Loss

To hypothesize if glibenclamide, which increases insulin levels, also increases leptin concentrations.. Leptin is a hormone that regulates weight in mice. In obese humans, leptin concentrations are increased, suggesting resistance to the effects of this hormone. Although short-term infusion of insulin during the hyperinsulinemiceuglycemic clamp does not increase leptin concentration, the effect of oral antidiabetic agents on leptin concentration is unknown. Differing effects can be expected, since glibenclamide acts via stimulation of insulin secretion, whereas acarbose inhibits alpha-glucosidases of the small intestine and has no direct effect on insulin levels. We examined the effect of acarbose (n = 4), glibenclamide (n = 6), and placebo (n = 6) on insulin and leptin levels during 24-h periods before and after 16 weeks of therapy.. We observed a significant diurnal variation in leptin concentrations. This was inversely related to insulin levels during the 24-h follow-up with usual diet. Neither the placebo nor acarbose altered leptin concentrations. However, glibenclamide increased leptin concentrations parallel to insulin levels. There were only minor changes in body weight during the l6-week follow-up: decrease in the placebo group (change -0.5 kg/m2, P = 0.07) and acarbose (change -0.7 kg/m2, P = 0.046) and increase in the glibenclamide group (change 0.8 kg/m2, P = 0.27). However, individual subjects who gained weight had increases in their leptin concentrations. The diurnal variation in leptin concentrations was preserved after glibenclamide.. Glibenclamide increases circadian leptin and insulin concentrations, whereas acarbose does not. This observation may help to explain weight gain in subjects treated with glibenclamide and stable weight in those treated with acarbose in the long run.

Topics: Acarbose; Analysis of Variance; Circadian Rhythm; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Glyburide; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Proteins; Trisaccharides

Insulin is known to increase expression of the ob gene product leptin in adipose tissue of rodents. We determined whether insulin increases circulating leptin concentrations in humans, and whether this effect might be altered in patients with noninsulin-dependent diabetes mellitus (NIDDM). Plasma leptin concentrations were determined during an 8.5-h hyperinsulinaemic clamp (serum free insulin approximately 480 pmol/l) and during an 8.5-h infusion of physiological NaCl solution (saline) in eight normal subjects (age 51 +/- 3 years, BMI 26.3 +/- 0.6 kg/m2, fasting plasma glucose 5.6 +/- 0.2 mmol/l) and seven patients with NIDDM (age 54 +/- 2 years, 27.0 +/- 0.9 kg/m2, 11.1 +/- 0.8 mmol/l). Fasting serum insulin level correlated with plasma leptin (r = 0.72, p < 0.005), even after adjusting for the percentage of body fat (p < 0.005). During the insulin infusion, a significant increase in the plasma leptin concentration was observed after 6 h (37 +/- 14%; 5.2 +/- 0.8. vs 3.9 +/- 0.6 ng/ml, 6 vs 0 h, p < 0.05) in the normal subjects and after 8.5 h (38 +/- 11%; 7.1 +/- 1.0 vs 5.5 +/- 0.9 ng/ml, 8.5 vs 0 h, p < 0.05) in the patients with NIDDM. During the saline infusion, plasma leptin concentrations decreased significantly in the normal subjects by 11 +/- 1% (p < 0.005) and in the patients with NIDDM by 14 +/- 1% (p < 0.01) after 2 h. During the infusion of insulin as compared to saline, plasma leptin concentrations were 32 +/- 13 (p < 0.05), 53 +/- 14 (p < 0.001), 106 +/- 15 (p < 0.001) and 165 +/- 21 (p < 0.001) % higher at 2, 4, 6 and 8.5 h in the normal subjects, and 11 +/- 9 (p < 0.05), 27 +/- 10 (p < 0.05), 58 +/- 7 (p < 0.001) and 106 +/- 13 (p < 0.001) % higher in the patients with NIDDM, respectively. No differences were observed in plasma leptin concentrations between the normal subjects and patients with NIDDM, under any conditions. We conclude that prolonged exposure to insulin increases plasma leptin concentrations in humans implying a role for insulin in chronic but not acute regulation of plasma leptin concentrations. The decrease in plasma leptin concentrations during saline infusion was greater than that expected on the basis of change in serum insulin concentrations, suggesting that factors other than insulin also contribute to regulation of plasma leptin concentrations.

Topics: Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Leptin; Male; Middle Aged; Patient Compliance; Protein Biosynthesis; Proteins; Reference Values

In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH.. Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs.. LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Hepatic Stellate Cells; Humans; Leptin; Lipocalin-2; Liver; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Obesity

Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown.. This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity.. We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization.. In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] -0.19 [-0.21 to -0.17]), body fat (-0.12 [-0.14 to -0.10), and fasting C-peptide (-2.04 [-2.46 to -1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (-0.5 [-0.7 to -0.4] and -0.5 [-0.6 to -0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, -1.72 [-2.86 to -0.58], and -0.20 [-0.36 to -0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R.. BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.

Topics: Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Receptors, Leptin

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug - also known as Snai2 - recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell-specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron-specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.

Topics: Animals; Diabetes Mellitus, Type 2; Hypothalamus; Leptin; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Leptin; Snail Family Transcription Factors; STAT3 Transcription Factor

Obesity is a major public health problem worldwide, and it is associated with many diseases and abnormalities, most importantly, type 2 diabetes. The visceral adipose tissue produces an immense variety of adipokines. Leptin is the first identified adipokine which plays a crucial role in the regulation of food intake and metabolism. Sodium glucose co-transport 2 inhibitors are potent antihyperglycemic drugs with various beneficial systemic effects. We aimed to investigate the metabolic state and leptin level among patients with obesity and type 2 diabetes mellitus, and the effect of empagliflozin upon these parameters. We recruited 102 patients into our clinical study, then we performed anthropometric, laboratory, and immunoassay tests. Body mass index, body fat, visceral fat, urea nitrogen, creatinine, and leptin levels were significantly lower in the empagliflozin treated group when compared to obese and diabetic patients receiving conventional antidiabetic treatments. Interestingly, leptin was increased not only among obese patients but in type 2 diabetic patients as well. Body mass index, body fat, and visceral fat percentages were lower, and renal function was preserved in patients receiving empagliflozin treatment. In addition to the known beneficial effects of empagliflozin regarding the cardio-metabolic and renal systems, it may also influence leptin resistance.

Topics: Adipokines; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Leptin; Obesity; Sodium-Glucose Transporter 2 Inhibitors

The goal was to investigate the correlations of peripheral blood Omentin-1 and leptin (LEP) levels with bone metabolism and plasma glucose in patients with type 2 diabetes mellitus (T2DM) complicated with oste-oporosis (OP).. One hundred patients with T2DM admitted from September 2019 to September 2021 were divided into group A (n = 36, OP with T-score ≤ -2.5), group B (n = 50, osteopenia with T-score between -1 and -2.5), and group C (n = 14, non-OP with T-score > -1) according to the values of bone mineral density (BMD). Thirty healthy adults physically examined in the same period were selected as group D. The levels of peripheral blood Omentin-1 and LEP, bone metabolism, and plasma glucose were compared among the four groups. The correlations of peripheral blood Omentin-1 and LEP levels with bone metabolism and plasma glucose were explored by Pearson's analysis.. In group A, the levels of Omentin-1 and LEP in peripheral blood were lowest, the serum levels of beta C-terminal cross-linked telopeptides of type I collagen (β-CTX) and osteocalcin (OCN) were highest, the serum level of total N-terminal propeptide of type I procollagen (tPINP) was lowest, and the levels of fasting plasma glucose (FPG), 2-hours postprandial plasma glucose (2hPG) and glycosylated hemoglobin A1c (HbA1c) were highest, se-quentially followed by those of group B, group C, and group D (p < 0.05). Omentin-1 and LEP in peripheral blood were negatively correlated with β-CTX, OCN, 2hPG, and HbA1c and positively correlated with tPINP and FPG (p < 0.05).. The expressions of Omentin-1 and LEP in peripheral blood have correlations with bone metabolism and plasma glucose in patients with T2DM complicated with OP.

Topics: Adult; Blood Glucose; Bone Density; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Leptin; Osteoporosis

Coffee is among the most consumed beverages worldwide. Coffee consumption has been associated with lower risk of type 2 diabetes mellitus (T2D), but underlying mechanisms are not well understood. We aimed to study the role of classic and novel-T2D biomarkers with anti- or pro-inflammatory activity in the association between habitual coffee intake and T2D risk. Furthermore, we studied differences by coffee types and smoking status in this association.. Using two large population-based cohorts, the UK-Biobank (UKB; n = 145,368) and the Rotterdam Study (RS; n = 7111), we investigated associations of habitual coffee consumption with incident T2D and repeated measures of insulin resistance (HOMA-IR), using Cox proportional hazards and mixed effect models, respectively. Additionally, we studied associations between coffee and subclinical inflammation biomarkers including C-reactive protein (CRP) and IL-13, and adipokines, such as adiponectin and leptin, using linear regression models. Next, we performed formal causal mediation analyses to investigate the role of coffee-associated biomarkers in the association of coffee with T2D. Finally, we evaluated effect modification by coffee type and smoking. All models were adjusted for sociodemographic, lifestyle and health-related factors.. During a median follow-up of 13.9 (RS) and 7.4 (UKB) years, 843 and 2290 incident T2D cases occurred, respectively. A 1 cup/day increase in coffee consumption was associated with 4% lower T2D risk (RS, HR = 0.96 [95%CI 0.92; 0.99], p = 0.045; UKB, HR = 0.96 [0.94; 0.98], p < 0.001), with lower HOMA-IR (RS, log-transformed β = -0.017 [-0.024;-0.010], p < 0.001), and with lower CRP (RS, log-transformed β = -0.014 [-0.022;-0.005], p = 0.002; UKB, β = -0.011 [-0.012;-0.009], p < 0.001). We also observed associations of higher coffee consumption with higher serum adiponectin and IL-13 concentrations, and with lower leptin concentrations. Coffee-related CRP levels partially mediated the inverse association of coffee intake with T2D incidence (average mediation effect RS β = 0.105 (0.014; 0.240), p = 0.016; UKB β = 6.484 (4.265; 9.339), p < 0.001), with a proportion mediated by CRP from 3.7% [-0.012%; 24.4%] (RS) to 9.8% [5,7%; 25.8%] (UKB). No mediation effect was observed for the other biomarkers. Coffee-T2D and coffee-CRP associations were generally stronger among consumers of ground (filtered or espresso) coffee and among never and former smokers.. Lower subclinical inflammation may partially mediate the beneficial association between coffee consumption and lower T2D risk. Consumers of ground coffee and non-smokers may benefit the most. KEYWORDS (MESH TERMS): coffee consumptions; diabetes mellitus, type 2; inflammation; adipokines; biomarkers; mediation analysis; follow-up studies.

Topics: Adiponectin; Biological Specimen Banks; Biomarkers; C-Reactive Protein; Coffee; Diabetes Mellitus, Type 2; Humans; Inflammation; Interleukin-13; Leptin; Risk Factors; United Kingdom

to study the relationships of leptin and leptin SR with adiposity indices, and glycemic indices in patients with type 2 diabetes mellitus (T2DM) compared to healthy subjects.. This cross-sectional study involved 65 patients with T2DM and 63 healthy controls. Fasting plasma levels of leptin, leptin SR, insulin and lipid profile were measured by enzyme linked immunosorbent essay, basal insulin resistance and beta-cell function were assessed using the homeostasis model assessment.. leptin SR level was significantly higher in T2DM patients than in controls (5.8 ± 1.6 and 4.8 ± 1.3 respectively; p= 0.001). In patients with T2DM, leptin SR was negatively correlated with homeostasis model of β-cell function and body fat mass while it has a significant positive correlation with glycosylated hemoglobin (HbA1c). The independent predictors for leptin SR in patients with T2DM were triglycerides (TG) and HbA1c.. elevated serum leptin SR level in patients with T2DM was positively correlated with TG and abnormal glucose metabolism which indicate that it plays a role in pathophysiology of T2DM. The association of elevated leptin SR level with high TG and deterioration of β-cell function indicate that in some individuals, particularly non-obese, dyslipidemia might be a cause rather than a complication of diabetes.

Topics: Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Leptin; Obesity; Receptors, Leptin; Triglycerides

Topics: Adiponectin; Adipose Tissue; Animals; Bees; Corticosterone; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Carbohydrates; Honey; Leptin; Male; Metabolic Syndrome; Rats; Rats, Wistar

Whether the levels of circulating inflammatory adipokines affect the progression of type 2 diabetes (T2D) remains unclear. This study aimed to assess the association between circulating inflammatory adipokine levels and risk of T2D.. This case-control study involved 130 individuals consisting of 66 healthy controls (Control group) and 64 patients with T2D (T2D group) in Lishui Municipal Central Hospital from January 2017 to June 2017. Multivariate logistic regression analysis was applied to assess the associations between circulating inflammatory adipokine levels and the risk of T2D.. There were significant differences in the levels of adiponectin (p = 0.013) and visfatin (p < 0.001) between the T2D and Control groups. In contrast, no significant differences in leptin (p = 0.113), TNF-α (p = 0.632), and IL-6 (p = 0.156) levels were found between the groups. Multivariate logistic regression indicated that elevated visfatin level was associated with an increased risk of T2D (OR: 3.543; 95% CI: 1.771-7.088; p < 0.001), while adiponectin (OR: 1.946; 95% CI: 0.925-4.094; p = 0.079), leptin (OR: 3.723; 95% CI: 0.788-17.583; p = 0.097), TNF-α (OR: 1.081; 95% CI: 0.911-1.281; p = 0.373), and IL-6 (OR: 0.878; 95% CI: 0.657-1.173; p = 0.379) were not associated with the risk of T2D.. This study found elevated visfatin levels are associated with an increased risk of T2D, while adiponectin, leptin, TNF-α, and IL-6 are not. These findings should be further verified by a large-scale prospective study.

Topics: Adipokines; Adiponectin; Case-Control Studies; Diabetes Mellitus, Type 2; East Asian People; Humans; Interleukin-6; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Prospective Studies; Tumor Necrosis Factor-alpha

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes.. We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19.. Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines.. Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

Topics: Adipokines; Adiponectin; C-Peptide; Child; Complement Factor D; COVID-19; Cytokines; Diabetes Mellitus, Type 2; Ghrelin; Glucagon; Granulocyte Colony-Stimulating Factor; Humans; Incretins; Interleukin-12; Interleukin-17; Interleukin-6; Leptin; Pancreatic Hormones; SARS-CoV-2; Tumor Necrosis Factor-alpha

Metabolic abnormalities, such as diabetes mellitus and obesity, can impact bone quantity and/or bone quality. In this work, we characterize bone material properties, in terms of structure and composition, in a novel rat model with congenic leptin receptor (LepR) deficiency, severe obesity, and hyperglycemia (type 2 diabetes-like condition). Femurs and calvaria (parietal region) from 20-week-old male rats are examined to probe bones formed both by endochondral and intramembranous ossification. Compared to the healthy controls, the LepR-deficient animals display significant alterations in femur microarchitecture and in calvarium morphology when analyzed by micro-computed X-ray tomography (micro-CT). In particular, shorter femurs with reduced bone volume, combined with thinner parietal bones and shorter sagittal suture, point towards a delay in the skeletal development of the LepR-deficient rodents. On the other hand, LepR-deficient animals and healthy controls display analogous bone matrix composition, which is assessed in terms of tissue mineral density by micro-CT, degree of mineralization by quantitative backscattered electron imaging, and various metrics extrapolated from Raman hyperspectral images. Some specific microstructural features, i.e., mineralized cartilage islands in the femurs and hyper-mineralized areas in the parietal bones, also show comparable distribution and characteristics in both groups. Overall, the altered bone microarchitecture in the LepR-deficient animals indicates compromised bone quality, despite the normal bone matrix composition. The delayed development is also consistent with observations in humans with congenic Lep/LepR deficiency, making this animal model a suitable candidate for translational research.

Topics: Animals; Bone Density; Diabetes Mellitus, Type 2; Femur; Humans; Leptin; Male; Obesity; Rats; Receptors, Leptin; Skull

db/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer's disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-κB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders.

Topics: Animals; Diabetes Mellitus, Type 2; Hepatitis; Inflammation; Kidney; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Receptors, Leptin

Multiple studies have independently investigated the associations of the consumption of individual beverage types and specific plasma biomarkers with the risk of type 2 diabetes (T2D). However, as individuals do not consume single beverage types exclusively and plasma biomarkers do not act in isolation, it remains unclear how patterns of beverage consumption and plasma biomarker networks associate both with each other and T2D risk.. We aimed to elucidate potential dietary determinants of T2D risk by defining a model that describes habitual beverage consumption profiles in relation to identified networks of circulating plasma biomarkers.. This study included 1,461 case and 1,568 control participants from case-control studies of T2D nested within the Nurses' Health Study. Participants completed validated semiquantitative food frequency questionnaires that assessed habitual beverage consumption, and they provided blood samples from which 27 plasma biomarkers of cardiometabolic risk were identified. Common exploratory factor analysis (EFA) identified factors that separately described beverage consumption profiles and biomarker networks. Multivariable-adjusted regression elucidated the relationships between beverage and biomarker factors and T2D risk.. EFA revealed five factors describing unique beverage consumption profiles and seven factors describing biomarker networks. The factor describing alcoholic beverage consumption was associated with a reduced risk of T2D (odds ratio [OR]: 0.50 [0.40, 0.64], P<0.001) mediated, in part, by the factor describing increased concentrations of adiponectin biomarkers (19.9% [12.0, 31.1] P = 0.004). The factor describing low-calorie sweetened beverage (LCSBs) consumption was associated with an increased risk of T2D (OR: 1.33 [1.03, 1.72], P = 0.021), and the factor describing lower concentrations of insulin-like growth factor binding proteins 1 and 2, and soluble leptin receptor, and increased leptin concentrations (P = 0.005).. Moderate alcohol consumption was associated with reduced T2D risk, mediated in part by increased circulating adiponectin. LCSB consumption was associated with both increased T2D risk and perturbed insulin-like growth factor and leptin signaling.

Topics: Adiponectin; Beverages; Biomarkers; Diabetes Mellitus, Type 2; Humans; Leptin; Risk Factors

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Leptin; Metformin; Plant Extracts; Rats; Squalene; Superoxide Dismutase

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genotype; Glycemic Control; Humans; Leptin; Metformin; Polymorphism, Single Nucleotide

To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes.. In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate β-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene.. Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; β=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; β=-0.31) and worst β-cell function (p=0.023; β=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin.. Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Topics: Adiponectin; Atherosclerosis; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin Resistance; Insulins; Leptin; Triglycerides

Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective β3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1β, and IL-6 gene expression and IL-1β and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.

Topics: Animals; Blood Glucose; Brain; Diabetes Mellitus, Type 2; Glucose; Hippocampus; Inflammation; Insulin; Leptin; Neuroinflammatory Diseases; Obesity; Rats; Rats, Wistar

Leptin (LEP) can cross the blood-brain barrier and facilitate cross-talk between the adipose tissue and central nerve system (CNS). This study aimed to investigate the effect of 8-week high-intensity interval training (HIIT) on the LEP signaling in the hippocampus of rats with type 2 diabetes. 20 rats were randomly divided into four groups: (i) control (Con), (ii) type 2 diabetes (T2D), (iii) exercise (EX), and (iv) type 2 diabetes + exercise (T2D + EX). The rats in the T2D and T2D + EX were fed a high-fat diet for two months, then a single dose of STZ (35 mg/kg) was injected to induce diabetes. The EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of V

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Diabetes Mellitus, Type 2; High-Intensity Interval Training; Hippocampus; Leptin; Mammals; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; tau Proteins; TOR Serine-Threonine Kinases

High-density lipoproteins (HDLs) have antiatherogenic properties related to their chemical structure. Adipose tissue (AT) influences HDL reverse cholesterol transport and plasma HDL cholesterol levels. However, whether AT dysfunction affects HDL subpopulations and their glycation in early type 2 diabetes (T2D) is still unknown.. To investigate the association of inflammation and AT dysfunction serum markers with the size and glycation of HDLs in normoglycemic, prediabetes, and T2D subjects.. We assessed HDL particle size and advanced glycation end-product (AGE) content in HDLs isolated from normoglycemic (n = 17), prediabetes (n = 17), and recently T2D-diagnosed (n = 18) subjects. Insulin, adiponectin, and plasminogen activator inhibitor 1 (PAI-1) were determined using the Bio-Rad Multiplex Platform, and free fatty acids (FFAs) and high sensitivity C-reactive protein (hs-CRP) were determined by standard procedures. The AT insulin resistance (ATIR) index and ATIR/adiponectin and adiponectin/leptin ratios were calculated.. HDL was progressively smaller (nm) and enriched with AGE (mg-BSA-AGE/mg protein) according to the glucose categories: 8.49 and 7.5 in normoglycemic subjects, 8.44 and 12.4 in prediabetic subjects, and 8.32 and 14.3 in T2D subjects (P = 0.033 and P = 0.009 for size and AGE, respectively). In multivariable regression analysis, the ATIR/adiponectin ratio was inversely associated with HDL size (β = -0.257, P = 0.046), and the ATIR ratio was directly associated with HDL glycation (β = 0.387, P = 0.036). In contrast, adiponectin and the adiponectin/leptin ratio were not associated with alterations in HDL particles. Furthermore, HDL size was associated with resistin (β = -0.348, P = 0.007) and PAI-1 (β = -0.324, P = 0.004). HDL and AGE were related to insulin concentrations (β = 0.458, P = 0.015). Analyses were adjusted for age, sex, body mass index, triglycerides, and HDL-cholesterol.. HDL size was significantly associated with the ATIR/adiponectin ratio and inflammation, whereas glycation was more strongly related to the ATIR index. These findings have important implications for the management and prevention of cardiovascular disease in T2D patients.

Topics: Adiponectin; Adipose Tissue; Biomarkers; Cholesterol, HDL; Diabetes Mellitus, Type 2; Glycation End Products, Advanced; Humans; Insulin; Leptin; Lipoproteins, HDL; Maillard Reaction; Plasminogen Activator Inhibitor 1; Prediabetic State

The global number of people living with diabetes mellitus (DM) continues to grow. Obesity, smoking, hypercholesterolemia, and hypertension are independently correlated with the risk of cardiovascular disease (CVD) in diabetic patients regardless of differences in race or ethnicity. We aimed to investigate the relationship between serum leptin levels and aortic stiffness in patients with type 2 DM to identify cardiovascular risk at the early stage.. A total of 128 diabetic patients were enrolled after screening for eligibility at a medical center in Eastern Taiwan. Aortic stiffness was defined as having a carotid-femoral pulse wave velocity (cfPWV) of >10 m/s using applanation tonometry. Fasting serum levels of leptin and other associated biomarkers were determined by enzyme immunoassay or biochemical analyses.. Forty-six diabetic patients with a cfPWV of >10 m/s were included in the aortic stiffness group. Compared with the control group (n = 82), our aortic stiffness group was significantly older (. The results suggested that serum leptin is positively associated with aortic stiffness in patients with type 2 DM.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Humans; Leptin; Pulse Wave Analysis; Risk Factors; Vascular Stiffness

Type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) have a significant impact on the expression of genes in peripheral blood mononuclear cells (PBMCs). The primary objective of this study was to investigate the role of two signaling pathways, STAT1/6, and two important modulators of immunometabolism, leptin and PPARs, in the development of T2DM with and without CVD. Furthermore, the study aimed to assess the correlation between these factors and the dynamics of CD14 in PBMCs. This research was conducted within the context of a growing body of literature on the complex pathophysiology of T2DM and its association with CVD. Prior studies have indicated that T2DM is characterized by an imbalance in immunometabolism and the involvement of various signaling pathways.. Blood samples were collected from a total of 47 subjects, including 7 healthy volunteers, 20 individuals diagnosed with diabetes and cardiovascular disease (D.CVD) and another 20 individuals diagnosed with diabetes only (D). PBMCs were isolated from these samples, and the expression levels of leptin, PPARγ, PPARα, and CD14 genes were measured using Real-Time PCR.. The most relevant result showed that diabetic patients with CVD had significantly higher levels of leptin expression, which was positively correlated with STAT1 (r = 0.7497, p = 0.0001). On the other hand, diabetic patients without CVD had elevated PPARγ expression, which was strongly correlated with STAT6 (r = 0.8437, p = 0.0001). Interestingly, we found a significant increase in the PPARγ/ PPARα ratio in the D.CVD group compared to the D group (4.273 ± 0.9531; 7.52 ± 3.556, p = 0.0479). Moreover, CD14 expression was significantly reduced in this group compared to diabetic patients without CVD.. These findings suggested that the immunometabolic imbalance in T2DM was driven by a STAT1/Leptin phenotype in diabetic patients with CVD and by a STAT6/PPARγ phenotype in diabetic patients without CVD. Taking into account STAT1/Leptin and STAT6/PPARγ profiling could help clinicians identify novel therapeutic targets for T2DM and other related diseases.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Leptin; Leukocytes, Mononuclear; Phenotype; PPAR alpha; PPAR gamma; RNA, Messenger

Insulin-stimulated glucose uptake in skeletal muscle is mediated by the glucose transporter GLUT4. The small GTPase Rac1 acts as a switch of signal transduction that regulates GLUT4 translocation to the plasma membrane following insulin stimulation. However, it remains obscure whether signaling cascades upstream and downstream of Rac1 in skeletal muscle are impaired by obesity that causes insulin resistance and type 2 diabetes. In an attempt to clarify this point, we investigated Rac1 signaling in the leptin-deficient (

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Glucose Transporter Type 4; Insulin; Insulin, Regular, Human; Leptin; Mice; Mice, Obese; Monomeric GTP-Binding Proteins; Muscle, Skeletal; rac1 GTP-Binding Protein; Signal Transduction

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10

Topics: Adaptor Proteins, Signal Transducing; Diabetes Mellitus, Type 2; Humans; Insulins; Leptin; Metabolic Diseases; Obesity

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

Topics: Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Insulin Resistance; Leptin; Obesity; Overweight; Plasminogen Activator Inhibitor 1

To investigate the effects of Moringa Oleifera Leaf Extract (MOLE) plus rosiglitazone (RSG) on glucose and lipid metabolism, serum leptin, and the Akt/GSK3β/β-Catenin signaling pathway in type 2 diabetic (T2D) rats.. Sixty male Sprague-Dawley (SD) rats were randomly divided into six groups: the normal group, the model group, the RSG group, the low- and high-dose MOLE group, and the MOLE+RSG group. The normal group was fed a standard rat diet, while the other groups were given a single intraperitoneal injection of low-dose streptozomycin (STZ) (35 mg/kg) and fed a high-sugar and high-fat diet. After 8 weeks, the treatment outcomes were evaluated by measuring key parameters of blood glucose and lipid metabolism and the protein kinase B (AKT) / Glycogen synthase kinase 3beta (GSK3β) /β-Catenin signaling pathway in the T2D rats.. Compared with the normal group, the model group showed significantly increased levels of blood glucose, blood lipids, serum leptin, free fatty acid (FFA), and tumor necrosis factor-α (TNF-α). Compared with the model group, the RSG, low-dose MOLE, and high-dose MOLE groups displayed effective control of blood glucose, blood lipids, serum leptin, FFA, and TNF-α. The MOLE+RSG group surpassed the RSG group in regulating glucose, lipid metabolism, and serum leptin levels in T2D rats. In addition, the MOLE+RSG group also had superiority over the RSG group in activating the AKT/GSK3β/β-Catenin pathway.. MOLE plus RSG can effectively reduce blood glucose and blood lipids in T2DM rats.

Topics: Animals; beta Catenin; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Glycogen Synthase Kinase 3 beta; Hypoglycemic Agents; Leptin; Lipid Metabolism; Lipids; Male; Moringa oleifera; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Rosiglitazone; Tumor Necrosis Factor-alpha

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Fatty Acid Synthase, Type I; Fatty Acid Synthases; Humans; Hyperglycemia; Leptin; Mice; Nitric Oxide Synthase; Non-alcoholic Fatty Liver Disease; Obesity

Children of mothers with gestational diabetes mellitus (GDM) are more prone to acquire type 2 diabetes and obesity as adults. Due to this link, early intervention strategies that alter the gut microbiome may benefit the mother and kid long-term. This work uses metagenomic and transcriptome sequencing to investigate how probiotics affect gut microbiota dysbiosis and inflammation in GDM.. GDM and control metagenomic sequencing data were obtained from the SRA database. This metagenomic data helped us understand gut microbiota abundance and function. KEGG detected and extracted functional pathway genes. Transcriptome sequencing data evaluated GDM-related gene expression. Finally, GDM animal models were given probiotics orally to evaluate inflammatory response, regulatory immune cell fractions, and leptin protein levels.. GDM patients had more Fusobacteria and Firmicutes, while healthy people had more Bacteroidetes. Gut microbiota composition may affect GDM by altering the L-aspartate and L-asparagine super pathways. Mannan degradation and the super pathway of L-aspartate and L-asparagine synthesis enhanced in GDM mice with leptin protein overexpression. Oral probiotics prevent GDM by lowering leptin. Oral probiotics increased Treg, Tfr, and Breg cells, which decreased TNF-α and IL-6 and increased TGF-β and IL-10, preventing inflammation and preserving mouse pregnancy.. Dysbiosis of the gut microbiota may increase leptin expression and cause GDM. Oral probiotics enhance Treg, Tfr, and Breg cells, which limit the inflammatory response and assist mice in sustaining normal pregnancy. Thus, oral probiotics may prevent GDM, enabling targeted gut microbiota modulation and maternal and fetal health.

Topics: Animals; Asparagine; Aspartic Acid; B-Lymphocytes, Regulatory; Diabetes Mellitus, Type 2; Diabetes, Gestational; Dysbiosis; Female; Humans; Inflammation; Leptin; Mice; Pregnancy; T-Lymphocytes, Regulatory

Adipokines dysregulation, the main reason for cognitive impairments (CI) induced by diabetes, shows a sex-dependent pattern inherently and in response to exercise. This study aimed to compare the attenuating effect of 8-week high intensity-interval training (HIIT) on type 2 diabetes (T2D)-induced CI between male and female rats with a special focus on adiponectin and leptin. 28 male & 28 female Wistar rats with an average age of 8 weeks were randomly assigned into four groups: control (Con), exercise (EX), Diabetes (T2D), and Type 2 diabetes + exercise (T2D + Ex). Rats in EX and T2D + EX groups performed HIIT for eight weeks (80-100% Vmax, 4-10 intervals). T2D was induced by 2 months of a high-fat diet and a single dose of STZ (35 mg/kg) administration. Leptin and adiponectin levels in serum were measured along with hippocampal expression of leptin and adiponectin receptors, AMP-activated protein kinase (AMPK), dephosphorylated glycogen synthase kinase-3 beta (Dep-GSK3β), Tau, and beta-amyloid (Aβ). Homeostasis model assessments (HOMAs) and quantitative insulin-sensitivity check index (QUICKI) indices were calculated. Our results showed that following T2D, serum levels of APN, and hippocampal levels of adiponectin receptor 1 (APNR1) were higher and HOMA-IR was lower in female than male rats (P < 0.05). However, after 8 weeks of HIIT, hippocampal levels of APNR1 and AMPK as well as QUICKI were lower and hippocampal levels of GSK, Tau, and Aβ were higher in females compared to male rats (P < 0.05). While the risk of CI following T2D was more in male than female rats HIIT showed a more ameliorating effect in male animals with APN1 as the main player.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Cognition; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Insulin Resistance; Leptin; Male; Rats; Rats, Wistar; Receptors, Adiponectin; Sex Characteristics

Roux-en-Y gastric bypass (RYGB) is associated with a high rate of type 2 diabetes (T2D) remission. Carriers of heterozygous variants in the leptin-melanocortin pathway (LMP) are more likely to experience weight recurrence after RYGB. Our aim was to investigate if carrier status and associated weight regain affects the rate of T2D remission after RYGB.. Carriers of LMP variants with a diagnosis of T2D prior to RYGB (N = 16) were matched to non-carriers (N = 32) based on sex, age, and BMI. We assessed for post-operative T2D remission status post-surgery on a yearly basis, for up to 15 years. Our primary endpoint was the proportion of patients achieving T2D remission at 1 year. We conducted a survival analysis for all patients that achieved remission at least at one time-point to evaluate for maintenance of T2D remission by using a log-rank test.. Both carriers and non-carriers had similar baseline and procedural characteristics. The proopiomelanocortin gene in the LMP pathway had the most variants (n = 5, 31%). Carriers had a lower total body weight loss percentage at nadir (28.7% ± 6.9) than non-carriers (33.7% ± 8.8, p = 0.04). The proportion of patients achieving T2D remission at 1 year was 68.8% for carriers and 71.9% for non-carriers (p = 1.0). Survival curves for maintenance of first remission were similar for both groups (p = 0.73), with a median survival of 8 years for both carriers and non-carriers.. Despite inferior weight loss outcomes at nadir, carriers had similar T2D remission rates when compared to non-carriers. Weight-independent metabolic benefits of RYGB might contribute to this observation.

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Leptin; Melanocortins; Obesity, Morbid; Retrospective Studies; Treatment Outcome

Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).

Topics: Agouti-Related Protein; Amphetamines; Animals; Appetite Regulation; Cocaine; Cytokines; Diabetes Mellitus, Type 2; Forkhead Box Protein O1; High-Intensity Interval Training; Hypothalamus; Insulin; Janus Kinase 2; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Wistar; STAT3 Transcription Factor

To study the prevalence and influence on metabolic profile of the prohormone-convertase-1 (PCSK1) N221D variant in childhood obesity, proven its role in the leptin-melanocortin signaling pathway as in proinsulin and other prohormone cleavage.. Transversal study of 1066 children with obesity (mean age and BMI Z-score 10.38 ± 3.44 years and +4.38 ± 1.77, respectively), 51.4 % males, 54.4 % prepubertal, 71.5 % Caucasians and 20.8 % Latinos. Anthropometric and metabolic features were compared between patients carrying the N221D variant in. No variants were found in 531 patients (49.8 %), while 68 patients carried the. The N221D variant in

Topics: Adaptor Proteins, Signal Transducing; Child; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Melanocortins; Metabolome; Pediatric Obesity; Proprotein Convertase 1; Proteins

Accumulating evidence has suggested a link between adipokines and diabetic retinopathy (DR). This study is aimed at investigating the risk factors for sight-threatening DR (STDR) and establishing a prognostic model for predicting STDR among a high-risk population of patients with type 2 diabetes mellitus (T2DM).. Plasma concentrations of adipokines were determined by enzyme-linked immunosorbent assay. In the case-control set, principal component analysis (PCA) was performed to select optimal predictive cytokines for STDR, involving severe nonproliferative DR (NPDR) and proliferative DR. Support vector machine (SVM) was used to examine the possible combination of baseline plasma adipokines to discriminate the patients with mild NPDR who will later develop STDR. An individual prospective cohort with a follow-up period of 3 years was used for the external validation.. In both training and testing sets, involving 306 patients with T2DM, median levels of plasma adiponectin (APN), leptin, and fatty acid-binding protein 4 (FABP4) were significantly higher in the STDR group than those in mild NPDR. Except for adipsin, the other three adipokines, FABP4, APN, and leptin, were selected by PCA and integrated into SVM. The accuracy of the multivariate SVM classification model was acceptable in both the training set (AUC = 0.81, sensitivity = 71%, and specificity = 91%) and the testing set (AUC = 0.77, sensitivity = 61%, and specificity = 92%). 110 T2DM patients with mild NPDR, the high-risk population of STDR, were enrolled for external validation. Based on the SVM, the risk of each patient was calculated. More STDR occurred in the high-risk group than in the low-risk group, which were grouped by the median value of APN, FABP4, and leptin, respectively. The model was validated in an individual cohort using SVM with the AUC, sensitivity, and specificity reaching 0.77, 64%, and 91%, respectively.. Adiponectin, leptin, and FABP4 were demonstrated to be associated with the severity of DR and maybe good predictors for STDR, suggesting that adipokines may play an important role in the pathophysiology of DR development.

Topics: Adipokines; Adiponectin; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Leptin; Prospective Studies

To investigate the effect of Bo's abdominal acupuncture (BOAA) on fibroblast growth factor 21 (FGF21) and its related adipokines in type 2 diabetes mellitus (T2DM) rats.. This study established obese T2DM rat model by high-fat diet (HFD) with a dose of streptozotocin (STZ, 30 mg/kg). Obese T2DM rats were randomly subdivided into four groups (. Treatment with BOAA attenuated the histopathological changes in visceral fat and restored the alterations in the levels of body weight, fasting blood glucose (FBG), homeostasis model assessment for insulin resistance (HOMA-IR). BOAA treatment significantly decreased the levels of triglyceride, total cholesterol, low density lipoprotein cholesterol, leptin, and increased the serum levels of high-density lipoprotein cholesterol, fibroblast growth factor 21 (FGF21), adiponectin (ADP), peroxisome proliferator-activated receptor γ (PPAR-γ), C-peptide (C-P) in obese T2DM rats. Furthermore, BOAA treatment significantly increased the mRNA expressions of FGF21, ADP, leptin, PPAR-γ, PPAR-α and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Besides, BOAA treatment upregulated the protein expressions of fibroblast growth factor receptors3 (FGFR3), PPAR-. BOAA treatment reduced FBG and body weight, and improved insulin sensitivity through regulating FGF21 signaling pathway and its related adipokine in obese T2DM rats.

Topics: Acupuncture Therapy; Adipokines; AMP-Activated Protein Kinases; Animals; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Fibroblast Growth Factors; Insulin Resistance; Leptin; Obesity; Peroxisome Proliferator-Activated Receptors; Rats

To investigate the effect of metformin combined with DPP-4 inhibitor on alveolar bone density in patients with type 2 diabetes mellitus and chronic periodontitis.. A total of 80 patients with type 2 diabetes mellitus and chronic periodontitis were selected and randomly divided into group A and group B by random number table, with 40 patients in each group. Group A (medication alone group): oral metformin and basic periodontal treatment; Group B (combination group): DPP-4 inhibitor (sitagliptin) was taken orally in addition to group A. Before treatment (T0) and 3 months (T1) and 6 months (T2) after treatment, alveolar bone mineral density (BDM), periodontal probing depth (PD), clinical attachment loss(CAL), probing bleeding (BOP), glycated hemoglobin (HbA1c),serum phosphorus, serum calcium, adiponectin (ADP), leptin (LEP), interleukin-6 (IL-6), C-reactive protein (HS-CRP), tumor necrosis factor (TNF-α) were detected. SPSS 23.0 software package was used for data analysis.. Three and 6 months after treatment, PD, CAL, BOP and HbAlc in group B were significantly lower than those in group A(P＜0.05). BDM in group B was significantly higher than that in group A (P＜0.05). Compared with group A, the levels of inflammatory cytokines (IL-6, Hs-CRP, TNF-α) and leptin in group B were significantly decreased, while the level of adiponectin was significantly increased (P＜0.05).. Metformin combined with DPP-4 inhibitor can increase alveolar bone density in patients with type 2 diabetes mellitus and chronic periodontitis, effectively improve periodontal clinical and serum biochemical indicators, and reduce periodontal inflammation.

Topics: Adiponectin; Bone Density; C-Reactive Protein; Chronic Periodontitis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Interleukin-6; Leptin; Metformin; Tumor Necrosis Factor-alpha

Hepatic insulin resistance (HIR) is considered to be an independent predictor of metabolic disorders and plays an important role in systemic inflammation, which contributes to abnormalities in cardiovascular disease (CVD) risk factors. The aim of this study was to investigate the relationship between HIR and new markers of cardiovascular risks, including leptin/adiponectin ratio (L/A), lipoprotein(a) [Lp(a)], and tumor necrosis factor alpha (TNF-α), at comparable whole body insulin sensitivity in non-diabetic individuals with or without CVD and at high risk of developing type 2 diabetes.. The HIR index, L/A, Lp(a), and TNF-α were measured in 50 participants with CVD and in 200 without CVD (1:4 ratio). These were also matched for the homeostatic model assessment for insulin resistance (HOMA-IR) and Matsuda-insulin sensitivity index (ISI) in an observational study design.. The HIR index (1.52 ± 0.14 vs. 1.45 ± 0.17, p < 0.02), L/A (3.22 ± 3.10 vs. 2.09 ± 2.27, p < 0.004), and levels of Lp(a) (66.6 ± 49.5 vs. 37.9 ± 3 6.8 mg/dL, p < 0.0001) and TNF-α (18.9 ± 21.8 vs. 5.4 ± 7.1 pg/mL, p < 0.0001) were higher in those with CVD than those without CVD. HOMA-IR and ISI were not significantly different (p = 0.88 and p = 0.35, respectively). The HIR index was directly correlated with L/A (r = 0.41, p < 0.0001), Lp(a) (r = 0.20, p < 0.002), TNF- α (r = 0.14, p < 0.03), and diastolic blood pressure (DBP) (r = 0.13, p < 0.03). The stepwise model analysis showed that L/A, Lp(a), and TNF-α explained about 20% of the variation in the HIR indices of all the participants (p < 0.02).. Our results suggest a positive association between HIR and new markers of cardiovascular risk [L/A, Lp(a), and TNF- α] at comparable whole body insulin sensitivity in those with or without CVD and at high risk of developing type 2 diabetes.

Topics: Adiponectin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Insulin Resistance; Leptin; Lipoprotein(a); Tumor Necrosis Factor-alpha

Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes.. The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice.. The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterizes obesity and diabetes, possibly in relation with gut microbiome alterations.

Topics: Adipose Tissue; Animals; Arachidonate 12-Lipoxygenase; Calcium Channels; Diabetes Mellitus, Type 2; Disease Models, Animal; Endocannabinoids; Gastrointestinal Microbiome; Gene Expression Regulation; Humans; Inflammation; Leptin; Mice; Mice, Inbred NOD; Mice, Obese; Obesity; Receptors, Leptin; Transcriptome; TRPV Cation Channels

Obesity and type 2 diabetes are chronic diseases characterized by insulin resistance, mitochondrial dysfunction and morphological abnormalities.. We have investigated if dysregulation of mitochondrial dynamics and biogenesis is involved in an animal model of obesity and diabetes.. The effect of short-term leptin and mdivi-1 - a selective inhibitor of Drp-1 fission-protein - treatment on mitochondrial dynamics and biogenesis was evaluated in epididymal white adipose tissue (WAT) from male ob/ob mice.. An increase in Drp-1 protein levels and a decrease in Mfn2 and OPA-1 protein expression were observed with enhanced and sustained mitochondrial fragmentation in ob/ob mice compared to wt C57BL/6 animals (p < 0.05). The content of mitochondrial DNA and PGC-1α mRNA expression -both parameters of mitochondrial biogenesis- were reduced in ob/ob mice (p < 0.05). Treatment with leptin and mdivi-1 significantly increased mitochondrial biogenesis, improved fusion-to-fission balance and attenuated mitochondrial dysfunction, thus inducing white-to-beige adipocyte transdifferentiation. Measurements of glucose and lipid oxidation in adipocytes revealed that both leptin and mdivi-1 increase substrates oxidation while in vivo determination of blood glucose concentration showed decreased levels by 50% in ob/ob mice, almost to the wt level.. Pharmacological targeting of Drp-1 fission protein may be a potential novel therapeutic tool for obesity and type 2 diabetes.

Topics: Adipose Tissue; Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Leptin; Male; Mice; Mice, Inbred C57BL; Mitochondrial Dynamics; Obesity

A novel classification has been introduced to promote precision medicine in diabetes. The current study aimed to investigate the relationship between leptin and resistin levels with novel refined subgroups in patients with type 2 diabetes mellitus (T2DM).. The k-means analysis was conducted to cluster 541 T2DM patients into the following four subgroups: mild obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild age-related diabetes (MARD). Individuals meeting the exclusion criteria were eliminated, the data for 285 patients were analyzed. Characteristics were determined using various clinical parameters. Both the leptin and resistin levels were determined using enzyme-linked immunosorbent assay.. The highest levels of plasma leptin were in the MOD group with relatively lower levels in the SIDD and SIRD groups (P < 0.001). The SIRD group had a higher resistin concentration than the MARD group (P = 0.024) while no statistical significance in resistin levels was found between the SIDD and MOD groups. Logistic regression demonstrated that plasma resistin was associated with a higher risk of diabetic nephropathy (odds ratios (OR) = 2.255, P = 0.001). According to receiver operating characteristic (ROC) curves, the area under the curve (AUC) of resistin (0.748, 95% CI 0.610-0.887) was significantly greater than that of HOMA2-IR (0.447, 95% CI 0.280-0.614) (P < 0.05) for diabetic nephropathy in the SIRD group.. Leptin levels were different in four subgroups of T2DM and were highest in the MOD group. Resistin was elevated in the SIRD group and was closely related to diabetic nephropathy.

Topics: Adult; Age Factors; Cluster Analysis; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Resistin

Studies have demonstrated the presence of low-affinity immunoglobulins (Igs) directed to leptin, a key hormone of the neuroendocrine axis that regulates appetite and metabolism, in adult healthy subjects, patients with obesity, and type 2 diabetes mellitus. In the present exploratory study, IgG leptin-reactive antibodies were analyzed for the first time in children and adolescents according to body mass index (BMI) and were correlated with biochemical profile (lipid profile, insulin, glucose, and leptin) and metabolic risk indexes [homeostasis model assessment for insulin resistance (HOMA-IR), homeostasis model assessment for β-cell function (HOMA-β), atherogenic index of plasma (AIP)]. One hundred and thirty-six participants were included (children n = 63, adolescents n = 73). An in-house enzyme-linked immunosorbent assay (ELISA) test was performed to measure IgG anti-leptin antibodies (free, total, and immune complexes). In adolescents, free and total IgG anti-leptin antibodies levels were higher in groups with overweight or obesity than in normal-weight group (P < 0.01), while in children, the total fractions were lower in groups with overweight and obesity than in normal weight (P < 0.02). Immune complexes percentage showed opposite correlations with BMI in children (r = 0.4004, P = 0.0473) and adolescents (r = -0.3983, P = 0.0133). IgG anti-leptin antibodies were also correlated with HOMA-IR in children (r = -0.4569, P = 0.0217) and adolescents (r = -0.3589, P = 0.0316), and with AIP (r = -0.3608, P = 0.0261) in adolescents. Our data suggest that the production and affinity of IgG anti-leptin antibodies can be affected by age, body composition, and metabolic conditions; additionally, in normal conditions, IgG anti-leptin antibodies may have a protective role in insulin resistance and cardiovascular events.

Topics: Adolescent; Adult; Antigen-Antibody Complex; Body Composition; Body Mass Index; Child; Diabetes Mellitus, Type 2; Humans; Immunoglobulin G; Insulin; Insulin Resistance; Leptin; Obesity; Overweight

Background and Objectives: In this study, we aimed to investigate the link between common -2548G>A (rs7799039) promoter variant of the human leptin gene (LEP) with leptin and serum glucose leptin levels in obese Saudi patients. Materials and Methods: A total of 206 Saudi adults (80 obese normotensive nondiabetics, 76 obese hypertensive with Type 2 Diabetes and 50 normotensive nondiabetic controls) were genotyped for -2548G>A LEP polymorphism using the polymerase chain reaction-restriction fragment-length polymorphism technique. Results: Participants with minor AA genotype had significantly higher blood glucose levels (6.8 ± 0.55 mmol/L vs. 5.8 ± 0.30 mmol/L; p < 0.04) and HOMA-IR (4.1 ± 0.84 vs. 2.6 ± 0.67; p = 0.03) against those carrying major GG genotype. Participants with heterozygous GA genotype had significantly higher serum leptin levels against those carrying major GG genotype (40.0 ± 2.6 ng/mL vs. 29.6 ± 2.6 ng/mL; p = 0.04). Further investigation showed that individuals with AA, GA, GA + AA genotypes are at greater risk of developing hyperglycemia compared to those with GG genotype [OR 3.7(1.6−8.4), p = 0.001; 3.2 (1.2−8.6), p = 0.03; 3.5 (1.6−7.7), p = 0.001, respectively]. Additionally, the -2548AA allele was shown to be a risk factor for hyperglycemia [OR 1.9 (1.2−3.0), p = 0.006]. Our data revealed no relationship between this variant of the LEP gene with systolic and diastolic BP, signifying that this genetic variant is not a significant marker of obesity and hypertension in the Saudi population. Conclusions: AA and GA genotypes and LEP gene -2548AA alleles may signify potent risk factors predisposing healthy individuals to develop T2DM regardless of blood-pressure profile.

Topics: Adult; Blood Pressure; Diabetes Mellitus, Type 2; Gene Frequency; Glucose; Humans; Leptin; Obesity; Polymorphism, Single Nucleotide; Saudi Arabia

Recently, we proposed two pathophysiologic subtypes of type 2 diabetes mellitus (T2DM), one related and one unrelated to metabolic syndrome. To begin to understand the pathophysiology of the subtype unrelated to metabolic syndrome, we now measured selected hormones and signaling molecules in affected individuals. In this cross-sectional analysis, we examined 138 women out of the monocenter, post gestational diabetes study PPSDiab. Of these women, 73 had prediabetes or screening-diagnosed T2DM, 40 related to metabolic syndrome and 33 unrelated. The remaining 65 women were normoglycemic controls. Our analysis included medical history, anthropometrics, oral glucose tolerance testing, laboratory chemistry, and cardiopulmonary exercise testing. In addition, plasma proinsulin/insulin ratio, growth hormone (hGH) nadir during oral glucose tolerance testing, Insulin-like Growth Factor I (IGF-I), Leptin, Resistin, Adiponectin, Fetuin-a, FGF21, and myostatin were measured. Compared to controls, women with prediabetes or screening-diagnosed T2DM unrelated to metabolic syndrome depicted higher plasma Leptin [10.47(6.6-14.57) vs. 5.52(3.15-10.02); p<0.0001] and IGF-I [193.01(171.00-213.30) vs. 167.97(138.77-200.64); p=0.0008], as well as a lower hGH nadir [0.07(0.05-0.15) vs. 0.14(0.08-0.22; p<0.0001]. These differences were independent of body adiposity. Women with prediabetes or T2DM related to metabolic syndrome, in comparison to controls, displayed elevated Leptin, Fetuin-a, and FGF21, as well as reduced Adiponectin and hGH nadir. Based on our study, altered Leptin and hGH/IGF-I signaling could potentially contribute to the pathophysiology of prediabetes and T2DM unrelated to metabolic syndrome. Further mechanistic investigations of these signaling pathways in the context of lean T2DM are necessary to test causal relationships.

Topics: Adiponectin; alpha-2-HS-Glycoprotein; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Insulin-Like Growth Factor I; Leptin; Metabolic Syndrome; Prediabetic State; Pregnancy

Topics: Adipokines; Adiposity; Bone Density; C-Peptide; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Blood; Humans; Infant; Infant, Newborn; Leptin; Obesity; Pregnancy; Prospective Studies; Vascular Endothelial Growth Factor A

Obesity is one of the main public health problems in Mexico and the world and one from which a large number of pathologies derive. Single nucleotide polymorphisms (SNPs) of various genes have been studied and proven to contribute to the development of multiple diseases. SNPs of the leptin pathway have been associated with the control of hunger and energy expenditure as well as with obesity and type 2 diabetes mellitus. Therefore, the present work focused on determining the association between anthropometric markers and biochemical and dietary factors related to obesity and SNPs of leptin pathway genes, such as the leptin gene (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), and the melanocortin 4 receptor (MC4R). A population of 574 young Mexican adults of both sexes, aged 19 years old on average and without metabolic disorders previously diagnosed, underwent a complete medical and nutritional evaluation, biochemical determination, and DNA extraction from the blood; DNA samples were subsequently genotyped. Association analyses between anthropometric, biochemical, and dietary variables with SNPs were performed using binary logistic regressions (p-value = 0.05). Although the sampled population did not have previously diagnosed diseases, the evaluation results showed that 33% were overweight or obese according to BMI and 64% had non-clinically elevated levels of body fat. From the 74 SNP markers analyzed from the five previously mentioned genes, 62 showed polymorphisms within the sampled population, and only 35 of these had significant associations with clinical variables. The risk associations (OR > 1) occurred between clinical markers with elevated values for waist circumference, waist−height index, BMI, body fat percentage, glucose levels, insulin levels, HOMA-IR, triglyceride levels, cholesterol levels, LDL-c, low HDL-c, carbohydrate intake, and protein intake and SNPs of the LEP, LEPR, PCSK1, and MC4R genes. On the other hand, the protective associations (OR < 1) were associated with markers including elevated values for insulin, HOMA-IR, cholesterol, c-LDL, energy intake > 2440 Kcal/day, and lipid intake and SNPs of the LEP and LEPR genes and POMC. The present study describes associations between SNPs in leptin pathway genes, revealing positive and negative interactions between reported SNPs and the clinical markers related to obesity in a sampled Mexican population. Hence, our results open the door for th

Topics: Biomarkers; Cholesterol; Diabetes Mellitus, Type 2; Diet; Female; Humans; Insulins; Leptin; Male; Obesity; Polymorphism, Single Nucleotide; Pro-Opiomelanocortin; Young Adult

People living with HIV have greater diabetes (T2DM) than the general population despite lower prevalence of overweight/obesity. Both insulin resistance (IR), a T2DM precursor, and HIV are independently associated with chronic inflammation. Inflammation may be a pathophysiological link explaining IR in people living with HIV who are not overweight but is not well understood.. To study the association between inflammation and IR in non-overweight and overweight people living with HIV.. In a cohort of adult people living with HIV with undetectable viral load in Pune, India, we measured fasting insulin, glucose, and 9 inflammatory markers. IR was defined as HOMA-IR ≥2, and non-overweight as BMI ≤23 kg/m. Of 288 participants, 66% (n = 189) were non-overweight. Among non-overweight, prevalence of IR was 34% (n = 65). Each doubling of MCP-1 and leptin was associated with IR on univariate analysis (prevalence ratio (PR) 1.29, 95%CI 1.07-1.53, p < 0.01; PR 1.13 95%CI 1.01-1.26, p = 0.03). Leptin remained associated with IR after adjustment for age, MCP-1, gender, cholesterol, and waist circumference (adjusted PR 1.20 95%CI 1.06-1.36, p < 0.01). Among overweight, prevalence of IR was 69% and no markers were associated with IR.. One in 3 non-overweight people living with HIV in India with controlled viremia have IR. Leptin was associated with IR among non-overweight people living with HIV and may provide insight into the pathophysiology of metabolic disease in this population.

Topics: Adult; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; HIV Infections; Humans; India; Inflammation; Insulin; Insulin Resistance; Leptin; Overweight

This investigation with aimed the effect of APOA2-265 T > C polymorphism and dietary acid load (DAL) as either potential renal acid load (PRAL) and net endogenous acid production (NEAP) intake interaction on metabolic markers in type 2 diabetes mellitus (T2DM). In present cross-sectional study, 737 patients with T2DM (290 men and 447 women) were enlisted from diabetes centers in Tehran. The dietary intakes of all participants during the last year was acquired by a validated semi-quantitative food frequency (FFQ) questionnaire. Polymerase chain reaction (PCR) was used for genotyping the APOA2-265 T > C. Biochemical indises containing leptin, ghrelin, total cholesterol (Bailey et al., J Clin Invest 97:1147-1453, 1996), low-density lipoprotein cholestrol (LDL-C), high-density lipoprotein cholestrol (HDL-C), triglyceride (TG), superoxide dismutase (SOD), high sensitivy C-reactive protein (hs-CRP), total antioxidant capacity (TAC), pentraxin-3 (PTX3), prostaglandin F2α (PGF2α) and interleukin 18 (IL18) were measured by standard method. Atherogenic indices (AIP, AC, CR-I, CR-II) were calculated. The gene-diet interactions were evaluated using an GLM. The frequency overall prevalence of rs5082 genotypes was 63.82 and 36.17% for T-allele and C-allele respectively. TG, Ghrelin, and hs-CRP concentrations were significantly higher among carriers with C allele than TT homozygotes. However, TC/CC genotypes have lower PTX3 than TT homozygotes (P < 0.05). C-allele carriers had highest mean of BMI (P

Topics: Apolipoprotein A-II; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet; Female; Genotype; Ghrelin; Humans; Iran; Leptin; Male; Triglycerides

(1) Objective: The aim of this study was to clarify the role of adipokines in the regulation of glucose metabolism in middle-aged obese subjects with impaired glucose tolerance in response to a long-term exercise and dietary intervention. (2) Methods: Skeletal muscle, plasma and serum samples were examined in 22 subjects from an exercise−diet intervention study aiming to prevent type 2 diabetes. The subjects were further divided into two subgroups (non-responders n = 9 and responders n = 13) based on their achievement in losing at least 3 kg. (3) Results: The two-year exercise−diet intervention reduced leptin levels and increased adiponectin levels in responders; the changes in leptin levels were significantly associated with changes in their weights (r = 0.662, p < 0.01). In responders, insulin sensitivity (Bennett and McAuley index) increased and was associated with changes in maximal oxygen uptake (VO2peak) (r = 0.831, p < 0.010 and r = 0.890, p < 0.01). In addition, the VO2peak and oxidative capacity of skeletal muscle improved in responders, but not in non-responders. However, there were no changes between the two groups in expressions of the glucose transporter protein-4 (GLUT-4) gene or of AMP-activated protein kinase (AMPK)-α1 or AMPK-α2 proteins. (4) Conclusions: The exercise−diet intervention decreased serum leptin and increased serum adiponectin concentrations, improved glucose control without affecting GLUT-4 gene expression in the skeletal muscle in responders.

Topics: Adipokines; Adiponectin; AMP-Activated Protein Kinases; Blood Glucose; Diabetes Mellitus, Type 2; Gene Expression; Glucose Intolerance; Glucose Transporter Type 4; Glycemic Control; Humans; Insulin Resistance; Leptin; Middle Aged; Muscle, Skeletal; Weight Loss

BDE-47 (2,2,4,4-tetrabromodiphenyl ether) is a polybrominated diphenyl ether (PBDE) congener, which has the characteristics of high biological detection rate, the highest content and strong biological toxicity, and is widely distributed in organisms. Many studies have found that BDE-47 may also be an environmental risk factor for metabolic diseases such as obesity, insulin resistance, type 2 diabetes, and hypertension. However, the way that PBDEs influence adipocyte differentiation remains unclear. The methylisobutylxanthine, dexamethasone, and insulin method was used to study the effect of BDE-47 on the differentiation of 3T3-L1 cells. The 3T3-L1 cells were exposed by different concentrations of BDE-47, and the effect of cell viability was detected at different stages. In addition, the lipid droplet aggregation of adipocytes was observed and the triglyceride (TG) levels in the cytoplasm were detected after differentiation. The relative mRNA expression levels of leptin, adiponectin, and PPARγ in cells were determined by RT-PCR, and differentially expressed genes were preliminarily screened by digital gene expression profile. Our study found that BDE-47 promoted the differentiation of 3T3-L1 cells. Restriction cubic spline analysis showed that BDE-47 bidirectionally. regulated the mRNA synthesis of TG, PPARγ, and leptin genes and the aggregation of lipid droplets. BDE-47 may induce adipocyte differentiation by activating PPARγ, resulting in the differential expression of genes related to the AMPK signaling pathway, insulin resistance, and other metabolic pathways. The highest and lowest-dose BDE-47 exposure groups had the greatest impact on adipocyte differentiation.

Topics: 3T3-L1 Cells; Animals; Cell Differentiation; Diabetes Mellitus, Type 2; Halogenated Diphenyl Ethers; Insulin Resistance; Leptin; Mice; PPAR gamma; RNA, Messenger

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Obesity

South-Asian immigrants to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) and increased adipose tissue insulin resistance (AT-IR), as compared to their Western counterparts. Fetuin-A is a hepatokine known to influence AT-IR.. Can plasma fetuin-A concentrations explain an ethnic difference in adipose tissue insulin resistance?. We performed a two-step euglycemic-hyperinsulinaemic clamp and measured plasma concentrations of fetuin-A and non-esterified fatty acids (NEFA), in 18 Pakistani and 21 Norwegians with T2DM (age 29-45y) in Norway. AT-IR was calculated as NEFA-suppression during the clamp. The adipokines/cytokines leptin, adiponectin, visfatin, PTX3, IL-1β, INF-γ, and IL-4 were measured in fasting plasma. Liver fat was estimated by CT-scans.. Despite a lower BMI, Pakistani patients displayed higher AT-IR than Norwegians. NEFA-suppression during clamp was lower in Pakistani than Norwegians (mean=-20.6%, 95%CI=[-40.8, -0.01] and p = 0.046). Plasma fetuin-A concentration was higher in Pakistani than Norwegians (43.4 ng/mL[12.7,74.0], p = 0.007) and correlated negatively to %NEFA-suppression during clamp (rho=-0.39, p = 0.039). Plasma fetuin-A concentration explained 22% of the ethnic difference in NEFA-suppression during the clamp. Pakistani patients exhibited higher plasma leptin and lower PTX3 levels than Norwegian, and plasma visfatin correlated positively to plasma fetuin-A levels in the Pakistani patients. We observed no correlation between plasma fetuin-A and liver fat, but fetuin-A correlated negatively with plasma IL-1β, INF-γ, and IL-4 concentrations. Plasma IL-4 concentration was lower in Pakistani than in Norwegian patients.. Fetuin-A may contribute to explain the discrepancy in T2DM prevalence between Pakistani and Norwegians patients by influencing AT-IR.

Topics: Adipose Tissue; Adult; alpha-2-HS-Glycoprotein; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Insulin Resistance; Interleukin-4; Leptin; Middle Aged; Nicotinamide Phosphoribosyltransferase; Norway; Pakistan

To investigate serum leptin levels in patients with type 2 diabetes mellitus (T2DM) and the relationship between leptin levels and T2DM complications and prevalence.. A total of 355 patients, 282 cases with T2DM and 73 normal controls, were recruited at 1st Medical Centre, Chinese PLA General Hospital (Beijing, China) between November 2013 and July 2014. Levels of serum leptin, biochemical markers and sexual hormones were measured, and clinical characteristics were retrieved through the electronic medical record system.. Leptin levels in females were higher than that in males. Leptin levels in T2MD patients were positively correlated with body mass index, percent body fat, triglyceride, cystatin C homocysteine and salivary acid, and negatively correlated with glycosylated serum protein and glycosylated albumin levels. Leptin levels in males were positively correlated with systolic pressure and estradiol, and negatively correlated with testosterone and high density lipoprotein cholesterol. Sex (female) was positively correlated with the duration of disease. Leptin levels in T2DM patients with complications such as hypertension, diabetic nephropathy, diabetic peripheral neuropathy and coronary heart disease were higher than that in patients without such complications. Leptin levels in females with diabetic retinopathy and diabetic macroangiopathy were higher than that in patients without such complications, but there was no difference in males.. Leptin has significant gender differences. Leptin levels are related to body mass index, percent body fat and sex hormone level in T2DM patients and may affect short-term blood glucose control in T2DM patients. Leptin levels are related to complications in patients with T2DM and affect the prevalence rates of complications.

Topics: Albumins; Biomarkers; Body Mass Index; Cholesterol, HDL; Cystatin C; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Estradiol; Female; Homocysteine; Humans; Leptin; Male; Polyesters; Testosterone; Triglycerides

Obesity is associated with metabolic syndrome (MBS), a cluster of components including central obesity, insulin resistance (IR), dyslipidemia, and hypertension. IR is the major risk factor in the development and progression of type 2 diabetes mellitus in obesity and MBS. Predicting preoperatively whether a patient with obesity would have improved or non-improved IR after bariatric surgery would improve treatment decisions.. A prospective cohort study was conducted between August 2019 and September 2021. We identified pre- and postoperative metabolic biomarkers in patients who underwent laparoscopic sleeve gastrectomy. Patients were divided into two groups: group A (IR < 2.5), with improved IR, and group B (IR ≥ 2.5), with non-improved IR. A prediction model and receiver operating characteristics (ROC) were used to determine the effect of metabolic biomarkers on IR.. Seventy patients with obesity and MBS were enrolled. At 12-month postoperative a significant improvement in lipid profile, fasting blood glucose, and hormonal biomarkers and a significant reduction in the BMI in all patients (p = 0.008) were visible. HOMA-IR significantly decreased in 57.14% of the patients postoperatively. Significant effects on the change in HOMA-IR ≥ 2.5 were the variables; preoperative BMI, leptin, ghrelin, leptin/ghrelin ratio (LGr), insulin, and triglyceride with an OR of 1.6,1.82, 1.33, 1.69, 1.77, and 1.82, respectively (p = 0.009 towards p = 0.041). Leptin had the best predictive cutoff value on ROC (86% sensitivity and 92% specificity), whereas ghrelin had the lowest (70% sensitivity and 73% specificity).. Preoperative BMI, leptin, ghrelin, LGr, and increased triglycerides have a predictive value on higher postoperative, non-improved patients with HOMA-IR (≥ 2.5). Therefore, assessing metabolic biomarkers can help decide on treatment/extra therapy and outcome before surgery.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Gastrectomy; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Obesity, Morbid; Prospective Studies

Secretion of insulin is compromised in type 2 diabetes (T2DM) individuals and inadequate to accommodate for insulin resistance (IR) in peripheral tissue. Hyperleptinemia reflects leptin resistance, which is a key factor in the production of IR in T2DM patients, making leptin a potential biomarker for evaluating IR levels. The objective of the study was to assess the association of serum leptin and insulin levels among T2DM patients. This case-control research was carried out on T2DM patients. A total of 73 patients diagnosed with T2DM (the case group) and 40 healthy participants (control; group 3) were enrolled according to the American Diabetes Association (ADA) criteria. In the case group, T2DM patients were enrolled with metabolic syndrome (group 1, n = 38) or without metabolic syndrome (group 2, n = 35) according to the WHO criteria. Metabolic profiles of T2DM patients with or without metabolic syndrome were evaluated, and compare these two groups with healthy controls. The subjects of all groups were age- and gender-matched. Body mass index (BMI, P < .01), fasting (P = .0133) and postprandial (P < .01) blood sugar levels, % glycated hemoglobin (HbA1c, P < .01), and lipid profile (P < .01) were found significantly different and higher in group 1 as compared to groups 2 and 3. Serum leptin and insulin levels were found higher and significant in patients with metabolic syndrome (P < .01 for both). The values of serum leptin levels were 10.01 ± 2.7 ng/mL, 6.9 ± 2.4 ng/mL, and 4.11 ± 1.8 ng/mL, and those of serum insulin 120 ± 40.7 µIU/mL, 20.43 ± 5.2 µIU/mL, and 11.4 ± 2.5 µIU/mL in groups 1, 2, and 3, respectively. There was a positive linear correlation between BMI, blood sugar, HbA1c, serum cholesterol (TC), and triglycerides (TG) with serum insulin and leptin levels in the case group. An extremely significant correlation (R = 0.74, P < .001) was found in BMI and serum leptin level in the case group. Serum leptin and insulin levels have a positive association, with serum leptin being a significant predictor of IR syndrome (Evidence Level: 5; Technical Efficacy: Stage 3).

Topics: Blood Glucose; Body Mass Index; Case-Control Studies; Cholesterol; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Triglycerides

The cardio-renal benefits of sodium glucose-like transporter 2 inhibitor (SGLT2i) therapies have been demonstrated in patients with and without type 2 diabetes. However, no studies have explored the long-term metabolic effects of SGLT2i, combined with dietary carbohydrate restriction. Our primary objective was to describe long-term changes in weight, energy expenditure, appetite and body composition after 12 months of Dapagliflozin therapy, with carbohydrate restriction, in people with type 2 diabetes and obesity. Our secondary objective was to assess changes in adiponectin and leptin.. This was a 12-month cohort study in a secondary care setting. Participants (n = 18) with type 2 diabetes (T2D) and class 3 obesity underwent baseline indirect calorimetry for determination of 24-h energy expenditure, body composition, fasting serum leptin and adiponectin levels, and appetitive assessments. Following initiation of Dapagliflozin (and dietary carbohydrate restriction), measurements were repeated at monthly intervals up to 12 months.. In this study, combined Dapagliflozin therapy and carbohydrate restriction in patients with T2D and obesity resulted in a significant reduction of body weight and fat mass at 12 months without any discernible changes in energy expenditure or appetite. These results offer a scientific and clinical rationale to conduct an exploratory trial investigating the effects of a low carbohydrate diet combined with SGLT2 inhibitors in patients with T2D.

Topics: Adiponectin; Cohort Studies; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dietary Carbohydrates; Humans; Leptin; Longitudinal Studies; Obesity; Sodium-Glucose Transporter 2 Inhibitors

Evolving type 2 diabetes (T2D) may influence locomotion and affective state, promoting metabolic dysfunction. We examined behaviour and neurobiology in a model of T2D, testing for benefits with dietary n-3 polyunsaturated fatty acid (PUFA).. Male C57Bl/6 mice received vehicle or 75 mg/kg streptozotocin (STZ) and 21 wks of control or Western diets (43 % fat, 40 % carbohydrate, 17 % protein). Sub-sets received dietary α-linolenic acid (ALA; 10 % of fat intake) for 6 wks. Behaviour was examined via open field and sucrose preference tests, and hippocampal and frontal cortex (FC) leptin and dopamine levels and inflammatory signalling assessed.. T2D mice exhibited weight gain (+15 %), hyperglycemia (+35 %), hyperinsulinemia (+60 %) and insulin-resistance (+80 % higher HOMA-IR), together with anxiety-like behaviour (without anhedonia) that appeared independent of body weight and glycemic status. Cortical leptin declined whereas receptor mRNA increased. Supplementation with ALA did not influence metabolic state, while enhancing locomotion and reducing anxiety-like behaviours in healthy but not T2D mice. Hippocampal dopamine was selectively increased by ALA in T2D mice, with a trend to reduced circulating leptin in both groups. Across all groups, anxiety-like behaviour was associated with declining cortical and hippocampal leptin levels and increasing receptor mRNA, while declining dopamine levels were accompanied by decreased dopamine/serotonin receptor transcripts.. Chronic T2D induced anxiogenesis in mice appears to be independent of metabolic homeostasis but linked to central leptin-resistance, together with disturbed dopamine and serotonin signalling. Despite anxiolytic effects of ALA in healthy mice, no metabolic or behavioural benefits were evident in T2D.

Topics: alpha-Linolenic Acid; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, Western; Dopamine; Fatty Acids; Leptin; Male; Mice; Neurobiology; RNA, Messenger

Obesity may also develop due to a viral infection caused by adenovirus 36. We aimed to detect the presence of neutralizing antibodies against Ad-36 in adult patients who developed type 2 diabetes due to obesity (BMI ≥ 30 kg/m2).. The patient group (PG) was composed of 80 obese people with type 2 diabetes, the patient control group (PCG) was composed of 40 non-obese people with type 2 diabetes, and the healthy control group (HCG) was com-posed of 40 non-obese people without type 1 or type 2 diabetes in this case-control study. The presence of Ad-36 neutralizing antibodies was studied by serum neutralization assay.. A significant difference was found between the PG and HCG in terms of Ad-36 antibody positivity (p < 0.0001) but no significant difference was detected between the PG and the PCG (p > 0.05). BMI, serum leptin, adiponectin, and triglyceride levels were significantly higher in the PG (p < 0.05). Conversely, TNF-α and IL-6 levels were significantly lower in the PG (p < 0.0001). When the two groups were compared, the mean levels of total cho-lesterol and LDL in the PG were found to be high, although not significant (p > 0.05). In type 2 diabetes patients (n = 120), age, BMI, HDL, LDL, triglyceride, total cholesterol, Ad-36 presence, leptin, adiponectin, TNF-α, and IL-6 parameters were taken as independent variables for logistic regression. While BMIs was found to be significant (odds ration [OR] = 2.358; p = 0.0001, 95% Cl 1.507 - 3.690, Ad-36 presence was found to be a significant (OR = 27.352; p = 0.003, 95% Cl 3.157 - 236.961). Our study showed that BMI and Ad-36 increase type 2 diabetes risk by 2.3 and 27.3-fold in the PG and PCG (type 2 diabetes patients) versus the HCG. There was also a significant difference between PCG and HCG.. We suggest that Ad-36 seropositivity is also a risk factor for the development of type 2 diabetes independent of being obese.

Topics: Adenoviridae; Adenoviridae Infections; Adiponectin; Adult; Antibodies, Neutralizing; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Interleukin-6; Leptin; Obesity; Triglycerides; Tumor Necrosis Factor-alpha

Fetal overgrowth "programs" an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors.. Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene-cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not.. Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.

Topics: Adiponectin; Adult; Carrier Proteins; Diabetes Mellitus, Type 2; Diabetes, Gestational; DNA Methylation; Female; Fetal Blood; Fetal Development; Fetal Macrosomia; Gestational Age; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Membrane Proteins; Placenta; Pregnancy

Biological sex and aging impact obesity development and type 2 diabetes, changing the secretion of leptin and adiponectin. The balance between these factors has been propounded as a reliable biomarker of adipose tissue dysfunction. Our proposal was to study sexual differences and aging on the adiponectin/leptin (Adpn/Lep) ratio in order to acquire a broader view of the impact of consuming an high-fat diet (HFD) on energy metabolism according to sex and age. Male and female C57BL/6J mice were fed a normal chow diet or an HFD for 12 or 32 weeks (n = 7−10 per group) and evolution of body weight, food intake and metabolic profile were registered. The HFD triggered an increase in body weight (p < 0.001), body weight gain (p < 0.01) and adiposity index (p < 0.01) in both sexes at 32 weeks of age, but female mice fed the HFD exhibited these changes to a significantly lower extent than males. Aged female mice showed an increase (p < 0.01) in the Adpn/Lep ratio, which was negatively correlated with body weight gain, changes in different fat depots and insulin resistance. Females were more metabolically protected from obesity development and its related comorbidities than males regardless of age, making the Adpn/Lep ratio a relevant factor for body composition and glucose metabolism.

Topics: Adiponectin; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Weight Gain

Several investigations revealed the association between ApoA2 concentration and lipid profile, inflammation and oxidative stress markers. Dietary habits also play a major role in the health status of individuals with type 2 diabetes mellitus (T2DM). This study aimed to investigate the interaction of ApoA2-256T > C with dietary indexes on ghrelin and leptin hormones together with biochemical markers among individuals with T2DM. A cross-sectional study was conducted on 726 randomly selected individuals with T2DM. A validated FFQ was used to evaluate Healthy Eating Index, Dietary Quality Index-International (DQI-I) and Dietary Phytochemical Index (DPI). ApoA2-256T > C genotypes were detected by real-time-PCR. Ghrelin, leptin and biochemical markers were also assessed. ANCOVA was used for the interaction between the polymorphism and dietary indexes. A significant interaction was observed between ApoA2-256T > C and DQI-I on high-sensitivity C-reactive protein (hs-CRP) level and superoxide dismutase (SOD) activity. Besides, the interaction of the SNP and DPI significantly affected hs-CRP and 8-isoprostane F2

Topics: Apolipoprotein A-II; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet, Healthy; Dinoprost; Ghrelin; Humans; Leptin; Phytochemicals; Superoxide Dismutase

Leptin, an adipocyte-derived signalling molecule that plays important role in the regulation of energy balance, body weight and glucose metabolism.. To evaluate leptin mRNA expression as a predictive biomarker in type 2 diabetes mellitus (T2DM).. To detect the expression patterns of leptin mRNA, a quantitative real-time polymerase chain reaction was performed on samples collected from 71 T2DM patients and 32 non-diabetic controls. The receiver operating characteristic curve (ROC) was utilised to assess the discriminatory power of leptin mRNA.. Leptin mRNA levels were reduced significantly in diabetic patients compared with non-diabetic controls (P ≤ .0001). The ROC curve analysis showed a significant association between leptin mRNA levels and T2DM (P ≤ .0001), with a high area under the ROC curve (AUC) of 0.95 (95% CI: 0.89-0.98). The analysis also showed that fasting blood glucose and glycosylated haemoglobin had high AUC values of 0.88 and 0.97 with (95% CI: 0.80-0.93 and 0.92-0.99), respectively.. This study shows that the reduced leptin mRNA expression level is significantly associated with T2DM and could be used as a predictive and diagnostic biomarker for T2DM.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Leptin; RNA, Messenger

Prediabetes is a strong predictor of type 2 diabetes and its associated cardiovascular complications, but few studies explore sexual dimorphism in this context. Here, we aim to determine whether sex influences physiological response to high-fat high-sucrose diet (HFS) and myocardial tolerance to ischemia-reperfusion injury. Male and female Wistar rats were subjected to standard (CTRL) or HFS diet for 5 months. Then, ex-vivo experiments on isolated perfused heart model were performed to evaluate tolerance to ischemia-reperfusion injury. HFS diet induced fasting hyperglycemia and increased body fat percent to a similar level in both sexes. However, glucose intolerance was more pronounced in female HFS. Cholesterol was increased only in female while male displayed higher level of plasmatic leptin. We observed increased heart weight to tibia length ratio only in males, but we showed a similar decrease in tolerance to ischemia-reperfusion injury in female and male HFS compared with respective controls, characterized by impaired cardiac function, energy metabolism and coronary flow during reperfusion. In conclusion, as soon as glucose intolerance and hyperglycemia develop, we observe higher sensitivity of hearts to ischemia-reperfusion injury without difference between males and females.

Topics: Animals; Cholesterol; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Sucrose; Energy Metabolism; Female; Glucose Intolerance; Humans; Hyperglycemia; Leptin; Male; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Prediabetic State; Rats; Rats, Wistar; Sex Factors; Weight Gain

This study is aimed at analyzing the relationship between leptin (LEP) signaling pathway and type 2 diabetes mellitus (T2DM) and at providing support for molecular genetic research on the pathogenesis of T2DM in Chinese Han population.. A case-control study was designed, including 1092 cases with T2DM and 1092 healthy controls of Chinese Han origin recruited from ten hospitals in Guangdong Province, Southern China. Twenty-three single nucleotide polymorphisms (SNPs) of 15 genes in LEP signaling pathway were genotyped by SNPscan™ kit. The Pearson chi-square test, Cochran-Armitage trend test, MAX3, and logistic regression were applied to analyze the association between single nucleotide polymorphism (SNP) and T2DM; unconditional logistic regression was used to analyze haplotype in LD block; and SNP set analysis based on logistic kernel machine regression was used to analyze pathway. All statistical analysis was performed by SPSS25.0, R2.14, Haploview4.2, SNPStats, and other statistical software packages.. In association analysis based on SNP, rs2167270 had statistical significance both in the adjusted and unadjusted covariate dominant model and in the unadjusted covariate overdominant model while it had no significant difference in the adjusted covariate overdominant model. Compared to GG genotype, rs2167270 of AG genotype had statistical significance in both the adjusted and unadjusted covariate codominant models. And rs16147 had statistical significance in robust test, stealth model and overdominant model, and adjusting and unadjusting covariate. This study found linkage disequilibrium existed between rs2167270 and rs4731426 of LEP, rs10889502 and rs17127107 of JAK1, rs2970847 and rs6821591 of PPARGC1A, rs249429 and rs3805486 of PRKAA1, rs1342382 and rs6588640 of PRKAA2, rs3766522 and rs6937 of PRKAB2, rs2970847 and rs6821591 of PRKAG2, and rs6436094 and rs645163 of PRKAG3. There was no positive finding with statistical significance from the unconditional logistic regression of the mentioned genes' haplotype of LD block.. LEP signaling pathway association with T2DM remained to be confirmed in Chinese Han population, although rs2167270 and rs16147 were significantly associated with T2DM.

Topics: Alleles; Asian People; Case-Control Studies; China; Diabetes Mellitus, Type 2; Ethnicity; Female; Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Leptin; Linkage Disequilibrium; Logistic Models; Male; Middle Aged; Polymorphism, Single Nucleotide; Signal Transduction

The aim of this study was to cross-sectionally and longitudinally examine whether higher hemoglobin (Hb) levels within the normal variation associate with key components of metabolic syndrome and total and cardiovascular mortality. The study included 967 Finnish subjects (age 40-59 years) followed for ≥ 20 years. The focus was on Hb levels, cardiovascular diseases (CVDs) and mortality rates. Higher Hb levels associated positively with key anthropometric and metabolic parameters at baseline. At the follow-up similar associations were seen in men. The highest Hb quartile showed higher leptin levels and lower adiponectin levels at baseline and follow-up (p < 0.05) and lower plasma ghrelin levels at baseline (p < 0.05). Higher baseline Hb levels associated independently with prevalence of type 2 diabetes at follow-up (p < 0.01). The highest Hb quartile associated with higher serum alanine aminotransferase levels (p < 0.001) and independently with increased risk for liver fat accumulation (OR 1.63 [1.03; 2.57]) at baseline. The highest Hb quartile showed increased risk for total (HR = 1.48 [1.01; 2.16]) and CVD-related mortality (HR = 2.08 [1.01; 4.29]). Higher Hb levels associated with an adverse metabolic profile, increased prevalence of key components of metabolic syndrome and higher risk for CVD-related and total mortality.

Topics: Adiponectin; Adult; Aged; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Female; Finland; Follow-Up Studies; Ghrelin; Hemoglobins; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Risk Factors

Topics: Adenylate Kinase; Allosteric Regulation; Animals; Area Under Curve; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Estradiol; Gene Expression Regulation; Glycated Hemoglobin; Insulin; Insulin Resistance; Leptin; Male; Metformin; Phosphorylation; Rats, Wistar; Receptors, LH; Seminiferous Tubules; Spermatogenesis; Steroids; Testosterone

Diabetes mellitus (DM) is a significant predictor of atherosclerosis, cardiovascular disease, and cardiovascular mortality. It is known that atherosclerosis occurs earlier in patients with diabetes, reducing the duration of their life. Leptin as well as other inflammatory markers can contribute to the progression of atherosclerosis in patients with DM, participate in the development of a local inflammatory reaction.. Determine the cells immunophenotype of atherosclerotic plaques in patients with diabetes.. We analyzed 24 patients (20 men and 4 women), who underwent aortofemoral bypass, femoral-tibial bypass or carotid endarterectomy. During the operation, a fragment of the arterial wall with an atherosclerotic plaque was obtained for further immunohistochemical studies. Five histologic plaque characteristics (CD68+, -SMA, CD34, leptin and leptin receptor) were compared.. No difference in the expression of CD68 (p=0.922), -SMA (p=0.192), CD34 (p=0.858), leptin receptor (p=0.741) and leptin (p=0.610) in atherosclerotic plaques were observed between patients with and without DM. The lack of significant differences between the two groups was possibly due to the small number of observations with DM. In particular, when assessing the expression of selected markers in atherosclerotic plaques, patients with DM showed significantly more leptin receptors than patients without DM (2160.716 and 1205.88 respectively); and also significantly less CD68+ (0.39 and 0.98 respectively) and -SMA+ (6.5 and 13.5 respectively).. Based on the expression of CD68, -SMA, CD34, leptin receptor and leptin, no significant differences were observed in atherosclerotic plaque between patients with and without DM. At the same time, despite the limitations of the study (a small number of patients, moderate severity of DM, elderly patients in the DM group), we found a tendency in the increased number of leptin receptors and a decreased number of -SMA+, CD68+ in DM atherosclerotic plaques. Further study needed, taking into account the limitations of this work.. Обоснование. Сахарный диабет (СД) является важным предиктором развития атеросклероза, сердечно-сосудистых заболеваний и смертности от сердечно-сосудистых заболеваний. Известно, что у больных СД атеросклероз возникает раньше, сокращая продолжительность их трудовой деятельности и жизни. Лептин, как и маркеры воспаления, могут способствовать прогрессированию атеросклероза при СД, участвовать в развитии местной воспалительной реакции и патогенезе развития атеросклеротической бляшки. Цель. Изучить иммунофенотип клеток, входящих в состав атеросклеротических бляшек у пациентов с СД. Материалы и методы. Проведено наблюдательное одномоментное двухцентровое исследование, в которое включены 24 пациента (20 мужчин и 4 женщины), подвергшиеся аорто-феморальному, бедренно-берцовому шунтированию или каротидной эндартерэктомии. В ходе проведения операции получен фрагмент артериальной стенки с атеросклеротической бляшкой для дальнейшего проведения иммуногистохимического исследования: оценки экспрессии CD68+ макрофагов, -SMA (-гладкомышечный актин), CD34, лептина и рецептора лептина. Результаты. При сравнении результатов оценки экспрессии CD68 (p=0,922), -SMA (p=0,192), CD34 (p=0,858), рецептора лептина (p=0,741) и лептина (p=0,610) в атеросклеротических бляшках статистически значимых различий между группами пациентов с СД и без СД не выявлено. Отсутствие достоверных различий между двумя группами, возможно, обусловлено небольшим количеством наблюдений пациентов с СД. В частности, при оценке экспрессии выбранных маркеров в атеросклеротических бляшках у больных СД отмечено значительно больше рецепторов лептина, чем у лиц без СД (2160,716 и 1205,88 соответственно), а также значительно меньше CD68+ (0,39 и 0,98 соответственно) и -SMA+ (6,5 и 13,5 соответственно). Заключение. На основании оценки экспрессии CD68, -SMA, CD34, рецептора лептина и лептина не выявлено достоверных различий в структуре атеросклеротической бляшки у пациентов с СД и без. В то же время, несмотря на ограничения исследования (небольшое число больных, умеренная тяжесть СД, пожилой возраст пациентов в группе с нарушением углеводного обмена), мы обнаружили тенденцию в увеличении количества рецепторов лептина и уменьшении количества -SMA+, CD68+ у больных СД. Требуется дальнейшее изучение этой проблемы с учетом ограничений данной работы.

Topics: Aged; Atherosclerosis; Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Plaque, Atherosclerotic; Receptors, Leptin

Diabetes mellitus is a serious threat to human health. Cyclocarya paliurus (Batal.) Iljinskaja (C.paliurus) is one of the traditional herbal medicine and food in China for treating type 2 diabetes, and the C. paliurus polysaccharides (CP) were found to be one of its major functional constituents. This research aimed at investigating the hypoglycemic mechanism for CP. It was found that CP markedly attenuated the symptoms of diabetes, and inhibited the protein expression of Bax, improved the expression of Bcl-2 in pancreas of diabetic rats, normalized hormones secretion and controlled the inflammation which contributed to the regeneration of pancreatic β-cell and insulin resistance. CP treatment increased the beneficial bacteria genus Ruminococcaceae UCG-005 which was reported to be a key genus for protecting against diabetes, and the fecal short-chain fatty acids levels were elevated. Uric metabolites analysis showed that CP treatment helped to protect with the diabetes by seven significantly improved pathways closely with the nutrition metabolism (amino acids and purine) and energy metabolism (TCA cycle), which could help to build up the intestinal epithelial cell defense for the inflammation associated with the diabetes. Our study highlights the specific mechanism of prebiotics to attenuate diabetes through multi-path of gut microbiota and host metabolism.

Topics: Animals; Blood Glucose; Cytokines; Diabetes Mellitus, Type 2; Fatty Acids, Volatile; Feces; Gastrointestinal Microbiome; Hydrogen-Ion Concentration; Hypoglycemic Agents; Insulin; Juglandaceae; Leptin; Male; Metabolomics; Pancreas; Phytotherapy; Plant Extracts; Plant Leaves; Polysaccharides; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar

Increased visceral adipose tissue (VAT) is associated with metabolic dysfunction, while subcutaneous adipose tissue (SAT) is considered protective. The mechanisms underlying these differences are not fully elucidated. This study aimed to investigate molecular differences in VAT and SAT of male Wistar rats fed a cafeteria diet (CD) or a standard rodent diet (STD) for three months. The expression of fatty acid metabolism genes was analysed by quantitative real-time PCR. Global and gene-specific DNA methylation was quantified using the Imprint® Methylated DNA Quantification Kit and pyrosequencing, respectively. Bodyweight, retroperitoneal fat mass, insulin resistance, leptin and triglyceride concentrations and adipocyte hypertrophy were higher in CD- compared to STD-fed rats. The expression of solute carrier family 27 member 3 (Slc27a3), a fatty acid transporter, was 9.6-fold higher in VAT and 6.3-fold lower in SAT of CD- versus STD-fed rats. Taqman probes confirmed increased Slc27a3 expression, while pyrosequencing showed Slc27a3 hypomethylation in VAT of CD- compared to STD-fed rats. The CD decreased global methylation in both VAT and SAT, although no depot differences were observed. Dysregulated fatty acid influx in VAT, in response to a CD, provides insight into the mechanisms underlying depot-differences in adipose tissue expansion during obesity and metabolic disease.

Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; DNA Methylation; Fatty Acid Transport Proteins; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Metabolic Diseases; Obesity; Rats; Rats, Wistar; Subcutaneous Fat

Obesogenic and diabetogenic high fat (HF) diets can influence genetic factors in disease development with sexual dimorphic responses. We investigated potential protective effects of tart cherry (TC), fish oil (FO) and TC+FO supplementation in TALLYHO/Jng (TH) and C57BL/6J (B6) mice fed HF diets. Male and female TH and B6 mice were weaned onto five different diets; low fat (LF), HF, and HF supplemented with TC, FO, or TC+FO and maintained. For both males and females on LF, TH mice were heavier and fatter than B6, which was accentuated by HF in males, but not in females. TH males, but not others, developed severe glucose intolerance and hyperglycemia on HF, with reduced mRNA levels of Adipoq and Esr1 in adipose tissue. Considering energy balance, locomotor activity was lower in TH mice than B6 for both sexes without diet effects, except B6 females where HF decreased it. Compared to LF, HF decreased energy expenditure, RER, and food intake (in grams) for both sexes without strain differences. In all mice, but B6 males, HF increased plasma IL6 levels compared to LF. No preventive effects of TC, FO or TC+FO were noted for HF-induced obesity or energy imbalance, but FO alleviated glucose intolerance in TH males. Further, TC and FO decreased plasma IL6 levels, especially in females, without additive or synergistic effects of these two. Collectively, obesogenic and diabetogenic impacts of HF diets differed depending on the genetic predisposition. Moreover, sexually dimorphic effects of dietary supplementation were observed for glucose metabolism and inflammatory markers.

Topics: Adiponectin; Animal Feed; Animals; Aromatase; Body Composition; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Fats; Estrogen Receptor beta; Female; Fish Oils; Fruit; Gene Expression Regulation; Interleukin-6; Leptin; Male; Mice; Mice, Inbred Strains; Obesity; Prunus avium; Sex Factors

Diabetes mellitus (DM), as a multiorgan syndrome, is an endocrine and metabolic disorder that is associated with male reproductive system dysfunction and infertility. Safflower (Carthamus tinctorius L.) as an herbal remedy improves DM and infertility-related disorders. The anti-hypercholesterolemic, anti-inflammatory, and antioxidative properties of this herb have been well documented, but its role in testosterone production, male reproductive system and zinc homeostasis has not been fully illustrated.. This study aimed to investigate the preventive and therapeutic properties of different doses of safflower seed oil against reproductive damage caused by type II DM by investigating zinc element homeostasis, inflammation and oxidative damage in testis tissue and their relationship with testosterone production and sperm parameters.. Eighty adult male Sprague-Dawley rats were randomly divided into eight groups and treated daily for 12 and 24 weeks in protective and therapeutic studies, respectively. Type II DM was induced by a High Fat Diet (HFD) in normoglycemic rats for three months. At the end of each study, serum level of glucose, testosterone, gonadotropins, TNF-α, insulin, and leptin were measured. Moreover, antioxidant enzymes activity, lipid peroxidation, zinc and testosterone along with the expression of Nrf-2, NF-κB, TNF-α, StAR, P450scc, and 17βHSD3 genes in the testis were detected.. After the intervention, the activity of antioxidant enzymes and the level of testosterone and gonadotropins significantly decreased in the rats with DM in comparison to the others. However, lipid peroxidation and serum level of insulin, leptin and TNF-α increased and the testicular level of zinc significantly changed in the rats with DM compared to the control groups (p < 0.05). The gene expression of NF-κB and TNF-α were also significantly increased and the gene expression of Nrf2, StAR, P450scc and 17βHSD3 were decreased in the testis of diabetic rats (p < 0.05). The results showed that pretreatment and treatment with safflower seed oil could improve these parameters in diabetic rats compared with untreated diabetic rats (p < 0.05).. HFD could impair the production of testosterone and sperm, and reduce gonadotropin by increasing the serum level of leptin and inducing insulin resistance, oxidative stress and inflammation. However, safflower oil in a dose-dependent manner could improve testosterone level and sperm parameters by improving the level of leptin, zinc and insulin resistance, and the genes expression involved in testosterone synthesis, inflammation and oxidative stress.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Eating; Gene Expression Regulation; Gonadotropins; Inflammation; Insulin; Leptin; Lipid Peroxidation; Lipogenesis; Male; Oxidative Stress; Rats, Sprague-Dawley; Safflower Oil; Seeds; Spermatogenesis; Spermatozoa; Steroids; Testis; Testosterone; Tumor Necrosis Factor-alpha; Zinc

The etiology of diabetic nephropathy in type 2 diabetes is multifactorial. Sustained hyperglycemia is a major contributor, but additional contributions come from the hypertension, obesity, and hyperlipidemia that are also commonly present in patients with type 2 diabetes and nephropathy. The leptin deficient BTBR ob/ob mouse is a model of type 2 diabetic nephropathy in which hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with leptin replacement can reverse the morphologic and functional manifestations of diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the hypertriglyceridemia, using an antisense oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the interactions of VLDL (very low density lipoproteins) with the LDL receptor, is sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment resulted in reduction of circulating ApoC-III protein levels and resulted in substantial lowering of triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate proteinuria or pathologic manifestations of diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of diabetic nephropathy are unlikely to be reduced by lipid-lowering therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other therapeutics commonly employed in the treatment of diabetes and its complications.

Topics: Animals; Apolipoprotein C-III; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Hypertriglyceridemia; Leptin; Male; Mice; Mice, Obese; Oligonucleotides, Antisense; Podocytes

Metabolic syndrome-related diseases affect millions of people worldwide. It is well established that changes in nutritional habits and lifestyle can improve or prevent metabolic-related pathologies such as type-2 diabetes and obesity. Previous reports have shown that nutritional supplements have the capacity to limit glucose intolerance and suppress diabetes development. In this study, we investigated the effect of dietary supplementation with fish-derived extracts on obesity and type 2 diabetes and their impact on gut microbial composition. We showed that nutritional supplements containing Fish Complex (FC), Fish Complex combined with Cod Powder (FC + CP), or Cod Powder combined with Collagen (CP + C) improved glucose intolerance, independent of abdominal fat accumulation, in a mouse model of diet-induced obesity and type 2 diabetes. In addition, collagen-containing supplements distinctly modulate the gut microbiome in high-fat induced obesity in mice. Our results suggest that fish-derived supplements suppress diet-induced type 2 diabetes, which may be partly mediated through changes in the gut microbiome. Thus, fish-derived supplements and particularly the ones containing fish collagen have potential beneficial properties as dietary supplements in managing type 2 diabetes and metabolic syndrome via modulation of the gut microbiome.

Topics: Abdominal Fat; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Female; Fishes; Gastrointestinal Microbiome; Glucose Intolerance; Hypoglycemic Agents; Insulin Resistance; Leptin; Mice, Inbred C57BL; Obesity; Tissue Extracts

Glycosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to weight loss and improved diabetes control, but a significant disparity exists between observed and expected weight loss with these medications, hindering clinical effects. This study investigated whether this discrepancy could be explained by compensatory increases in appetite and associated alterations in appetite-regulating hormones.. This was a prospective single-center observational pilot study. Adults 18-70 years old newly prescribed an SGLT2 inhibitor through usual care were invited to participate. Fasting and postprandial appetite was assessed immediately before, 1 week after, and 12 weeks after SGLT2 inhibitor initiation. Serum samples were collected at corresponding time points to measure ghrelin, leptin, and peptide tyrosine-tyrosine (PYY). Seven patients were included. At 1 and 12 weeks after SGLT2 inhibitor initiation, self-reported appetite did not change significantly and trended toward a decrease in appetite. There were no significant differences in fasting or postprandial ghrelin, leptin, or PYY.. Results suggest the discrepancy between expected and observed weight loss with SGLT2 inhibitors cannot be explained by increases in appetite or changes in appetite-regulating hormones. Further studies are needed to investigate alternative metabolic compensatory mechanisms to optimize weight loss with SGLT2 inhibitor use.

Topics: Aged; Appetite Regulation; Biomarkers; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Peptide YY; Pilot Projects; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome; Weight Loss

The aim of the study was to investigate the association of adipokines (resistin, leptin and adiponectin) with obesity, insulin resistance (IR) and inflammation in type 2 diabetes mellitus (T2DM). A total of 284 patients with T2DM were included. Concentrations of resistin, leptin, adiponectin, and inflammatory markers [high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6)] were measured and homeostatic model assessment for IR (HOMA-IR) index was calculated. Resistin correlated negatively with estimated glomerular filtration rate (eGFR) and positively with hsCRP, TNF-α, IL-6, and white blood cell count (WBC). Leptin correlated positively with HOMA-IR, whereas adiponectin correlated negatively. Leptin also correlated positively with body mass index (BMI), waist circumference, IL-6, WBC and negatively with eGFR. Adiponectin correlated negatively with waist circumference, WBC, and eGFR. Multivariate logistic regression indicated lower eGFR and higher WBC and IL-6 as independent predictive factors of resistin concentration above the upper quartile (CAQ3), whereas female sex and higher BMI and HOMA-IR of leptin CAQ3, and lower HOMA-IR and older age of adiponectin CAQ3. In conclusion, in contrast to leptin and adiponectin, in T2DM patients, resistin is not associated with BMI and IR, but with inflammation and worse kidney function.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Inflammation; Insulin Resistance; Kidney Function Tests; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Resistin

Leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are commonly used mice models mimicking the conditions of obesity and type 2 diabetes development. However, although ob/ob and db/db mice are similarly gaining weight and developing massive obesity, db/db mice are more diabetic than ob/ob mice. It remains still unclear why targeting the same pathway-leptin signaling-leads to the development of two different phenotypes. Given that gut microbes dialogue with the host via different metabolites (e.g., short-chain fatty acids) but also contribute to the regulation of bile acids metabolism, we investigated whether inflammatory markers, bacterial components, bile acids, short-chain fatty acids, and gut microbes could contribute to explain the specific phenotype discriminating the onset of an obese and/or a diabetic state in ob/ob and db/db mice.. Six-week-old ob/ob and db/db mice were followed for 7 weeks; they had comparable body weight, fat mass, and lean mass gain, confirming their severely obese status. However, as expected, the glucose metabolism and the glucose-induced insulin secretion were significantly different between ob/ob and db/db mice. Strikingly, the fat distribution was different, with db/db mice having more subcutaneous and ob/ob mice having more epididymal fat. In addition, liver steatosis was more pronounced in the ob/ob mice than in db/db mice. We also found very distinct inflammatory profiles between ob/ob and db/db mice, with a more pronounced inflammatory tone in the liver for ob/ob mice as compared to a higher inflammatory tone in the (subcutaneous) adipose tissue for db/db mice. When analyzing the gut microbiota composition, we found that the quantity of 19 microbial taxa was in some way affected by the genotype. Furthermore, we also show that serum LPS concentration, hepatic bile acid content, and cecal short-chain fatty acid profiles were differently affected by the two genotypes.. Taken together, our results elucidate potential mechanisms implicated in the development of an obese or a diabetic state in two genetic models characterized by an altered leptin signaling. We propose that these differences could be linked to specific inflammatory tones, serum LPS concentration, bile acid metabolism, short-chain fatty acid profile, and gut microbiota composition. Video abstract.

Topics: Animals; Diabetes Mellitus, Type 2; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1β from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.

Topics: Diabetes Mellitus, Type 2; HMGB1 Protein; Humans; Hyperglycemia; Hyperinsulinism; Interleukin-2; Leptin; Leukocytes, Mononuclear

Topics: Adiponectin; Anthropometry; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Leptin; Taiwan; Waist Circumference

An original model of diabetes linked to carbohydrate and lipid intake is presented and applied to predict the effects on biomarkers of various diets. The variables (biomarkers) are concentrations of fasting plasma glucose, insulin, leptin, glucagon, non-esterified fatty acids (NEFA) and very low density lipoprotein triglyceride (VLDLTG), as well as muscle lipids, hepatic lipids, pancreatic lipids, fat mass and mass of β-cells. The model predicts isocaloric high carbohydrate low fat (HCLF) diet and low carbohydrate high fat (LCHF) diet trajectories to health which vary in fat mass by at most a few kilograms at steady state. The LCHF trajectories to health are faster than isocaloric HCLF trajectories with respect to fat mass loss, although these trajectories may be slower initially if parameters are adjusting from HCLF values. On LC diets, leptin sensitivity and VLDLTG clearance are thought to increase. Increasing leptin sensitivity and VLDLTG clearance is predicted to lower lipids including fat mass and VLDLTG. The model predicts that changes in VLDLTG due to a change in diet happen rapidly, approaching steady state values after a few weeks, reflecting leptin sensitivity and VLDLTG clearance which are much harder to measure. The model predicts that if only insulin sensitivity increases on a LC diet, steady state fat mass would increase slightly. If leptin and insulin sensitivities increase concurrently, the combined effect could be a decrease in fat mass, consistent with the fact that increasing insulin sensitivity is often associated with fat mass loss in trials. The model predicts trajectories to fat type II diabetes with hypertriglyceridemia due to high carbohydrate moderate fat diets, on which insulin rises before falling, as ectopic fat deposits increase; made fatter and more diabetic by higher lipid consumption. It predicts trajectories to non-diabetic states with raised fat mass, VLDLTG and muscle, hepatic and pancreatic lipids due to moderate carbohydrate high fat diets. The model predicts paths to lean type II diabetes, on a diet of moderate energy but low β-cell replication rate or high death rate.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diet; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipoproteins, VLDL; Models, Theoretical; Triglycerides

Diabetes mellitus has become a worldwide concern in recent years. In this study, the effect of Holothuria leucospilota polysaccharide (HLP) on type 2 diabetes mellitus (T2DM) was investigated in Goto-Kakizaki (GK) rats. The results showed that HLP significantly improved glucose intolerance and regulated blood lipid and hormone levels (p < 0.05). Pathological analysis showed that HLP repaired the impairments of the pancreas and colon in diabetic rats. In addition, a high dose of HLP (200 mg/kg) significantly upregulated the gene expression of peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), phosphoinositide 3-kinase (PI3K), protein kinase B (PKB/AKT), glucose transporter-4 (GLUT4) and anti-apoptotic (Bcl-2), and downregulated the mRNA levels of pro-apoptotic (Bax) and cluster of differentiation 36 (CD36) in diabetic rats (p < 0.05). Furthermore, HLP treatment increased the short-chain fatty acid-producing bacteria and decreased the opportunistic bacterial pathogen in the feces of diabetic rats. These results demonstrated that HLP has the potential to ameliorate T2DM in GK rats.

Topics: Adiponectin; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Insulin; Leptin; Lipids; Male; Peroxisome Proliferator-Activated Receptors; Phosphatidylinositol 3-Kinases; Polysaccharides; Proto-Oncogene Proteins c-akt; Rats; Sea Cucumbers; Signal Transduction

There is growing evidence that type 2 diabetes or insulin resistance is linked to cognitive impairment. We recently confirmed altered lipid composition, down-regulation of insulin receptor expression and impaired basal synaptic transmission in the hippocampus of our transgenic murine model of adipocyte insulin resistance (AtENPP1-Tg). Here we evaluated whether the correction of adipose tissue dysfunction [via the subcutaneous transplantation of mesenchymal stem cells (MSC)] can improve the hippocampal synaptic transmission in AtENPP1-Tg mice versus their wildtype littermates. Animals were simply randomized to receive MSC, then weighed weekly for 12 weeks. At euthanasia, we assessed leptin in the collected serum and hippocampal synaptic high-frequency stimulation long-term potentiation (HFS-LTP) using brain slices. MSC transplantation normalized AtENPP1-Tg body and epididymal fat weights and was associated with increased leptin levels, a sign of adipocyte maturation. More importantly, transplantation restored the deficiency observed in AtENPP1-Tg HFS-LTP, the cellular readout of memory. Our results further corroborate the role of adipocyte maturation arrest in adipose tissue and highlight a role for the adipose tissue in modulating hippocampal cellular mechanisms. Further studies are warranted to explore the mechanisms for the MSC-induced improvement of hippocampal HFS-LTP.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Acids, Nonesterified; Hippocampus; Humans; Insulin Resistance; Leptin; Long-Term Potentiation; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphoric Diester Hydrolases; Pyrophosphatases; Synaptic Transmission

Although novel pharmacological options for the treatment of type 2 diabetes mellitus (DM2) have been observed to modulate the functionality of several key organs in glucose homeostasis, successful regulation of insulin resistance (IR), body weight management, and pharmacological treatment of obesity remain notable problems in endocrinology. Leptin may be a pivotal player in this scenario, as an adipokine which centrally regulates appetite and energy balance. In obesity, excessive caloric intake promotes a low-grade inflammatory response, which leads to dysregulations in lipid storage and adipokine secretion. In turn, these entail alterations in leptin sensitivity, leptin transport across the blood-brain barrier and defects in post-receptor signaling. Furthermore, hypothalamic inflammation and endoplasmic reticulum stress may increase the expression of molecules which may disrupt leptin signaling. Abundant evidence has linked obesity and leptin resistance, which may precede or occur simultaneously to IR and DM2. Thus, leptin sensitivity may be a potential early therapeutic target that demands further preclinical and clinical research. Modulators of insulin sensitivity have been tested in animal models and small clinical trials with promising results, especially in combination with agents such as amylin and GLP-1 analogs, in particular, due to their central activity in the hypothalamus.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypothalamus; Insulin Resistance; Leptin; Obesity

To investigate the relationships among serum resistin, adiponectin, and leptin and microvascular complications in patients with type 2 diabetes mellitus (T2DM).. A total of 120 patients with T2DM were divided into non-microangiopathy and microangiopathy groups. Sixty age- and sex-matched healthy subjects were used as a normal control (NC) group. Body height, body mass, waist circumference, and blood pressure were determined, and waist/hip ratio (WHR), body mass index, blood glucose, lipids, resistin, leptin, adiponectin, free fatty acids (FFA), high-sensitivity C-reactive protein (hs-CRP), fasting insulin, hemoglobin A1c, and homeostatic model assessment of insulin resistance (HOMA-IR) were compared among the three groups.. Serum levels of resistin, leptin, FFA, and hs-CRP were significantly higher and levels of adiponectin were significantly lower in patients in the non-microangiopathy (n = 60) and microangiopathy groups (n = 60) compared with the NC group (n = 60). Serum resistin and leptin levels in patients with T2DM were positively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but negatively correlated with high-density lipoprotein-cholesterol (HDL-C). Serum adiponectin levels in patients with T2DM were negatively correlated with WHR, hs-CRP, FFA, HOMA-IR, and triglycerides, but positively correlated with HDL-C.. Serum resistin, adiponectin, and leptin levels correlate with the occurrence of T2DM and microvascular complications.

Topics: Adiponectin; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Resistin; Vascular Diseases

Periodontitis is often associated with diabetes mellitus and may be considered one of the chronic complications of this disease. Increasing evidence indicates that periodontal disease (gingivitis and periodontitis) has an adverse effect on glycemic control and participates in the pathophysiology of complications related to type 2 diabetes mellitus. Thus, this study aimed to evaluate the influence of obesity on clinical periodontal parameters of patients with type 2 diabetes mellitus with stage II or III periodontitis grade C after conventional periodontal treatment.. For this study, 36 patients, aged 25 to 65 years, were evaluated; 20 patients with type 2 diabetes mellitus and moderate to severe periodontitis (Non-Obese Group) and 16 patients with type 2 diabetes mellitus with obesity and moderate to severe periodontitis (Obese Group). These patients underwent conventional periodontal treatment and were evaluated using plaque index, probing depth, clinical attachment level, bleeding on probing and gingival crevicular fluid analysis, as well as laboratory tests of glycated hemoglobin, fasting glycemia, total cholesterol, and fractions of triglycerides. Periodontal and laboratory parameters were evaluated at baselineand six months.. The results showed improvements in periodontal and clinical laboratory parameters(p less than 0.05) in the evaluated periods; however, the non-obese group presented significantly better results when compared to the obese group.. It can be concluded that the presence of obesity may hinder the improvement of periodontal clinical parameters after conventional periodontal treatment in patients with diabetes mellitus and periodontitis.

Topics: Adiponectin; Adult; Aged; Animals; Chemokine CCL5; Chronic Periodontitis; Diabetes Mellitus, Type 2; Gingival Crevicular Fluid; Humans; Interleukin-18; Interleukin-6; Leptin; Middle Aged; Periodontal Attachment Loss; Periodontal Index; Rats

To correlate serum leptin levels in obese and non-obese type 2 diabetic patients and compare them with healthy individuals.. The case-control study was conducted at the Lady Reading Hospital, Peshawar, and the Rehman Medical College, Peshawar, Pakistan, from June to November 2017, and comprised type 2 diabetic patients and and an equal number of healthy controls. Fasting blood glucose, glycated haemoglobin, serum leptin, and body mass index were assessed in obese and non-obese subjects. Relation between body mass index and serum leptin level was explored. Data was analysed using SPSS 20.. Of the 96 subjects, 48(50%) were in each of the two groups. Among the cases, there were 23(48%) men and 25(52%) women with an overall mean age of 51.27±11.7 years. The control group had 28(58%) men and 20(42%) women with an overall mean age of 49.3±12.1 years. Serum leptin levels were significantly higher in obese 9.42±1.87ng/ml and non-obese 7.21±3.78 ng/ml patients than the controls 5.38±2.20 ng/ml (p<0.05). Serum leptin concentration was significantly correlated with body mass index, fasting blood glucose and BMI, FBG and glycated haemoglobin (p<0.001 each).. Increased levels of serum leptin could be used as a risk factor in the development of type 2 diabetes mellitus.

Topics: Adult; Blood Glucose; Blood Pressure; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Leptin; Male; Middle Aged; Obesity; Pakistan

Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.

Topics: Adipocytes; Adipose Tissue, Brown; Animals; Cold Temperature; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Ferroptosis; Frataxin; Friedreich Ataxia; Hyperlipidemias; Insulin Resistance; Iron-Binding Proteins; Leptin; Lipid Metabolism; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; RNA-Seq; Thermogenesis

Disturbances in adipocytokine profiles can contribute to peripheral insulin resistance and impairment of insulin production, which are 2 primary pathophysiological mechanisms involved in type 2 diabetes mellitus (T2DM). Previous studies of disturbed adipocytokine profiles have resulted in ambiguous findings; therefore, we conducted the current study comparing leptin, resistin, and adiponectin concentrations in patients with newly diagnosed T2DM who had normal body mass index (BMI) and those who were obese.We studied a population-based cohort of healthy participants and those with newly diagnosed T2DM. A normal BMI group was randomly selected; age- and sex-matched obese participants were recruited. Circulating leptin, resistin, and adiponectin concentrations were measured and compared between groups using analysis of variance; binary logistic regression analysis was then performed to compare the normal BMI and obese groups.In total, 85 healthy participants and 38 patients with diabetes (19 with normal BMI and 17 who were obese) were enrolled. After adjustment for BMI and waist circumference, the median leptin concentration was higher in the obese group (6.77 (3.89-10.73) ng/mL) than in the normal BMI group (1.69 (0.80-3.89) ng/mL) (P = .007), whereas the median adiponectin concentration was lower in the obese group (1.03 (0.75-2.36) μg/mL vs 3.36 (0.59-7.63) μg/mL, P = .03). In addition, the adiponectin/leptin ratio was higher in the normal BMI group (145.6 (41.3-495.9) ng/mL) than in the obese group (20.55 (8.74-36.94) ng/mL, P = .002).Compared with the normal BMI T2DM group, the obese T2DM group exhibited a disturbed adipocytokine profile in the form of a significantly increased leptin concentration and reduced adiponectin level. Further studies are needed to determine the causal relationship for this difference and evaluate its importance for personalized diabetic treatment.

Topics: Adiponectin; Adult; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity; Resistin; Waist Circumference

Topics: Adipose Tissue, Brown; Animals; Brain; Diabetes Mellitus, Type 2; Feeding Behavior; Gene Expression; Insulin; Leptin; Liver; Male; Malonyl Coenzyme A; Obesity; Rats, Zucker; Thermogenesis; Thinness

Survivors of Childhood Brain Tumors (SCBT) are at a higher risk of developing cardiovascular disease and type 2 diabetes compared to the general population. Adiposity is an important risk factor for the development of these outcomes, and identifying biomarkers of adiposity may help the stratification of survivors based on their cardiovascular risk or allow for early screening and interventions to improve cardiometabolic outcomes. Leptin is an adipokine that positively correlates with the adipose mass in the general population and is a predictor of adverse cardiometabolic outcomes, yet its association with adiposity in SCBT has not been studied. The aim of this study was to determine if leptin levels are associated with the adipose mass in SCBT, and to define its predictors. This cross-sectional study included 74 SCBT (n = 32 females) with 126 non-cancer controls (n = 59 females). Total adiposity was measured using Bioelectrical Impendence Analysis (BIA) and central adiposity was measured using waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). We used multivariable linear regression analysis to determine if leptin predicts adiposity in SCBT and adjusted for age, sex, puberty, and cancer status. Leptin correlated strongly with total (p < 0.001) and central (WHR p = 0.001; WHtR p < 0.001) adiposity in SCBT and non-cancer controls. In conclusion, leptin is a potential biomarker for adiposity in SCBT, and further investigation is needed to clarify if leptin is a predictor of future cardiometabolic risk in SCBT.

Topics: Adiposity; Adolescent; Biomarkers; Brain Neoplasms; Cancer Survivors; Cardiovascular Diseases; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Early Diagnosis; Female; Humans; Leptin; Male; Predictive Value of Tests; Risk Factors; Waist-Height Ratio; Waist-Hip Ratio

Many animal models that are currently used in appetite and obesity research share at least some main features of human obesity and its comorbidities. Hence, even though no animal model replicates all aspects of "common" human obesity, animal models are imperative in studying the control of energy balance and reasons for its imbalance that may eventually lead to overt obesity. The most frequently used animal models are small rodents that may be based on mutations or manipulations of individual or several genes and on the exposure to obesogenic diets or other manipulations that predispose the animals to gaining or maintaining excessive weight. Characteristics include hyperphagia or changes in energy metabolism and at least in some models the frequent comorbidities of obesity, like hyperglycemia, insulin resistance, or diabetes-like syndromes. Some of the most frequently used animal models of obesity research involve animals with monogenic mutations of the leptin pathway which in fact are useful to study specific mechanistic aspects of eating controls, but typically do not recapitulate "common" obesity in the human population. Hence, this review will mention advantages and disadvantages of respective animal models in order to build a basis for the most appropriate use in biomedical research.

Topics: Animals; Animals, Genetically Modified; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Leptin; Mice; Mice, Mutant Strains; Obesity; Rats; Rats, Mutant Strains

Previous studies have shown that red blood cell distribution width (RDW) is an independent predictor of poor prognosis in type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). The mechanisms underlying increased anisocytosis in patients with T2D and confirmed ASCVD remain poorly understood.. We sought to evaluate the relationship among the leptin-to-adiponectin ratio, systemic low -grade inflammation, and RDW in optimally treated patients with T2D and established ASCVD.. A total of 68 patients, aged 47 to 85 years (mean [SD], 65.3 [6.8] years) and including 21 women (30.9%), were enrolled and grouped according to median RDW into those with RDW <13.5% (n = 33) and those with RDW ≥13.5% (n = 35).. Patients with RDW ≥13.5% had a significantly higher median (interquartile range [IQR]) serum leptin-to-adiponectin ratio (1.7 [0.49-2.3] ng/μg vs 0.66 [0.31-1.25] ng/μg; P = 0.04) and median (IQR) tumor necrosis factor α levels (1.58 [1.42-1.97] pg/ml vs 1.39 [1.18-1.57] pg/ml; P = 0.02). There were no significant differences in the concentrations of other inflammatory markers. The leptin-to-adiponectin ratio (r = 0.25; P = 0.04) and levels of tumor necrosis factor α (r = 0.32; P = 0.01) and soluble intercellular adhesion molecule 1 (r = 0.31; P = 0.01) were positively correlated with RDW, which was confirmed by univariate linear regression analysis. A multivariable regression model, which included demographic, clinical, and laboratory data, showed that white blood cell count (β = 0.25; 95% CI, 0.05-0.45; P = 0.01), soluble intercellular adhesion molecule 1 levels (β = 0.21; 95% CI, 0.02-0.41; P = 0.03), and mean corpuscular hemoglobin concentration (MCHC), (β = -0.48; 95% CI, 0.67 to -0.28; P < 0.001) were independent predictors of RDW in our patients.. In well-controlled patients with T2D and ASCVD, the RDW values are associated with leptin-to-adiponectin imbalance and selected inflammatory markers.

Topics: Adiponectin; Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Erythrocyte Indices; Female; Humans; Inflammation; Leptin; Male; Middle Aged

In our study, we focused on possible effects of supplementation with glucan and vitamin D on total numbers of NK cells in patients with diabetic retinopathy. We evaluated possible relations among nutritional state (BMI), leptin levels, and total numbers of NK cells in patients supplemented with (1) glucan and vitamin D, (2) vitamin D and placebo, and (3) vitamin D alone. Our results show that 3 months of supplementation with both glucan and vitamin D resulted in significant improvements of NK cell numbers. In addition, we found statistically significant correlation between NK cell numbers and leptin levels. Based on these results, we propose that the molecule responsible for these changes is glucan, as vitamin D alone or together with placebo caused no effects.

Topics: Aged; beta-Glucans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dietary Supplements; Female; Humans; Immunomodulation; Killer Cells, Natural; Leptin; Lymphocyte Count; Male; Middle Aged; Vitamin D

Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, Western; Disease Models, Animal; Female; Humans; Intervertebral Disc; Intervertebral Disc Degeneration; Leptin; Male; Mice; Mice, Inbred NOD; Obesity; Receptors, Leptin; Sex Characteristics; Signal Transduction; Spine

Topics: Adiponectin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Inflammation; Leptin; Risk Factors

To compare the clinical efficacy of gastric bypass in obese patients with T2DM with different BMI. Serum leptin, adiponectin, triglyceride (TG), cholesterol (CHOL) were measured as the indicators to show clinical efficacy after laparoscopic gastric bypass surgery (LRYGB). For patients with high BMI and patients with low BMI, the therapeutic effect of LRYGB surgical diabetes is more significant. The postoperative remission rate of diabetes in the high BMI group was not correlated with the preoperative lipid metabolism index but was positively correlated with the postoperative lipid metabolism index CHOL, TG, leptin, adiponectin. The postoperative remission rate of diabetes in the low BMI group was positively correlated with the preoperative abnormal lipid metabolism of the patients, and positively correlated with the postoperative remission of leptin and adiponectin, but was not correlated with the postoperative remission of total CHOL and TG. The increase of serum adiponectin level and the decrease of leptin resistance after LRYGB surgery restored the metabolic balance of leptin and adiponectin, improved insulin resistance (IR), and thus improved blood glucose level. Therefore, LRYGB has a definite therapeutic effect on obese patients with T2DM, and elevated adiponectin and improved leptin resistance are some of the mechanisms of surgical treatment of diabetes.

Topics: Adiponectin; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Leptin; Lipid Metabolism; Male

Obesity is a major risk factor in aetiology of type 2 diabetes mellitus (T2DM). Leptin (LEP) is an anti-obesity hormone which regulates food intake, energy expenditure and glucose metabolism. The genetic variants in leptin and leptin receptor gene (LEPR) may play major role in the pathogenesis of T2DM and obesity. The current study aimed to investigate the association of polymorphisms in LEP (rs7799039, -2548G/A and rs2167270, 19G/A) and LEPR (rs1137101, 668A/G) gene with type 2 diabetes in North Indian Punjabi population.. A total of 817 subjects were included for the present case-control study, consisting of 417 T2DM patients and 400 healthy controls. The anthropometric, physiometric and biochemical measurements were taken from all the subjects. The genotyping of LEP and LEPR gene variants were carried out by polymerase chain reaction based restriction fragment length polymorphism method (PCR-RFLP), followed by genotyping of 10% of the samples for each polymorphism by Sanger sequencing method for quality control measurement.. The risk genotype frequencies were found to be significantly higher in T2DM cases than control subjects (rs7799039, p = 0.001; rs2167270, p = 0.019 and rs1137101, p = 0.003). Under recessive genetic model LEPrs7799039 and LEPRrs1137101 polymorphism conferred 3.4 and 2.1 fold risk towards the development of T2DM after adjustment of various covariates (OR = 3.44, 95%CI: 1.768-6.681, p = 0.001 and OR: 2.12, 95%CI: 1.256-3.569, p = 0.005, respectively). In the stratified analysis of LEP variant rs7799039 by age, gender, BMI and alcohol use, a significantly increased risk of T2DM was found in female, BMI ≥ 23 and never drinking subgroups. However, in the LEPR variant rs1137101, significantly increased risk of T2DM was observed in age <50, male, BMI ≥ 23 and never drinking subgroup. The A-G haplotype combination of rs7799039A and rs2167270G conferred significant 2 fold risk towards T2DM (OR = 2.35, 95%CI: 1.34-4.12, p = 0.002). In control group, the genetic variants rs7799039 and rs1137101 were significantly associated with levels of random blood sugar and low density lipoprotein cholesterol levels.. The present study revealed the association of LEP rs7799039 and LEPR rs1137101 with type 2 diabetes mellitus, which suggest its predominant role in the estimation of type 2 diabetes mellitus in North Indian Punjabi population.

Topics: Adult; Aged; Asian People; Biomarkers; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genotype; Humans; India; Leptin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Prognosis; Receptors, Leptin

Joint damage in patients with diabetes mellitus (DM) is a common complication and is associated with the induction of metabolic inflammation against the background of increased catabolic processes in various joint structures. The aim of our work was to study the level of insulin, leptin, osteocalcin, as well as biochemical markers of connective tissue metabolism in patients with diabetes-associated osteoarthritis. We examined 77 patients who were divided into groups by type of diabetes, the presence and severity of diabetic arthropathy. The content of insulin and leptin, osteocalcin in the blood serum was determined by the enzyme immunoassay, the level of glycosaminoglycans, hydroxyproline, hyaluronidase, collagenase according to traditional biochemical methods. Among the examined patients, diabetic arthropathy was diagnosed in more than 70%. Patients with diabetic arthropathy significantly increased levels of insulin (with type 1 diabetes by 38.5%, with type 2 diabetes by 55.6%) and leptin (with type 1 diabetes by 43.8%, with type 2 diabetes by 53.7,%), the level of osteocalcin (only with type 1 diabetes by 53.9%) There is a direct correlation between the severity of joint damage and the level of insulin and leptin. The severity of arthopathy in patients with type 2 diabetes is directly correlated with indicators of insulin resistance. In patients with diabetes-associated osteoarthritis, indicators that characterize catabolic processes in the connective tissue (hydroxyproline free and collagenase (p<0.001) are increased. The chances of detecting arthropathy with type 1 diabetes increase 3.8 times with an increase in insulin levels, with an increase in leptin 1.3 times, in patients with type 2 diabetes, 2.6 and 1.2 times, respectively. For this sample, it was found that the development of arthropathy does not depend on the type of diabetes. In women with type 2 diabetes, the chances of developing arthropathy are six times higher. 4 times than men. An increase in insulin and leptin levels can serve as a marker for the presence and progression of arthropathy in patients with diabetes. Patients with arthropathies have increased levels of hydroxyproline and collagenase, which reflects an increase in catabolic processes in the connective tissue, which may be one of the mechanisms for the development of joint structures in patients with diabetes.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Osteoarthritis

Obesity leads a crucial importance in metabolic disorders, as well as type 2 diabetes mellitus. Our present study was designed to assess the potential role of irisin, adiponectin, leptin and gene polymorphism of PNPLA3, leptin and adiponectin as predictive markers of diabetes associated with obesity. One hundred eighty subjects were distributed to three groups including; healthy non-diabetic non obese volunteers as a control group, diabetic non obese group, and diabetic obese group (n = 60 for each group). Fasting blood samples of all groups were collected to determine fasting blood glucose, insulin levels, insulin resistance, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triacylglycerol, irisin, adiponectin, leptin; as well as, polymorphism of PNPLA3, adiponectin and leptin. The results showed that glucose, insulin resistance, total cholesterol, irisin, leptin, LDL-C, triacylglycerol concentrations were significantly increased, however, insulin, HDL-C, adiponectin were significantly decreased in diabetic obese patients in relation to diabetic non-obese patients as well as in healthy volunteers. The polymorphism of PNPLA3 rs738409 was linearly related to irisin and leptin but was not related with circulating concentrations of adiponectin. We concluded that increased irisin and leptin levels can predict the insulin resistance in obese patients. Moreover, patients who have mutant genotype of PNPLA3 I148 gene (rs738409) C>G, ADIPOQ gene (rs266729) G>C and LEP gene (rs2167270) G>A showed a significant higher susceptibility rate for DM in obese people than those with wild type. This could be considered as an adjustable retort to counter the impact of obesity on glucose homeostasis.

Topics: Adiponectin; Adult; Diabetes Mellitus, Type 2; Female; Fibronectins; Genetic Markers; Genetic Predisposition to Disease; Humans; Insulin Resistance; Leptin; Lipase; Male; Membrane Proteins; Obesity; Polymorphism, Genetic; Young Adult

Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice.. Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro.. ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice.. The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes. Graphical abstract.

Topics: Adipocytes; Adiponectin; Animals; CCAAT-Enhancer-Binding Proteins; Circadian Rhythm; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Susceptibility; Eating; Fatty Acid-Binding Proteins; Feeding Behavior; Glucose Tolerance Test; Hyperphagia; Leptin; Locomotion; Mice; Obesity; PPAR gamma

Both selenium and probiotics have shown antidiabetic effects in a type 2 diabetes model. The objective of this study is to investigate the alleviating effects of selenium-enriched Bifidobacterium longum DD98 (Se-B. longum DD98) on diabetes in mice and explore the possible underlying mechanism. A type 2 diabetes model was established using a high-fat diet and streptozotocin (STZ) injection in mice. To investigate the beneficial effects of Se-B. longum DD98, diabetic mice were then treated with B. longum DD98, Se-B. longum DD98, or sodium selenite (Na

Topics: Animals; Bifidobacterium longum; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Feces; Glucose Tolerance Test; Hypoglycemic Agents; Leptin; Male; Mice; Mice, Inbred C57BL; Pancreas; Probiotics; Selenium; Sodium Selenite

Anthocyanins (ACNs) are polyphenols that might reduce pathological processes associated with type 2 diabetes mellitus and other chronic diseases, but their bioavailability is still controversial. In this study, the metabolic activity of oral delivery of ACN-loaded niosomes was investigated and evaluated in a diet-induced obesity (DIO) mice model.. ACNs extracted from Vaccinium Meridionale by the supercritical fluid extraction method were loaded in niosomes. The niosomal formulation was physically characterized and further administrated in drinking water to obese, insulin resistant mouse. We evaluated the effect of ACN loaded niosomes on hyperglycemia, glucose and insulin intolerance and insulin blood levels in C57BL/6 J mice fed with a high-fat diet.. The ACN-loaded particles were moderately monodisperse, showed a negative surface charge and 57% encapsulation efficiency. The ACN-loaded niosomes ameliorated the insulin resistance and glucose intolerance in the DIO mice model. Additionally, they reduced animal weight and plasma insulin, glucose, leptin and total cholesterol levels in obese mice.. ACN-loaded niosomes administration, as a functional drink, had a beneficial effect on the reversal of metabolic abnormalities associated with obesity.

Topics: Animals; Anthocyanins; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Compounding; Drug Liberation; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liposomes; Male; Mice, Inbred C57BL; Mice, Obese; Nanocapsules; Obesity; Plant Extracts; Streptophyta

Obesity has been recognized as a low-grade, chronic inflammatory disease that leads to an increase in obesity-associated disorders, including type 2 diabetes (T2D), fatty liver diseases and cancer. Glucagon-like peptide-1 (GLP-1) is an effective drug for T2D, and it not only has glucose-regulating effects but also has anti-inflammatory effects in obesity. In our previous study, we designed a novel GLP-1 analogue, (E

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Cytokines; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Inflammation; Leptin; Macrophage Activation; Macrophages; Male; Mice, Inbred C57BL; Mice, Obese; NF-kappa B; Obesity; Signal Transduction

Extracellular beta-amyloid (Aβ), intra-neuronal hyper-phosphorylated tau protein, and chronic inflammation are neuropathological hallmarks of Alzheimer's Disease (AD). A link between AD, insulin dysfunction, and tumor necrosis factor-alpha (TNF-α) in promoting both tau and Aβ pathologies in vivo has been proposed.. MA-[D-Leu-4]-OB3 was given, with or without insulin, to streptozotocin (STZ)-treated male Swiss Webster mice, and to male diet-induced obese (DIO) mice. Brains were excised, and coronal sections were imaged with fluoro jade-C (FJC), thioflavin-S, or hematoxylin and eosin (H&E). Serum TNF-α and IGF-1 were measured by ELISA. Histopathological changes in the cerebral cortex (CC) and hippocampus (HC) were correlated with changes in glycemic regulation, episodic memory, and serum levels of TNF-α and IGF-1.. In STZ-treated mice, blood glucose and serum TNF-α and IGF-1 were reduced by insulin alone, and normalized when MA-[D-Leu-4]-OB3 was given in combination with insulin. Improvement in episodic memory was inversely correlated with the number of FJC-positive cells in the CC and HC and serum TNF-α and IGF-1. FJC, thioflavin-S and H&E staining indicated no Aβ deposition. Similar results were observed in DIO mice treated with MA-[D-Leu-4]-OB3.. The mechanism by which MA-[D-Leu-4]-OB3 improves episodic memory in mouse models of TIDM and T2DM appears to be related to improved insulin sensitivity and reduced TNF-α-induced neurodegeneration.. MA-[D-Leu-4]-OB3 may have application to human pre-clinical and clinical AD and AD-like dementia by interrupting the cascade of insulin resistance, neuro-inflammation, and neurodegeneration, that characterizes these diseases.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Insulin Resistance; Leptin; Male; Memory, Episodic; Mice; Neuroprotective Agents; Peptides; Tumor Necrosis Factor-alpha

We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). In a discovery phase, we investigated associations between 88 plasma proteins, assessed with a proximity extension assay, and plasma leptin in a cohort of middle-aged patients with T2DM. Associations passing the significance threshold of a False discovery rate of 5% (corresponding to p < 0.0017) were replicated in patients with T2DM in an independent cohort. We also investigated if proteins mediated the longitudinal association between plasma leptin and the incidence of major cardiovascular events (MACE). One protein, adipocyte fatty acid binding protein (A-FABP), was significantly associated with leptin in both the discovery phase [95% CI (0.06, 0.17) p = 0.00002] and the replication cohort [95% CI (0.12, 0.39) p = 0.0003]. Multiplicative interaction analyses in the two cohorts suggest a stronger association between A-FABP and leptin in men than in women. In longitudinal analyses, the association between leptin and MACE was slightly attenuated after adding A-FABP to the multivariate model. Our analysis identified a consistent association between leptin and A-FABP in two independent cohorts of patients with T2DM, particularly in men.Trial registration: ClinicalTrials.gov identifier NCT01049737.

Topics: Aged; Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Proteomics

In view of the association of Ramadan intermittent fasting with profound changes in lifestyle both in nondiabetic and diabetic patients, the aim of this study was to investigate the effect of Ramadan fasting on adiponectin, leptin and leptin to adiponectin ratio (LAR), growth hormone (GH), human-sensitive C-reactive protein (hs-CRP), and diabetic and metabolic syndrome factors in patients with Type 2 Diabetes Mellitus (Type 2 DM), their first-degree relatives (FDRs), and healthy controls.. This cohort study involved 98 Yemeni male subjects aged 30-70 years old: 30 Type 2 DM, 37 FDRs of Type 2 diabetic patients, and 31 healthy control subjects. Subjects' body mass index (BMI), waist circumference (WC), and blood pressure (BP) were measured, and venous blood samples were collected twice: the first samples were collected a couple of days prior to Ramadan fasting (baseline) and the second samples after 3 weeks of fasting.. Ramadan fasting did not affect BMI, WC, and BP in Type 2 DM and their FDRs with respect to the baseline levels prior to Ramadan, whereas triglyceride and cholesterol were borderline significantly decreased in Type 2 DM with no effect in FDRs. Fasting blood glucose was not affected in Type 2 DM but was significantly increased in FDRs and control groups, whereas glycated haemoglobin (HbA1c) was slightly decreased in Type 2 DM, FDRs, and healthy controls. C-peptide, insulin, and insulin resistance (HOMA-IR) were significantly increased in Type 2 DM and FDRs, with no effect in the control group, whereas. Ramadan intermittent fasting decreased adiponectin and increased leptin, LAR, insulin, and insulin resistance in both Type 2 DM and FDRs as well as decreased GH in both FDRs and healthy controls and increased hs-CRP in healthy controls. Moreover, Ramadan intermittent fasting neither worsens a patient's glycemic parameters nor improves it, with the exception of a slight improvement in HbA1c in Type 2 DM, FDRs, and healthy controls.

Topics: Adipokines; Adiponectin; Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; C-Reactive Protein; Cohort Studies; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Triglycerides; Waist Circumference

One of the complications of type 2 diabetes mellitus in men is steroidogenic and spermatogenic dysfunctions. There is evidence of a restoring effect of the antidiabetic drug metformin on them. We studied the effect of MF therapy (4 weeks, 200 mg/kg/day) on the hormonal parameters of the gonad axis and on the morphological characteristics of epididymal spermatozoa in male rats with a severe form of T2DM caused by a high-fat diet and a low-dose streptozotocin. It has been shown that MF therapy, along with the restoration of the metabolic parameters, normalizes the plasma levels of testosterone and leptin and the content of testosterone, its precursors, leptin and its receptors in the testes, and also increases sperm motility, which is reduced in T2DM. This is the result of both the systemic action of MF and its direct effect on testicular cells.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Hypoglycemic Agents; Leptin; Male; Metformin; Progesterone; Rats, Wistar; Receptors, Leptin; Spermatogenesis; Spermatozoa; Steroids; Testis

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep

Topics: Agouti-Related Protein; Animals; Astrocytes; Blood Glucose; Cell Communication; Cell Nucleus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Sucrose; Fibroblast Growth Factor 1; Humans; Hypoglycemic Agents; Hypothalamus; Injections, Intraventricular; Leptin; Male; Melanocortins; Melanocyte-Stimulating Hormones; Mice; Mice, Knockout; Neurons; Oligodendroglia; Receptor, Melanocortin, Type 4; Receptors, Melanocortin; Recombinant Proteins; Remission Induction; RNA-Seq; Signal Transduction; Single-Cell Analysis; Stereotaxic Techniques; Transcriptome

Adipocytokines are numerous proteins secreted by adipose tissue predominantly. They regulate many key physiological processes in human body. High or low levels of thyroid hormones in various thyropathies may have influence on levels of various adipocytokines, especially adiponectin, resistin and visfatin. However, results of studies are controversial or miss. Perplexing influence could have associate diseases of metabolic character (e. g. insulin resistance and type 2 diabetes mellitus or developing atherosclerosis).

Topics: Adipokines; Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin

Bariatric surgery is a first-line treatment for patients with obesity and diabetes. It is uncertain whether leptin has an influence on glycemia in the postoperative period.. A cohort study of thirty-eight individuals with obesity and diabetes who underwent laparoscopic Roux-en-Y gastric bypass was undertaken. The levels of leptin, glucose, and glycosylated hemoglobin were verified in the preoperative period and in the first and third postoperative months.. The search for factors that influence diabetes control after bariatric surgery is of major importance in clinical practice. Our study reported a level of leptin that can predict the prognosis of glycemic control after the intervention. This finding still needs to be validated and confirmed in other populations.

Topics: Bariatric Surgery; Blood Glucose; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glycemic Control; Humans; Leptin; Middle Aged; Obesity, Morbid; Treatment Outcome; Weight Loss

The adipocyte-derived hormone leptin increases trafficking of K

Topics: Animals; Cell Line; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Leptin; Membrane Potentials; Mice; Mice, Mutant Strains; Mutation; Obesity; Phosphorylation; Receptors, N-Methyl-D-Aspartate; src-Family Kinases

Evaluation of serum concentration of leptin, adiponectin, resistin, and MCP-1 in pregnant patients with different types of diabetes mellitus (DM) considering preconception planning and method of DM correction in 11-14th and 30-34th weeks of pregnancy.. Longitudinal, prospective study included 130 pregnant women divided into the following comparison groups: type 1 DM (T1DM, n = 40), type 2 DM (T2DM, n = 35), GDM (n = 40), and the control group (n = 15). The ELISA method defined the levels of leptin, resistin, adiponectin, and MCP-1 concentration in serum, which was assessed in 11-14th and 30-34th weeks of pregnancy. Statistical analysis was accomplished using SPSS 23.0 and "Prism 8-GraphPad" software.. The leptin level in the 1st trimester was the highest in T2DM insulin group compared to the control due to gestational age, hence in the 3rd trimester in all groups its serum concentrations appeared higher than in healthy patients (p = 0.0001). In the 1st trimester leptin levels directly correlated with women's BMI, newborns' weight and macrosomia rate, in the 3rd trimester - with OGTT levels, HbA1c, gestational hypertension, and preeclampsia rates. Resistin levels in the 1st and 3rd trimesters were increased in almost all DM groups compared to the control group (p = 0.0001). The study established direct positive correlation between resistin and HbA1c, birth weight, and preeclampsia. In the 1st trimester, adiponectin demonstrated the lowest levels in T2DM insulin compared to T1DM and the control group (p = 0.0001) while in the 3rd trimester, adiponectin levels declined alongside gestational age in DM patients and all the groups compared to the control group (p < 0.05). Adiponectin negatively correlated with BMI, OGTT levels, and preeclampsia rate. MCP-1 levels in T2DM appeared higher than in T1DM patients and the control group in the 1st trimester, whereas in the 3rd trimester MCP-1 declined, correlating with BMI, preeclampsia and OGTT levels.. High rate of adverse perinatal outcomes in diabetic pregnancy might be developed due to more severe metabolic failures and further disturbances of adipokines expression.

Topics: Adipokines; Adiponectin; Chemokine CCL2; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Infant, Newborn; Leptin; Pregnancy; Prospective Studies; Resistin

Evidences support the view that central obesity is an independently cardiovascular risk. It is thought that leptin contributes to autonomic dysfunction and cardiovascular risks in type 1 and type 2 diabetes mellitus (T1DM and T2DM). This raises the possibility that leptin might mediate the relationship between central obesity and the severity of cardiovascular autonomic neuropathy (CAN) in patients with well-controlled T2DM and prediabetes.. The complete cardiovascular reflex tests and biomarkers were assessed for each patient. The severity of CAN was assessed using composite autonomic scoring scale (CASS). A single-level three-variable mediation model was used to investigate the possible relationships among central obesity [as indicated by waist circumference (WC)], leptin level, and severity of CAN (as indicated by CASS value).. A total of 107 patients were included in this study: 90 with diabetes and 17 with prediabetes. The results demonstrate that increased WC is associated with increased severity of CAN (r = 0.242, P = 0.017). We further discovered that leptin level is positively correlated with WC (r = 0.504, P < 0.0001) and the CASS value (r = 0.36, P < 0.0001). Further mediation analysis shows that leptin level serves as mediators between higher WC and higher CASS.. Our results highlighted the relationship among leptin, central obesity, and severity of CAN. As the leptin level serves as mediator between central obesity and severity of CAN, a longitudinal study is needed to confirm that control of WC can decrease leptin levels and can be effective in reducing CAN progression.

Topics: Body Mass Index; Diabetes Mellitus, Type 2; Humans; Leptin; Longitudinal Studies; Obesity, Abdominal; Prediabetic State; Risk Factors; Waist Circumference

The potential effect of adipokines on the development of AF is yet to be established. The aim of this study was to investigate the association of baseline serum adipokines with 1) the presence of AF at baseline and 2) future risk of AF development.. The current study is a sub-analysis of the prospective, randomised AVOCADO (Aspirin Vs./Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes) trial. The AVOCADO study included patients with type 2 DM burdened with at least two additional cardiovascular risk factors and receiving acetylsalicylic acid. In patients included in the current analysis adipokines and inflammatory biomarker levels were measured. Information on the subsequent AF diagnosis was collected after a median of 5.4 years of follow-up.. A total of 273 patients with type 2 DM (median age 68 years; 52% male) were included in the initial analysis comparing patients with and without AF at baseline. Patients with diagnosed AF (12%) had higher levels of serum resistin [8.5 (5.8-10.5) vs. 6.9 (5.6-8.7) ng/mL; p = 0.034], adiponectin [6.9 (5.6-8.7) vs. 2.7 (1.8-4.2) ng/mL; p = 0.032], and N-terminal pro-B-type natriuretic peptide [336 (148-473) vs. 108 [45-217]; p < 0.001) than non-AF patients. There were no significant differences in serum leptin, IL-6, and TNF-alpha concentrations between the two groups. From subjects without known AF at study entry, 19% developed AF at follow-up. In logistic regression analysis, baseline adipokine levels did not predict AF development.. In type 2 DM, patients with AF have higher resistin and adiponectin concentrations than patients with no AF. None of the studied adipokines proved a predictor of future AF development.

Topics: Adipokines; Adiponectin; Aged; Atrial Fibrillation; Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Prospective Studies; Randomized Controlled Trials as Topic; Resistin

Recent evidence suggests that insulin resistance may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, the probable role of insulin resistance in the pathogenesis of AD was investigated in patients with Type 2 Diabetes Mellitus (T2DM).. Serum amyloid beta (Aβ) (1-42), insulin like growth factor-1 (IGF-1), sirtuin1 (SIRT1) and leptin protein levels were measured in serum samples of control (n = 26), probable AD (n = 26), and probable AD+T2DM patients (n = 12) using ELISA method. Mini mental state examination (MMSE) was performed to the patient and control groups.. Serum IGF-1 significantly increased in the probable AD+T2DM group as compared to the control and probable AD groups (p ˂ 0.05). The levels of serum leptin significantly decreased in the probable AD and AD+T2DM groups as compared to the control (p ˂ 0.05). There were no statistically significant differences in serum Aβ (1-42) and SIRT1 levels among groups (p > 0.05).. The significant decrease in serum leptin levels in AD patients may indicate that it may be a therapeutic marker in AD. The level of serum Aβ peptide and SIRT1 proteins can vary depending on the stage of the disease. Therefore, this study should be supported by more comprehensive studies in terms of the number of patients in advanced stage (Tab. 1, Fig. 4, Ref. 29).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Sirtuin 1

To evaluate adipokine serum values of irisin, retinol-binding protein 4, and leptin in Saudi cases with type 2 diabetes mellitus (T2DM) for providing markers of T2DM macrovascular complications. Methods: This case-control research was carried out at Erfan Hospital, Jeddah, Saudi Arabia. The study included 138 subjects, classified into 3 groups: 46 T2DM patients with macrovascular complications, 46 T2DM without macrovascular complications, and 46 controls. Participants evaluated clinically and some biochemical parameters were measured. Results: Diabetic with and without macrovascular complications showed elevation of retinol-binding protein 4 (RBP4) and leptin; decreased irisin serum levels versus controls. Serum irisin was lower (p=0.007), while RBP4 was higher (p less than 0.0001) in T2DM patients with macrovascular complications versus without. Irisin showed negative correlations with fasting blood glucose (FBG), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), RBP4, hemoglobin A1C (HbA1C), triglyceride, cholesterol, and low-density lipoprotein cholesterol. While RBP4 showed positive correlations with fasting blood glucose, insulin, HOMA-IR, leptin, and HbA1c; but a negative association with high-density lipoprotein cholesterol. Conclusion: Type 2 DM patients had raised RBP4 and leptin, but lower irisin levels versus controls. Irisin was lower, but RBP4 was higher in T2DM patients with macrovascular complications versus without, suggesting T2DM patients in pro-inflammatory conditions. These results suggested that irisin is protective, while RBP4 is a risk factor for T2DM macrovascular complications.

Topics: Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fibronectins; Humans; Leptin; Male; Middle Aged; Retinol-Binding Proteins, Plasma; Risk Factors; Saudi Arabia

Leptin, an adipokine, has effects on the cardiovascular system with both protective and harmful role. This study aimed to assess the relationship between leptin and 3-month prognosis in ischemic stroke patients with type 2 diabetes.. As a prospective single-center observational study, we collected consecutive first-ever acute ischemia stroke with type 2 diabetes mellitus from February 2019 to February 2020. Serum samples were obtained at admission, and leptin serum levels were tested by the ELISA method. Logistic regression models were used to assess leptin's prognostic value to predict the functional outcome and mortality within three months.. Finally, two hundred and eleven patients were included, and the mean leptin serum level was 16.8 (SD. 6.9) ng/mL. At admission, 53.6% of those included patients (N=113) were defined as severe stroke (NIH Stroke Scale [NIHSS]>5). In multivariable models adjusted for other factors, leptin levels<11.6ng/mL (lowest quartile, Q1) related to severe stroke and the risk increased 175% (odds ratios [OR] =2.75; 95% confidence interval [CI]=2.13-3.38; P=0.002). Serum leptin levels on admission in patients with poor outcomes and nonsurvivors were significantly reduced (P<0.001 and P<0.001). Leptin levels <11.6ng/mL (lowest quartile, Q1) related to a higher risk of poor functional impairment (OR=5.13; 95% CI =3.25-6.86; P<0.001) and mortality (OR=3.19; 95% CI =2.03-4.25; P<0.001).. The data shows that leptin serum level is a useful prognostic biomarker in ischemic stroke patients with type 2 diabetes, and this relationship is negative.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Hospitalization; Humans; Ischemic Stroke; Leptin; Logistic Models; Male; Middle Aged; Odds Ratio; Prognosis; Prospective Studies; Severity of Illness Index

Osteoporosis is known to be intimately related to sympathetic nerve activity. We examined the relationship of plasma leptin with cortical and trabecular bone components in patients with type 2 diabetes mellitus.. The present cross-sectional study included 182 type 2 diabetes mellitus patients (93 men, 89 women). Cortical thickness (CoTh) and trabecular bone mineral density (BMD) were determined at the 5.5% distal radius using an LD-100 ultrasonic bone densitometry device. Plasma leptin along with physical and laboratory measurements was simultaneously determined.. Plasma leptin, but not body mass index (BMI), was inversely correlated with CoTh (ρ = -0.487, P < 0.001), while BMI, but not plasma leptin, was positively correlated with trabecular BMD (ρ = 0.369, P < 0.001). In multivariable regression analysis, after adjustments for age, sex, duration of diabetes, glycated hemoglobin A1c, albumin, estimated glomerular filtration rate, parathyroid hormone and handgrip strength, plasma leptin was inversely associated with CoTh (β = -0.258, P < 0.001), but not trabecular BMD. Furthermore, plasma leptin level retained a significant association with CoTh after further adjustment for BMI (β = -0.237, P < 0.001) and BMI plus waist-to-hip ratio (β = -0.243, P < 0.001). In contrast, the "sex × leptin" interaction was not significant (P = 0.596).. Leptin level in plasma, independent of BMI and BMI plus waist-to-hip ratio, was shown to be inversely associated with CoTh, but not trabecular BMD, suggesting that hyperleptinemia resulting from obesity might contribute to cortical porosis in patients with type 2 diabetes mellitus.

Topics: Aged; Biomarkers; Bone Density; Cortical Bone; Cross-Sectional Studies; Densitometry; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Prognosis; Radius; Ultrasonography

The associations of serum leptin/soluble leptin receptor (sObR) and leptin resistance with symptoms of depression and anxiety were investigated in patients with type 2 diabetes (T2D).. We report the results of two cross-sectional studies, performed 2 years apart, that included 216 and 237 T2D patients, respectively. Symptoms of depression and anxiety were assessed with specific questionnaires (Patient Health Questionnaire-9, Center for Epidemiologic Studies Depression Scale, and Generalized Anxiety Disorder-7, respectively). Laboratory data (including leptin and sObR) were collected, and free leptin index (FLI), as an estimate of leptin resistance, was calculated. One hundred forty patients had laboratory data available on both occasions, and were evaluated longitudinally. Simple and multiple correlations between depression/anxiety and parameters of interest were performed.. In both studies, serum leptin levels were higher, whereas resting energy expenditure/leptin ratios were lower in T2D patients with depressive and moderate-severe anxiety symptoms. In the second study, patients with depressive symptoms had higher FLI and lower sObR levels, while those with moderate-severe anxiety only had higher FLI. Depression scores correlated with serum leptin (r = 0.29, [95%CI: 0.14-0.42]; r = 0.32, [95%CI: 0.18-0.45]) and FLI (r = 0.30, [95%CI: 0.15-0.43]; r = 0.32, [95%CI: 0.17-0.45]; P < 0.0001 for all). Multiple regression analyses identified leptin (β = 0.167; t ratio = 1.98) and FLI (β = 2.935, t ratio = 2.44) (P < 0.05 for both) as variables that significantly contributed to depressive symptoms. Depressive symptoms were present in significantly more patients with leptin levels in the highest versus the lowest quartiles on both evaluations (odds ratio: 5.98, 95%CI [1.76-20.32], P < 0.01).. Depressive and moderate-severe anxiety symptoms were associated with high leptin concentrations and leptin resistance in T2D patients.

Topics: Adult; Anxiety; Cross-Sectional Studies; Depression; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Receptors, Leptin

Insulin resistance is an important clinical feature of metabolic syndrome, which includes obesity and type 2 diabetes. Increased adipose energy storage in obesity promote insulin resistance and other metabolic adverse effects. To identify a new link between adipocyte and insulin resistance, we performed targeted metabolite profiling of differentiated adipocytes and studied the association between adipogenic metabolites and insulin resistance. We found a correlation between 2-aminoadipic acid (2-AAA) and adipogenic differentiation. Also, circulatory 2-AAA was positively associated with obesity-related factors (fat mass, fat percent, waist circumference, BMI, BMI z-score, triglycerides, insulin, and HOMA-IR) at baseline and after 2 years in the children cohort study. Of these factors, increased BMI z-score and HOMA-IR were the primary independent factors associated with higher 2-AAA levels, and the baseline 2-AAA level was an indicator of the BMI z-score after 2 years. To validate the relationship between 2-AAA and obesity-related factors, we analyzed changes in 2-AAA levels following obesity intervention programs in two independent studies. In both studies, changes in 2-AAA levels during the intervention period were positively correlated with changes in the BMI z-score and HOMA-IR after adjusting for confounders. Moreover, the 2-AAA levels were increased in cell and mouse models of obesity-related insulin resistance. Excess 2-AAA levels led to impaired insulin signaling in insulin-sensitive cells (liver, skeletal muscle and adipose cells) and caused abnormal gluconeogenesis. Our results demonstrate that 2-AAA is associated with adipogenesis and insulin resistance. In this regard, 2-AAA could be a potential biomarker of obesity and obesity-related metabolic disorders.

Topics: 2-Aminoadipic Acid; Adipocytes; Adipogenesis; Adipose Tissue; Adiposity; Adolescent; Animals; Biomarkers; Blood Glucose; Body Mass Index; Cell Differentiation; Child; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Pediatric Obesity; Republic of Korea; Triglycerides; Waist Circumference

Diabetes-specific nutritional formulas (DSNFs) are frequently used by patients with type 2 diabetes (T2D) as part of nutrition therapy to improve glycemic control and reduce body weight. However, their effects on hunger and satiety hormones when compared to an isocaloric standardized breakfast are not fully understood. This study aims to evaluate the postprandial effects of two DSNFs-Glucerna (GL) and Ultra Glucose Control (UGC)-versus oatmeal on selected satiety and hunger hormones.. After an overnight fast, 22 patients with T2D (mean age 62.3 ± 6.8 years, A1C 6.8 ± 0.7%, body weight 97.4 ± 21.3 kg, and BMI 33.2 ± 5.9 kg/m²) were given 200 kcal of each meal on three separate days. Blood samples for amylin, cholecystokinin (CCK), ghrelin, glucagon, leptin, and peptide-YY (PYY) were collected at baseline and 30, 60, 90, 120, 180, and 240 min after the start of each meal. Incremental area under the curve (iAUC. iAUC. Intake of DSNFs significantly increases secretion of PYY and glucagon, two important satiety hormones. While subjective satiety was not directly evaluated, the increased effect on satiety hormones may partially explain the mechanism of body weight loss associated with DSNF use.

Topics: Aged; Blood Glucose; Cholecystokinin; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Food, Formulated; Ghrelin; Glucagon; Humans; Hunger; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Peptide YY; Postprandial Period; Satiation

Type 2 diabetes mellitus is a major health concern worldwide; however, the molecular mechanism underlying its development is poorly understood. The hormone amylin is postulated to be involved, as human amylin forms amyloid in the pancreases of diabetic patients, and oligomers have been shown to be cytotoxic to β-cells. As rodent amylin is non-amyloidogenic, mice expressing human amylin have been developed to investigate this hypothesis. However, it is not possible to differentiate the effects of amylin overexpression from β-cell loss in these models. We have developed transgenic mice that overexpress [

Topics: Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Phenotype; Phosphorylation; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

The objective of this study was to evaluate the relationship between blood levels of adiponectin and leptin with lean body and trunk adipose mass in women with and without type 2 diabetes mellitus (T2DM).. This cross-sectional study analyzed baseline data from five previous clinical studies involving postmenopausal women (n = 95). Body composition was assessed by dual-energy x-ray absorptiometry, and appendicular lean mass was calculated based on body mass index (ALMBMI). Adipokines and cytokines were measured by enzyme-linked immunosorbent assay. Linear mixed-effect models with a random study effect were used to investigate the relationship between predictors (eg, adiponectin, leptin), outcomes (eg, ALMBMI, trunk adipose mass), and co-variables (T2DM status, age, interleukin-6, and C-reactive protein).. Postmenopausal women with T2DM had lower ALMBMI than those without T2DM. There was a positive association between blood adiponectin and ALMBMI in postmenopausal women without T2DM, but no association in those with T2DM. Blood leptin was negatively associated with ALMBMI for women regardless of T2DM diagnosis. Blood adiponectin was negatively associated, whereas blood leptin was positively associated with trunk adipose mass for the entire cohort.. T2DM status moderated the relationship between blood adiponectin and ALMBMI, where blood adiponectin was positively associated with ALMBMI in postmenopausal women without T2DM, but not those with T2DM. Dysregulated metabolism in T2DM may contribute to lower muscle mass in women with T2DM, but future research is required to elucidate this mechanistic link. The negative association between blood leptin and ALMBMI was a novel finding. Future studies will need to more clearly define the relationship between these variables.

Topics: Absorptiometry, Photon; Adiponectin; Body Composition; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Middle Aged; Torso

Ghrelin, a peptide hormone mostly produced by stomach, plays an important role in regulation of feeding behavior, energy balance and glucose homeostasis.. to determine the relationships between fasting serum levels of ghrelin, body composition, adipose tissue endocrine function and glucose variability (GV) in type 2 diabetic subjects with and without obesity.. We observed 124 individuals with type 2 diabetes, including 42 non - obese subjects and 82 patients with obesity. Thirty non - obese healthy subjects were acted as control. The concentrations of ghrelin, leptin, resistin, and visfatin in the fasting serum were determined by Multiplex analysis. Body composition was assessed with DEXA. The 24-hour and nocturnal GV parameters were derived from continuous glucose monitoring.. Ghrelin levels in patients with diabetes were decreased significantly as compared to control (p.. Грелин - пептидный гормон, продуцируемый главным образом в желудке, играет важную роль в регуляции пищевого поведения, энергетического баланса и гомеостаза глюкозы. Цель исследования. Определить взаимосвязи между уровнем грелина в сыворотке крови натощак, композитным составом тела, эндокринной функцией жировой ткани и параметрами вариабельности гликемии (ВГ) у больных сахарным диабетом (СД) 2-го типа с наличием и отсутствием ожирения. Материалы и методы. Обследовано 124 пациента с СД 2-го типа, в том числе 42 без ожирения и 82 с ожирением. Контролем являлись 30 здоровых лиц без ожирения. Концентрации грелина, лептина, резистина, висфатина в сыворотке крови натощак определяли с помощью мультиплексного анализа. Композитный состав тела исследовали с помощью двухэнергетической рентгеновской абсорбциометрии. Суточные и ночные параметры ВГ рассчитывали по данным непрерывного мониторинга уровня глюкозы. Результаты и обсуждение. Уровень грелина у больных СД оказался достоверно ниже в сравнении с контролем (p.

Topics: Adipose Tissue; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Ghrelin; Glucose; Humans; Leptin; Obesity

This paper aimed to investigate the regulating role of adipokine expression level in body fat distribution of patients with type 2 diabetes mellitus (T2MD) as well as its correlation with metabolic syndrome (MS).. One hundred forty patients with T2MD admitted in the Endocrinology Department of the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine from January 2017 to July 2017 were selected; their body height and weight were measured to calculate Body Mass Index (BMI); patients with a BMI ≤23.9 kg/m2 were included into control group (N.=49), and those with a BMI ≥24 kg/m2 into observation group (N.=91). Based on whether the patients were complicated with MS, they were divided into non-metabolic syndrome (N-MS) group (N.=79) and MS group (N.=61); the levels of serum dipeptidyl peptidase-4 (DPP-4), adiponectin (ADPN) and leptin as well as the contents of body fat and lean tissue of the two groups of patients were measured.. The serum DPP-4 level in observation group was remarkably elevated compared with that in control group (P<0.05), but there were no significant differences in the leptin and ADPN levels between the two groups (P>0.05). The serum DPP-4 and leptin levels were positively correlated with the total body fat mass (FAT) of the patients in observation group (r=0.461, P=0.004; r=0.433, P=0.007); DPP-4 level had a positive correlation with trunk fat mass (TRUNK F) (r=0.545, P=0.001) and limb fat mass (LIMB F) (r=0.412, P=0.005); the leptin level was positively correlated with LIMB F (r=0.513, P=0.001); the leptin and ADPN levels were negatively correlated with the content of lean tissue (r=-0.476, P=0.001; r=-0.344, P=0.021). Compared with those in N-MS group, the levels of serum DPP-4 and leptin were increased significantly, while the ADPN level was decreased notably (P<0.05) in MS group.. The adipokines DPP-4 and leptin in the serum can influence the body fat distribution of patients with T2MD; there is an important association of DPP-4, leptin and ADPN levels with MS, which may be used as therapeutic targets for multiple metabolism disorders of T2MD.

Topics: Absorptiometry, Photon; Adipokines; Adiponectin; Adult; Body Fat Distribution; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged

We aimed to study whether macronutrient intake could modify the association between ApoB Ins/Del and lipid profile, and serum leptin and ghrelin in type 2 diabetes mellitus (T2DM) patients.. In this study, 700 T2DM patients were recruited. Anthropometric, biochemical and molecular data were collected, and Diet was assessed using a food frequency questionnaire. The interactions were tested using ANCOVA.. Del-allele carriers with high-MUFA and carbohydrate (≥ 12 and ≥ 54% of energy, respectively) had significantly higher TG (P = 0.04) and LDL-C (P = 0.02) compared to Ins/Ins homozygotes, and these were not significant in subjects with low-MUFA and -carbohydrate (< 12 and < 54%, respectively). A significant interaction was observed between ApoB Ins/Del and diet on TG in both unadjusted (P = 0.03) and adjusted models (model 2 and 3, P = 0.04 and P = 0.04, respectively), and on LDL-C only in adjusted models (model 2 and 3, P = 0.03 and P = 0.029, respectively). Besides, Del-allele carriers with protein, SFA, MUFA and n-3PUFA of ≥ 14, 9, 12 and 0.6%, respectively, had a significant increase in their serum leptin than Ins/Ins homozygotes (P < 0.05). However, these associations were not significant between the two genetic groups in subjects with low intakes of protein, SFA, MUFA and n-3PUFA. Moreover, Del-allele carriers with low carbohydrate (< 54%) had significantly higher leptin and ghrelin than Ins/Ins homozygotes (P < 0.05), however, in high-carbohydrate group, leptin and ghrelin were not significantly lower.. These findings indicate that the interaction between ApoB Ins/Del and dietary intake of MUFA, SFA, n-3PUFA, carbohydrate and protein could modulate the serum levels of TG, LDL-C, leptin and ghrelin in T2DM patients.

Topics: Adult; Aged; Apolipoproteins B; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gene Deletion; Ghrelin; Humans; Leptin; Lipids; Male; Middle Aged; Mutagenesis, Insertional; Nutrients; Polymorphism, Genetic

Topics: Adult; Anthropometry; Antipsychotic Agents; Blood Glucose; Body Composition; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Psychotic Disorders; Siblings; Signal Transduction; Triglycerides

The incidence of hypertension and diabetes is increasing, it is reported that adipocytokines might be involved in the pathogenesis of diabetes and hypertension. We aimed to investigate the features of adipocytokines, included of Leptin, Irisin, LGR4, and Sfrp5 in type 2 diabetes mellitus (T2DM) patients with hypertension, simultaneously analyzed the connection of the alteration of adipocytokines with blood pressure and glucose. 424 patients with T2DM and 90 healthy subjects were included in the study. The patients with T2DM were divided into 4 groups based on the blood pressure. The levels of adipocytokines (Leptin, Irisin, LGR4, and Sfrp5) were determined by enzyme-linked immunosorbent assay (ELISA). Significantly higher levels of Leptin and lower levels of Irisin, LGR4 and Sfrp5 were seen in patients with diabetes compared with non-diabetes (P < 0.05), the mean values of Leptin level was ascending and Irisin, LGR4, and Sfrp5 levels were declining with promoting of blood pressure in hypertension as compared to the non-hypertension with diabetic patients. Multiple stepwise linear regression analysis showed that the concentrations of Leptin, Irisin, Sfrp5, and LGR4 were found to be closely associated with the control of blood pressure and glucose.

Topics: Adaptor Proteins, Signal Transducing; Adipokines; Adult; Aged; Blood Glucose; Blood Pressure; Case-Control Studies; Diabetes Mellitus, Type 2; Eye Proteins; Female; Fibronectins; Humans; Hypertension; Leptin; Male; Membrane Proteins; Middle Aged; Receptors, G-Protein-Coupled

Ectopic fat deposition is associated with increased tissue production of ceramides. Recent genetic mouse studies suggest that specific sphingolipid C16:0 ceramide produced by ceramide synthase 6 (CerS6) plays an important role in the development of insulin resistance. However, the therapeutic potential of CerS6 inhibition not been demonstrated. Therefore, we pharmacologically investigated the selective ablation of CerS6 using antisense oligonucleotides (ASO) in obese insulin resistance animal models.. We utilized ASO as therapeutic modality, CerS6 ASO molecules designed and synthesized were initially screened for in-vitro knock-down (KD) potency and cytotoxicity. ASOs with >85% inhibition of CerS6 mRNA were selected for further investigations. Most promising ASOs verified for in-vivo KD efficacy in healthy mice. CerS6 ASO (AAGATGAGCCGCACC) was found most active with hepatic reduction of CerS6 mRNA expression. Prior to longitudinal metabolic studies, we performed a dose titration target engagement analysis with CerS6 ASO in healthy mice to select the optimal dose. Next, we utilized leptin deficiency ob/ob and high fat diet (HFD) induced obese mouse models for pharmacological efficacy study.. CerS6 expression were significantly elevated in the liver and brown adipose, this was correlated with significantly elevated C16:0 ceramide concentrations in plasma and liver. Treatment with CerS6 ASO selectively reduced CerS6 expression by ∼90% predominantly in the liver and this CerS6 KD resulted in a significant reduction of C16:0 ceramide by about 50% in both liver and plasma. CerS6 KD resulted in lower body weight gain and accompanied by a significant reduction in whole body fat and fed/fasted blood glucose levels (1% reduction in HbA1c). Moreover, ASO-mediated CerS6 KD significantly improved oral glucose tolerance (during oGTT) and mice displayed improved insulin sensitivity. Thus, CerS6 appear to play an important role in the development of obesity and insulin resistance.. Our investigations identified specific and selective therapeutic valid ASO for CerS6 ablation in in-vivo. CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes.

Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Ceramides; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Gene Knockdown Techniques; Hep G2 Cells; Humans; Insulin Resistance; Leptin; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligonucleotides, Antisense; Sphingosine N-Acyltransferase; Thionucleotides; Weight Gain

The prevalence of obesity, metabolic syndrome and type 2 diabetes mellitus is increased among patients with severe mental disorders, and particularly use of second generation antipsychotic drugs is associated with metabolic side effects. Antipsychotics have been found to alter levels of adipokines which regulate insulin sensitivity, but their role in antipsychotic-associated insulin resistance is not established, and it is unclear whether adipokines affect insulin resistance independently of body mass index (BMI).. We included 1050 patients with severe mental disorders and 112 healthy controls aged 18-65 years from the Oslo area, Norway. Clinical variables, BMI and use of medication were assessed, fasting blood samples were obtained for calculation of the leptin/adiponectin ratio (L/A ratio) and estimate of insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Case-control analyses were followed by mediation analyses to evaluate the possible direct effect of antipsychotics on HOMA-IR and indirect effect mediated via the L/A ratio. This was performed both with and without adjustment for BMI, in the total sample and in an antipsychotic monotherapy subsample (N = 387).. BMI, L/A ratio and HOMA-IR were significantly higher in patients than controls (p < 0.001-p = 0.01). There was a significant direct effect from use of antipsychotics in general on HOMA-IR both without (b = 0.03, p = 0.007) and with adjustment for BMI (b = 0.03, p = 0.013), as well as a significant mediating effect via L/A ratio both without (b = 0.03, p < 0.001) and with adjustment for BMI (b = 0.01, p = 0.041). Use of olanzapine (b = 0.03, p < 0.001) or aripiprazole (b = 0.04, p < 0.001) in monotherapy showed significant effects on HOMA-IR mediated via L/A ratio.. The study suggests that use of antipsychotics may alter adipokine levels, and that increased L/A ratio may play a role in the development of insulin resistance associated with use of antipsychotics also independently of BMI.

Topics: Adipokines; Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Mental Disorders; Metabolic Syndrome; Middle Aged; Norway; Obesity

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve blood glucose control, as well as reducing bodyweight by promoting urinary glucose excretion. The weight loss is less than expected from urinary glucose loss, however, likely because of an increase in food intake. To investigate whether SGLT-2 inhibitors might increase appetite by affecting related hormones, we examined the effects of the SGLT-2 inhibitor, ipragliflozin, including those on appetite-regulating hormones, in individuals with suboptimally controlled type 2 diabetes.. Both glycated hemoglobin level (from 7.9 ± 0.8 to 7.1 ± 0.7%) and bodyweight (from 75.2 ± 12.6 to 72.6 ± 12.4 kg) were significantly decreased after treatment for 16 weeks. The fasting serum leptin level was significantly decreased after 2 weeks (from 19.5 ± 13.1 to 18.1 ± 12.4 ng/mL) and remained decreased up to 16 weeks, even after adjustment for bodyweight, whereas the plasma active ghrelin level showed no significant change. The visual analog scale score for hunger was significantly increased at 2 and 8 weeks.. The present results suggest that ipragliflozin improved glycemic control and reduced bodyweight, but also reduced serum leptin levels and might thereby have increased appetite.

Topics: Appetite; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Eating; Female; Follow-Up Studies; Ghrelin; Glucosides; Glycated Hemoglobin; Glycemic Index; Humans; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Weight Loss

Irisin is a myokine involved in adipocyte transformation. Its main beneficial effects arise from increased energy expenditure. Irisin production is particularly stimulated by physical exercise. The present study investigates the changes of plasma irisin in type 2 diabetic patients performing 2 different training modalities. Fourteen type 2 diabetic patients underwent 4 week of supervised high-intensity interval training (HIT; n=8) or continuous moderate-intensity training (CMT; n=6), with equivalent total amounts of work required. Plasma samples were collected in the resting state atbaseline and one day after the exercise intervention to analyse resting plasma irisin, blood lipids, blood glucose, hsCRP, Adiponectin, Leptin and TNF-α concentrations. In addition, body composition and VO

Topics: Adiponectin; Aged; Blood Glucose; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Fibronectins; High-Intensity Interval Training; Humans; Leptin; Lipids; Male; Middle Aged; Oxygen Consumption; Tumor Necrosis Factor-alpha

Protein tyrosine phosphatase 1B (PTP1B) has been considered as a validated biological target for type 2 diabetes treatment, but past endeavors to develop inhibitors of PTP1B into drugs have been unsuccessful. Two challenging aspects are selective inhibition and cell permeability. A structure-based strategy was employed to develop uncharged bromophenols as a new series of PTP1B inhibitors. The most potent compound 22 (LXQ46) inhibited PTP1B with an IC

Topics: Animals; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Enzyme Inhibitors; Insulin; Insulin Resistance; Leptin; Mice; Molecular Docking Simulation; Obesity; Phenols; Phosphorylation; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Safety; Signal Transduction

Topics: Adult; Aged; Aged, 80 and over; Asian People; Cardiovascular Diseases; Case-Control Studies; Chemokine CXCL12; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Linear Models; Logistic Models; Male; Mexico; Middle Aged; Obesity; Polymorphism, Genetic; White People

Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet-induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits

Topics: Adiponectin; Adipose Tissue; Animal Feed; Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Fibroblast Growth Factors; Humans; Hyperglycemia; Insulin; Leptin; Liver; Male; Methionine; Mice; Mice, Obese; Vegans; Weight Gain

Mitochondria play a central role in the regulation of energy metabolism, and the biogenesis of mitochondria is enhanced by the action of nitric oxide (NO), which is the key signaling molecule in the regulation of vascular homeostasis. A disturbance in the regulation of energy metabolism can be a key reason for the formation of insulin resistance and type 2 diabetes mellitus. Moreover, mitochondrial dysfunction leads to oxidative stress, which increases the production of proinflammatory cytokines. In this regard, the aim of this study was to identify the relationship of the copy number of mtDNA in adipose tissue from different locations (subcutaneous adipose tissue (SAT), mesentery (Mes), greater omentum (GO)), liver biopsy samples and mononuclear blood cells (MNCs) with endothelial dysfunction markers (eNOS, ET-1, iCAM-1, vCAM-1, VEGF) and inflammatory mediators (TNF-α, IL-6, IL-8, CRP, leptin) in obese patients (body mass index (BMI) > 35 kg/m. The study included 88 obese patients (BMI > 35 kg/m2) treated at the Kaliningrad Region Hospital. The control group consisted of 20 healthy donors. To measure mtDNA copy number we used droplet digital PCR. The concentrations of molecules (TNF-α, IL-6, IL-8, VEGF, eNOS, ET-1, iCAM-1, vCAM-1, VEGF) were measured in plasma using the following sandwich enzyme-linked immunosorbent assays (ELISAs). Quantitative determination of leptin was evaluated by flow-fluorimetry on a «Bio-Plex Protein Assay System». Statistical analysis and graphs were obtained in R Statistical Software (version 3.3.1).. The systemic character of chronic subclinical inflammation in obesity is established, and an increase in the level of endothelial dysfunction molecules was observed in the blood plasma. The levels of TNF-a, IL-6, and IL-8 were positively correlated with increases in BMI, serum glucose and cholesterol levels.. The copy number of mtDNA in various fat stores was higher in obese patients with type 2 diabetes than in obese patients without diabetes or in the control subjects and was related to the levels of leptin and proinflammatory cytokines.

Topics: Adipose Tissue; Biomarkers; Body Mass Index; Case-Control Studies; Cholesterol; Diabetes Mellitus, Type 2; DNA Copy Number Variations; DNA, Mitochondrial; Endothelin-1; Humans; Intercellular Adhesion Molecule-1; Leptin; Obesity; Tumor Necrosis Factor-alpha

Bone mineral density (BMD) and fracture risk are elevated in adults with impaired fasting glucose (IFG) or type 2 diabetes mellitus (T2D). This study aimed to compare bone health among Inuit women with IFG, T2D and normoglycemia. The study included Inuit women (≥40 y) with IFG (n = 57), T2D (n = 72) or normoglycemia (n = 340) from the International Polar Year Inuit Health Survey 2007-2008 in Canada. Distal one-third forearm BMD (FaBMD) was measured using a peripheral instantaneous x-ray imager. Anthropometry, fasting plasma glucose (FPG), serum adiponectin, leptin and 25-hydroxyvitamin D (25(OH)D) were measured. Traditional food intakes were surveyed. Data were analysed using mixed model ANOVA and regression models. The median age was 53 (IFG: IQR 48, 67) y and 56 (T2D: IQR 49, 63) y. Compared to normoglycemic women, FaBMD and T-scores were significantly lower in women with T2D, but not with IFG. Frequency of marine mammal intakes (ß = 0.145; 95%CI: 0.018, 0.053, p = 0.0001) positively related to FaBMD. The odds ratio of having a T-score consistent with osteoporosis was lower among women with T2D and higher BMI, while aging increased the risk. Although T2D associates with lower BMD among Inuit women, risk of osteoporosis is tempered, possibly by maintenance of a traditional lifestyle.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Body Weights and Measures; Bone Density; Canada; Diabetes Mellitus, Type 2; Female; Forearm; Health Behavior; Health Status; Humans; Inuit; Leptin; Middle Aged; Prediabetic State; Vitamin D

Leptin has been shown to stimulate the hypothalamus-pituitary-thyroid (HPT) axis in vivo and vitro. Its role in thyroid axis regulation after weight loss induced by bariatric surgery is still unknown. The aim of this study was to evaluate the influence of leptin on weight loss and thyroid function variation induced by Roux-en-Y gastric bypass (RYGB) surgery in euthyroid individuals with obesity and type 2 diabetes mellitus (T2DM).. 65 Chinese individuals with obesity and T2DM who underwent RYGB, and 27 healthy volunteers were enrolled in this retrospective study. Participants were evaluated for changes in anthropometric parameters, metabolic indexes, thyroid function, and leptin levels before and 12 months after surgery.. After RYGB, all of these patients experienced significant weight reduction and improved glucose control. Metabolic parameters were significantly ameliorated after surgery compared with baseline. Thyroid hormones including free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) declined in parallel. Median (IQR) plasma leptin levels decreased from 33.7 ng/mL (17.9-63.1) to 10.3 ng/mL (4.0-18.5). Pearson correlation analysis showed that TSH was significantly positively correlated with body mass index, C-reactive protein (CRP), and leptin. Multiple stepwise linear regression indicated that leptin and CRP were independent factors affecting TSH. The β coefficients were 0.38 (p = 0.001) and 0.32 (p = 0.004), respectively. There was a significant positive correlation between ΔTSH and Δleptin (r = 0.33, p = 0.01).. Decreased or normalized TSH levels after weight loss induced by RYGB might be mediated by the decline in leptin. There could be cross talk between adipose tissue and the HPT axis.

Topics: Adult; Bariatric Surgery; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Leptin; Male; Middle Aged; Obesity; Retrospective Studies; Thyroid Gland; Thyrotropin; Weight Loss

This study was conducted to find the association between leptin and adiposity indices. Secondly, to identify optimal threshold of various anthropometric indices for obesity, as assessed by 75th percentile of leptin levels, within a clinic sample of non-diabetic and diabetic Pakistani adults. Fasting serum leptin levels were compared with anthropometric markers of obesity in 164 diabetic and non-diabetic subjects (90 male, 74 female), aged 35 to 65 years. Obesity was defined by body mass index (BMI) of 25 kg/m2 in either sex. The cutoff point of leptin was taken as the 75th percentile in non-obese subjects. Diagnostic accuracy for detecting excess fatness was evaluated through receiver operating characteristics (ROC) analyses with leptin taken as reference test against anthropometric indices as test variables. The 75th percentile of leptin in male and female was 7.0ng/mL and 17.9ng/mL, respectively. Leptin levels were significantly higher in females (p<0.001) and had strong positive correlation (p<0.001) with most anthropometric indices of obesity in both sexes; hip circumference (HC) being most prominent among these. Largest area under ROC curve (AUC) was between WC and leptin (AUC=0.844; CI=0.764, 0.925) in males and BMI and leptin (AUC=0.832; CI=0.740, 0.923) in females. The optimum thresholds for obesity indices in our study were: BMI, WC and HC as 25 kg/m2, 96.25cm, 99.25cm for males; 27 kg/m

Topics: Adult; Aged; Biomarkers; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity; ROC Curve; Sensitivity and Specificity; Waist Circumference

The aim of the present study was to evaluate the effect of non-surgical periodontal therapy (NSPT) on gingival crevicular fluid (GCF) and serum leptin levels and glycemic status in periodontally healthy patients with chronic periodontitis (CP) with and without type 2 diabetes mellitus (T2DM).. Ninety patients were divided into three groups: periodontally healthy (group 1), CP (group 2) and CP with T2DM (group 3). The groups were evaluated for clinical parameters of probing pocket depth (PPD), clinical attachment level (CAL), plaque index, gingival index, biochemical parameters of GCF, serum leptin levels, and glycemic status pre- and post-NSPT.. The baseline PPD and CAL for group 2 was 4.98 ± 0.49 mm and 5.35 ± 0.55 mm, respectively; for group 3 it was 5.60 ± 0.38 mm and 6.01 ± 0.38 mm, respectively. There was a considerable reduction in these parameters post-NSPT, with group 2 showing better resolution. Pretreatment serum leptin levels revealed increasing values from group 1 to group 3 and decreasing GCF values from group 3 to group 1, exhibiting an inverse relationship. Group 3 also showed an improvement in glycemic status post-NSPT.. NSPT was effective in improving clinical parameters, increasing GCF, reducing serum leptin levels, and also improving glycemic status in patients with CP and CP with T2DM.

Topics: Chronic Periodontitis; Diabetes Mellitus, Type 2; Gingival Crevicular Fluid; Humans; Leptin; Periodontal Attachment Loss; Periodontal Index

Currently, one of the approaches to correct metabolic disorders in the type 2 diabetes mellitus (DM2) with obesity are bariatric surgery (BS), including sleeve gastrectomy (SG), gastric bypass (GB) and ileal transposition (IT). However, their effectiveness and impact on the hypothalamic signaling and hormonal status in severe forms of DM2 without obesity remain little studied. The aim of the work was to study the effect of IT, SG and GB on the insulin, leptin, ghrelin and glucagon-like peptide-1 (GLP-1) levels in the blood and on the expression of the genes encoding the main components of the hypothalamic signaling systems in rats with decompensated form of DM2, which was induced by a high-fat diet (3 months) and a single low dose of streptozotocin (25 mg/kg, 2 months after the start of the diet). In diabetic rats, a significantly expressed hyperglycemia, an impaired glucose tolerance, a decrease in glucose-stimulated GLP-1 level, a slight decrease in the insulin and leptin levels and an slight increase in ghrelin level were detected. In the hypothalamus, the expression of the genes encoding GLP-1 receptor, orexigenic agouti-related peptide (AgRP), as well as phosphotyrosine phosphatase 1B and SOCS3, the negative regulators of the leptin and insulin pathways was increased. In diabetic rats, the IT reduced the glucose levels 120 minutes after glucose load, increased the basal and glucose-stimulated GLP-1 levels, normalized the gene expression for phosphotyrosine phosphatase 1B, SOCS3, AgRP and GLP-1 receptor, which indicates the restoration of the hypothalamic signaling responsible for the control of energy metabolism and insulin sensitivity. In the case of SG and GB, an improvement in the glucose tolerance was found, and in the case of SG, an increase in the basal and glucose-stimulated GLP-1 levels was shown. However, no significant effect on the expression of the hypothalamic genes in SG and GB was found. Thus, IT is the most effective of all studied BS in the treatment of severe forms of DM2 without obesity.. В настоящее время одним из вариантов коррекции метаболических нарушений при сахарном диабете 2-го типа (СД2), который сопровождается ожирением, являются бариатрические операции, в том числе продольная резекция желудка (ПРЖ), гастрошунтирование (ГШ) и илеотранспозиция (ИТ). Однако их эффективность и влияние на гипоталамический сигналинг и гормональный статус при тяжелых формах СД2 без ожирения остаются малоизученными. Целью работы была оценка влияния ИТ, ПРЖ и ГШ на уровни инсулина, лептина, грелина и глюкагоноподобного пептида-1 (ГПП-1) в крови и на экспрессию генов, кодирующих ключевые компоненты гипоталамических сигнальных систем, у крыс с декомпенсированной формой СД2, которую вызывали высокожировой диетой (3 мес) и однократной низкой дозой стрептозотоцина (25 мг/кг, через 2 мес после начала диеты). У диабетических крыс отмечали сильно выраженную гипергликемию, нарушенную толерантность к глюкозе, снижение стимулированного глюкозой уровня ГПП-1, небольшое снижение содержания инсулина и лептина и повышение уровня грелина. В гипоталамусе была повышена экспрессия генов, кодирующих рецептор ГПП-1, орексигенный агутиподобный пептид (АПП), а также фосфотирозинфосфатазу 1B и SOCS3, негативные регуляторы лептинового и инсулинового путей. Проведение ИТ у диабетических крыс снижало уровень глюкозы через 120 мин после глюкозной нагрузки, повышало базальный и стимулированный глюкозой уровень ГПП-1, нормализовало экспрессию генов для фосфотирозинфосфатазы 1B, SOCS3, АПП и рецептора ГПП-1, что свидетельствует о восстановлении гипоталамической сигнализации, ответственной за контроль энергетического обмена и инсулиновой чувствительности. В случае ПРЖ и ГШ отмечали улучшение толерантности к глюкозе, а в случае ПРЖ также повышение базального и стимулированного глюкозой уровня ГПП-1, но заметного влияния на экспрессию гипоталамических генов выявлено не было. Таким образом, ИТ является наиболее эффективной из всех изученных бариатрических операций при лечении тяжелой формы СД2 без ожирения.

Topics: Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Insulin; Leptin; Rats

To investigate the effects of aerobic exercise and glutamine (Gln) on anti-oxidative stress and inflammatory factors in type 2 diabetes mellitus (T2MD) rats.. Diabetic rat model was induced by streptozotocin (STZ). Fifty 6-week old male SD rats were randomly divided into 5 groups (n=10), including quiet control group (N), diabetes control group (D), diabetic aerobic exercise group (DE), diabetic glutamine group (DG) and diabetic aerobic exercise glutamine group (DEG). After 6 weeks, the related indicators of glucose and lipid metabolism, anti-oxidative stress and inflammatory factors in diabetic rats were detected, and the possible mechanism affecting inflammatory response were explored.. Compared with group N, the levels of serum malondialdehyde(MDA), blood glucose, total cholesterol(TC), triglyceride(TG), insulin, leptin and tumor necrosis factor-α(TNF-α) in group D were increased significantly (P＜0.01). Compared with group D, serum levels of MDA, blood glucose, TC, TG, insulin, leptin and TNF-α in three intervention groups were decreased significantly, while the levels of SOD, GSH-Px and adiponectin were increased, and the combined effect was more obvious (P＜0.01).. Both aerobic exercise and Gln can relieve the glucose and lipid metabolism and disturbance, oxidative stress injury and inflammation in diabetic rats.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glutamine; Leptin; Lipid Metabolism; Lipids; Male; Malondialdehyde; Oxidative Stress; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Sprague-Dawley

Kindlin-2 regulates integrin-mediated cell adhesion to and migration on the extracellular matrix. Our recent studies demonstrate important roles of kindlin-2 in regulation of mesenchymal stem cell differentiation and skeletal development. In this study, we generated adipose tissue-specific conditional knockout of kindlin-2 in mice by using Adipoq-Cre BAC-transgenic mice. The results showed that deleting kindlin-2 expression in adipocytes in mice caused a severe lipodystrophy with drastically reduced adipose tissue mass. Kindlin-2 ablation elevated the blood levels of nonesterified fatty acids and triglycerides, resulting in massive fatty livers in the mutant mice fed with high-fat diet (HFD). Furthermore, HFD-fed mutant mice displayed type II diabetes-like phenotypes, including elevated levels of fasting blood glucose, glucose intolerance, and peripheral insulin resistance. Kindlin-2 loss dramatically reduced the expression levels of multiple key factors, including PPARγ, mTOR, AKT, and β-catenin proteins, and suppressed adipocyte gene expression and differentiation. Finally, kindlin-2 loss drastically reduced leptin production and caused a high bone mass phenotype. Collectively, these studies establish a critical role of kindlin-2 in control of adipogenesis and lipid metabolism as well as bone homeostasis.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; Adiposity; Animals; Blood Glucose; Cytoskeletal Proteins; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Nonesterified; Fatty Liver; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipodystrophy; Liver; Male; Mice; Mice, Knockout; Muscle Proteins; Severity of Illness Index; Triglycerides

We investigated the biomarkers of insulin action as well as changes in free fatty acids and lactate concentration after an acute soccer session pre and post training with caloric-restricted diet versus diet alone in type 2 diabetes (T2D) patients.. Fifty-one middle-aged (61.1 ± 6.4 years) T2D patients were randomly allocated to the soccer+diet group (SDG) or the diet group (DG). The control group comprised T2D patients observing a caloric-restricted diet who did not receive soccer training. Over 12 weeks, SDG performed 3 × 40 min per week of soccer training.. The first soccer session for SDG induced acute increases in blood lactate (1.4 ± 0.1-6.0 ± 0.7 mmol/l, P < 0.05) and glucagon levels (112.1 ± 6.2-142.9 ± 8.0 pg/ml, P < 0.05), whereas glucose and insulin levels remained unchanged. Moreover, this session showed suppressed insulin levels as well as higher free fatty acids, lactate levels and glucagon/insulin ratio compared to DG (p < 0.05). After 12 weeks, a baseline decrease was observed in glucagon, leptin and lactate levels in SDG and DG (p < 0.05), whereas HOMA-IR, Adipo-IR and glucose levels were lower only in SDG (p < 0.05). At the last soccer training session, the blood lactate response was significantly lower than for the first session (4.0 ± 0.4 vs 6.0 ± 0.7 mmol/l). At 48 h pre intervention, a decrease was observed in leptin levels (p < 0.05), which remained lower post intervention. The positive correlation between leptin and insulin, and the lower levels after training, could be attributed to the improved insulin sensitivity along with the weight loss observed in both groups (~3.4 kg for DG and 3.7 kg for SDG).. Acute soccer sessions markedly improved insulin action markers in T2D patients, while the cumulative effects enhanced insulin sensitivity and decreased risk factors associated with cardiovascular disease after 12 weeks of intervention better than caloric-restricted diet.

Topics: Aged; Biomarkers; Blood Glucose; Body Composition; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise Therapy; Female; Glucagon; Humans; Insulin; Insulin Resistance; Lactic Acid; Leptin; Male; Middle Aged; Physical Conditioning, Human; Soccer; Treatment Outcome

Topics: Adipose Tissue; Animals; Body Composition; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucose; Insulin; Leptin; Male; Mice; Mice, Inbred NOD; Pancreatic Hormones; Plasminogen Activators; Resistin

The leptin gene was transferred into the liver of streptozocin- and high fat diet-induced type 2 diabetic (T2D) mice by hydrodynamic-based gene delivery. The food intake, water consumption, glucose concentration, and triglyceride and total cholesterol levels of T2D mice were significantly decreased. Meanwhile, plasma leptin was remarkably increased after gene transfer for 2, 3, 5, and 7 days, while plasma adiponectin was also significantly increased at day 2. To understand the mechanism of action of leptin on T2D mice, gene expressions related to glycometabolism and energy metabolism in the liver, epididymal adipose tissue, hypothalamus, and muscle were measured. The mRNA expression levels of adiponectin receptor 1 (ADR1), glucose transporter 4 (GLUT4), glucose-6-phosphase, and peroxisome proliferator-activated receptor γ in the liver, leptin, adiponectin, and hormone-sensitive lipase in adipose tissue, leptin, leptin-receptor, ADR1 in the hypothalamus, and ADR1, GLUT4, and insulin 1 in the gastrocnemius significantly increased. Moreover, the hepatic glycogen of the leptin-gene-treated group was significantly increased in comparison to the control group. Meanwhile, the significant decrease of forkhead box O1, adiponectin receptor 2, and peroxisome proliferator-activated receptor α in the liver, and agouti-related protein and proopiomelanocortin genes in the hypothalamus were also observed. In fat tissue and hypothalamus, leptin and adiponectin protein levels were also significantly increased, whereas the neuropeptide Y protein level was significantly decreased. These results indicated that the leptin gene transfer could improve the symptoms of T2D mice by regulating the leptin-hypothalamus signaling pathway and improving the insulin resistance of the peripheral tissues of T2D mice.

Topics: Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Genetic Therapy; Humans; Hypothalamus; Insulin Resistance; Leptin; Liver; Mice; Signal Transduction; Transfection

Recent studies reported that Fat Mass and Obesity-associated gene (FTO) single nucleotides polymorphisms (SNPs), especially rs9939609, have association with obesity and type 2 diabetes mellitus. On the other hand, many researches confirmed that leptin, an adipocytokine, is related to the obesity and Body Mass Index (BMI) in patients who suffered from Type 2 Diabetes (T2DM).. In this study, the correlation of FTO rs9939609 polymorphism and leptin level was investigated in the obese women who suffered from T2DM.. In case-control study, metabolic and anthropometric parameters, and leptin level of 38 obese diabetic and 38 non-diabetic women were investigated. Genotyping of rs9939609 FTO gene was completed by sequencing of PCR amplicons for all cases.. According to the results, FBS, age, HbA1c, insulin level, HOMA index and leptin level showed statistically significant difference between diabetic and non-diabetic women (P < 0.05). Based on the adjusting of FTO rs9939609 SNP with anthropometric and metabolic parameters, no significant difference was found between the three genotypes (AA, TA and TT) in non-diabetic women (P > 0.05). But, in the diabetic group, only TC had significant difference and mean of TC was higher in mutant genotypes (AA and TA) than wild genotype (TT). Also, BMI, insulin, LDL and HDL showed negative correlation with leptin level in both groups but these correlations were not statistically significant.. The results of our study (with little sample size) showed that the mean of leptin level in diabetic women was lower than non-diabetic women (significant difference). However, the level of leptin was not statistically significant between three genotypes, and odds ratio of rs9939609 was higher in diabetic women in comparison with non-diabetic women.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Leptin; Middle Aged; Obesity; Polymorphism, Single Nucleotide

Lysyl oxidase (LOX) is an enzyme crucial for collagen fibre crosslinking and thus for fibrosis development. Fibrosis is characterised by a surplus of collagen fibre accumulation and is amongst others also a feature of obesity-associated dysfunctional adipose tissue (AT) which has been linked with type 2 diabetes. We hypothesised that in type 2 diabetes and obesity LOX expression and activity will be increased as a consequence of worsening AT dysfunction. This study aimed to provide a comprehensive characterisation of LOX in human AT.. LOX mRNA expression was analysed in omental and abdominal subcutaneous AT obtained during elective surgery from subjects with a wide range of BMI, with and without diabetes. In addition, LOX expression was studied in subcutaneous AT before and 9.5months after bariatric surgery. To study the mechanism of LOX changes, its expression and activity were assessed after either hypoxia, recombinant human leptin or glucose treatment of AT explants. In addition, LOX response to acute inflammation was tested after stimulation by a single injection of lipopolysaccharide versus saline solution (control) in healthy men, in vivo. Quantity of mRNA was measured by RT-qPCR.. LOX expression was higher in obesity and correlated with BMI whilst, in vitro, leptin at high concentrations, as a potential feedback mechanism, suppressed its expression. Neither diabetes status, nor hyperglycaemia affected LOX. Hypoxia and lipopolysaccharide-induced acute inflammation increased LOX AT expression, latter was independent of macrophage infiltration.. Whilst LOX may not be affected by obesity-associated complications such as diabetes, our results confirm that LOX is increased by hypoxia and inflammation as underlying mechanism for its upregulation in adipose tissue with obesity.

Topics: Adult; Bariatric Surgery; Diabetes Mellitus, Type 2; Fibrosis; Humans; Hyperglycemia; Leptin; Male; Obesity; Omentum; Protein-Lysine 6-Oxidase; Subcutaneous Fat

To investigate the associations between irisin and leptin levels in obesity and insulin resistance in a cross sectional study. To assess the potential role of irisin and leptin as a predictive marker of T2DM using a nested case-control study.. Both studies were designed within the longitudinal VA NAS cohort. The cross sectional study involved 111 non obese and 105 obese subjects who were subdivided into two groups based on their fasting glucose tolerance. In the nested 1:3 case-control study, 47 subjects with T2DM and 140 non-diabetic controls were selected. Serum samples collected 3-5 years before the diagnosis of T2DM were analyzed. Irisin and leptin concentrations were measured using a validated ELISA and radioimmunoassay respectively.. In the cross-sectional study, irisin did not differ between groups based on their fasting glucose tolerance. When subjects were grouped based on obesity status, both irisin and leptin concentrations were significantly higher in obese compared to the non-obese group (p=0.03 and <0.001, respectively). Irisin concentrations positively correlated with leptin concentrations (r= 0.392, P < 0.001). In the nested case control study, leptin concentrations were a significant predictor of developing diabetes (p=0.005) in unadjusted models, but not after correcting for BMI, whereas irisin concentrations did not play a role of comparable significance.. Leptin concentrations are higher in the obese group irrespective of their glucose tolerance. Obese individuals with impaired fasting glucose have higher concentrations of circulating irisin compared to non-obese subjects with normal glucose tolerance. Irisin concentrations do not predict risk of developing diabetes prospectively.

Topics: Aged; Aging; Body Mass Index; Case-Control Studies; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Fibronectins; Glucose Tolerance Test; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Prospective Studies

Although high levels of sitting time are adversely related to health, it is unclear whether moving from sitting to standing provides a sufficient stimulus to elicit benefits upon markers of chronic low-grade inflammation in a population at high risk of type 2 diabetes (T2DM). Three hundred and seventy two participants (age = 66.8 ± 7.5years; body mass index (BMI) = 31.7 ± 5.5kg/m

Topics: Actigraphy; Adult; Aged; Biomarkers; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Exercise; Female; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Posture; Risk Factors; Sedentary Behavior; Sex Factors

We investigated whether cardiometabolic risk factors measured in serum (total cholesterol [TC], high-density lipoprotein [HDL], triglyceride, leptin, insulin, glucose and insulin resistance) are associated with the retinal microvasculature, a marker of cardiovascular aging, in healthy children and adolescents. Moreover, we tested whether these associations are due to direct biological effects or more indirectly due to adiposity-related side effects.. We recruited 168 healthy Flemish children (7-16 years old, 54.8% boys). Blood samples and retinal photographs were taken during clinical examinations. Arteriolar and venular vessel calibers were calculated using a semi-automated computer program. Multivariable regression models were used and adjusted for age, sex, mean arterial pressure (MAP) and alternate retinal caliber. In a second step, we adjusted for body mass index z-score (zBMI).. Only continuous serum leptin was associated with retinal parameters, i.e. wider arterioles; however, this disappeared after adjustment for zBMI. Children with high cardiometabolic risk factors (>90th percentile for serum leptin, insulin and insulin resistance) had wider arterioles compared to children with lower concentrations, even after additional adjustment for zBMI. No significant associations were found with lipids.. In this healthy population of children and adolescents, the hormones insulin and leptin and insulin resistance were associated with retinal microvasculature alterations, mainly in children with high cardiometabolic factors (>90th percentile), while lipids were not. These associations were independent of zBMI.

Topics: Adiposity; Adolescent; Belgium; Biomarkers; Body Mass Index; Cardiovascular Diseases; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Health Surveys; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Longitudinal Studies; Male; Microvessels; Ophthalmoscopy; Retinal Vessels; Risk Factors

Mouse models of obesity (ob/ob) and diabetes (db/db) in which the leptin (Lep) and leptin receptor (Lepr) genes have been mutated, respectively, have contributed to a better understanding of human obesity and type 2 diabetes and to the prevention, diagnosis, and treatment of these metabolic diseases. In this study, we report the first CRISPR-Cas9-induced Lep and Lepr knockout (KO) mouse models by co-microinjection of Cas9 mRNA and sgRNAs that specifically targeted Lep or Lepr in C57BL/6J embryos. Our newly established Lep and Lepr KO mouse models showed phenotypic disorders nearly identical to those found in ob/ob and db/db mice, such as an increase in body weight, hyperglycemia, and hepatic steatosis. Thus, Cas9-generated Lep and Lepr KO mouse lines will be easier for genotyping, to maintain the lines, and to use for future obesity and diabetes research.

Topics: Animals; CRISPR-Cas Systems; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Mice, Inbred C57BL; Mice, Knockout; Microinjections; Mutation; Obesity; Receptors, Leptin; RNA, Messenger

Little is known about the iron efflux mechanism in adipocytes. Here, we used hephaestin (Heph) and ceruloplasmin (Cp) single-knockout (KO) mice and Heph/Cp double-KO mice to investigate the roles of multicopper ferroxidases (MCFs) in this process. We show that both HEPH and CP are expressed in subcutaneous adipose tissue. Ablation of either MCF leads to a compensatory increase in the other, which contributes to the balance of iron status. However, ablation of both MCFs together induces severe iron deposition in adipocytes which is associated with decreased adiponectin and leptin mRNA expression. Furthermore, Heph/Cp KO mice display disordered carbohydrate metabolism characterized as type 2 diabetes. Together, these results demonstrate the protective roles of HEPH and CP in preventing iron overload in adipocytes.

Topics: Adipocytes; Adiponectin; Animals; Ceruloplasmin; Diabetes Mellitus, Type 2; Gene Knockout Techniques; Iron; Leptin; Male; Membrane Proteins; Mice

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Evidence-Based Medicine; Heart; Heart Failure; Humans; Hypoglycemic Agents; Leptin; Myocardium; Obesity; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume

The microtubule-associated protein tau is highly expressed in pancreatic islets. Abnormally phosphorylated tau aggregates assemble into neurofibrillary tangles linked to Alzheimer's disease pathology and has also been found in islets of patients with type 2 diabetes. However, the significance of tau in islet function remains relatively unexplored. Therefore, we investigated the role of tau on β cell function and glucose homeostasis using tau knockout (tauKO) mice. TauKO mice were hyperglycemic and glucose intolerant at an early age. Islet insulin content was reduced and proinsulin levels were significantly elevated in tauKO mice, resulting in impaired glucose-stimulated insulin secretion. Loss of tau also resulted in increased epididymal fat mass and leptin levels, reduced glucose production, and insulin resistance at later ages, leading to complete onset of diabetes. Transgenic expression of human tau in islets was unable to rescue those defects in glucose regulation, indicating structural and/or functional differences between mouse and human tau. Cumulatively, these results suggest an important role for tau in the proper maintenance of pancreatic β cell function and glucose homeostasis.-Wijesekara, N., Gonçalves, R. A., Ahrens, R., De Felice, F. G., Fraser, P. E. Tau ablation in mice leads to pancreatic β cell dysfunction and glucose intolerance.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Glucose Intolerance; Humans; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Knockout; Proinsulin; Species Specificity; tau Proteins

Leptin is an adipokine which regulates appetite and energy balance through a mechanism partially mediated by neurotensin (NT) in central nervous system. Besides acting as a neurotransmitter, NT is expressed in human intestine where it promotes fat absorption and its circulating levels associate with obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Whether a relation exists between circulating leptin and NT levels has not been investigated yet. The aim of this study was to test the hypothesis of an association between plasma leptin and NT concentration in adults with or without T2DM.. We recruited a population of 72 subjects (M/F: 39/33; age: 49.5 ± 10.6 years; BMI: 26.5 ± 4.7 kg/m. Circulating leptin is associated with higher proNT levels independent of diabetes, obesity and metabolic syndrome components; besides its effects on central leptin signaling, NT may influence energy balance by modulating circulating leptin concentration likely through a mechanism involving gut fat absorption.

Topics: Adult; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Neurotensin; Obesity

This study aimed to evaluate serum leptin and high sensitivity C-reactive protein (hsCRP) concentrations in obese Ghanaians with or without type 2 diabetes and to find out the extent to which their levels are influenced by underlying disorders.. Obese subjects with type 2 diabetes had lower leptin but higher hsCRP levels compared with obese non-diabetic controls. There were negative correlations within the control group for glucose vs % muscle mass (r = - 0.378, p = 0.016), leptin vs % muscle mass (r = - 0.555, p = 0.001) and within the obese diabetic group for leptin vs % muscle mass (r = - 0.602, p = 0.001). Obese persons without diabetes were about three times more likely to have higher leptin levels compared with their obese diabetic counterparts (Odds ratio = 3.315, p < 0.001). Obese females independently had a tenfold increase in leptin levels compared with obese males.

Topics: Adult; C-Reactive Protein; Comorbidity; Diabetes Mellitus, Type 2; Female; Ghana; Humans; Leptin; Male; Middle Aged; Obesity

Many adipose tissue-related diseases, such as obesity and type 2 diabetes, are worldwide epidemics. For studying these diseases, relevant human cell models are needed. In this study, we developed a vascularized adipose tissue model where human adipose stromal cells and human umbilical cord vein endothelial cells were cocultured with natural adipogenic and defined serum-free angiogenic media for 14 days. Several different protocols were compared to each other. The protocols varied in cell numbers and plating sequences. Lipid accumulation was studied with AdipoRed reagent, relative cell number with WST-1 reagent, gene expression of glut4, leptin, aP2, adiponectin, PPARγ and PPARγ2 with RT-qPCR. Secretion of adiponectin, leptin and aP2 was analysed with ELISA. The immunostained vascular network was imaged with Cell-IQ and area quantified using ImageJ. In this study, both angiogenesis and adipogenesis were successfully induced. Protocols produced strong lipid accumulation, good vascular network formation and induced adipocyte-specific protein secretion and expression of studied adipocyte genes. Results showed that cell numbers and cell plating sequences are important factors when aiming at in vitro standardized tissue model. Presence of mature vasculature appeared leads to faster the maturation of adipocytes judged by the lipid accumulation and gene expression results. The developed vascularized adipose tissue model is simple to use, easily modifiable to suit various applications and as such, a promising new tool for adipose tissue research when, for example, studying the effect of different cell types on adipose tissue function or for mechanistic studies.

Topics: Adipocytes; Adipogenesis; Adiponectin; Adipose Tissue; Cell Culture Techniques; Coculture Techniques; Culture Media, Serum-Free; Diabetes Mellitus, Type 2; Fatty Acid-Binding Proteins; Glucose Transporter Type 4; Human Umbilical Vein Endothelial Cells; Humans; Leptin; Lipid Metabolism; Neovascularization, Physiologic; Obesity; PPAR gamma; RNA, Messenger

Poor sleep quality is associated with obesity and diabetes. The adipocyte-derived hormone, leptin, was recently shown to underlie the link between abnormal sleep and obesity. We aimed to investigate the association between leptin and sleep quality in type 2 diabetes patients.. In the present cross-sectional study, we studied 182 type 2 diabetes patients, among whom 113 were diagnosed with obesity (body mass index ≥25 kg/m. Using unadjusted analyses, the obese type 2 diabetes patients, but not their non-obese counterparts, showed a positive correlation between plasma leptin levels and a parameter for deep sleep assessed by delta power during the first sleep cycle. Multivariate analysis showed that plasma leptin levels were positively associated with delta power, but not with the total sleep time, after adjusting for potential confounders including age, body mass index and the apnea-hypopnea index, in the obesity group. However, neither delta power nor total sleep time was associated with leptin in the non-obesity group.. Plasma leptin levels are independently associated with sleep quality in obese, but not in non-obese, type 2 diabetes patients. The present study indicates a favorable relationship between leptin and sleep quality in obese type 2 diabetes patients.

Topics: Aged; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Japan; Leptin; Male; Middle Aged; Obesity; Sleep

Non-digestible carbohydrates present in cereals such as fructans and arabinoxylans represent promising prebiotic nutrients to prevent the development of obesity and related metabolic disorders.. The aim of this study was to determine the corrective effects of wheat bran-derived arabinoxylan oligosaccharides in obese mice fed a western diet (WD). WD was given for 4 weeks before wheat bran extract (WBE) supplementation (5%) for an additional 4 weeks, whereas a control group received the standard diet.. Bifidogenic effect of WBE was evidenced by an induction of both Bifidobacterium animalis and Bifidobacterium pseudolongum in the caecal content. WBE supplementation normalised WD-induced fat-mass expansion, steatosis, hypercholesterolemia, hyperleptinemia, hyperglycemia and hyperinsulinemia reaching the values of control mice. The reduced glucose-dependent insulinotropic polypeptide (GIP) release observed in WD + WBE mice may be a protective mechanism in terms of reducing adipose tissue storage, hepatic steatosis and glucose homoeostasis.. We found that WBE completely abolished WD-induced metabolic disorders. Those results might be useful to take into account nutritional advices to treat obesity and related metabolic disorders such as type 2 diabetes, hypercholesterolaemia and fatty liver diseases when obesity was already established.

Topics: Adipose Tissue; Animals; Bifidobacterium; Blood Glucose; Cecum; Diabetes Mellitus, Type 2; Diet, Western; Dietary Fiber; Fatty Liver; Gastric Inhibitory Polypeptide; Hypercholesterolemia; Hyperglycemia; Hyperinsulinism; Leptin; Liver; Male; Metabolic Diseases; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligosaccharides; Prebiotics; Triticum; Xylans

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypothalamus; Leptin; Obesity; Receptors, Leptin; Signal Transduction

Objects To compare insulin resistance (IR) and metabolic aspects of patients with neurofibromatosis type 1 (NF1) and individuals without the disease. Subjects and methods Forty patients with NF1 were matched by sex, age, and body mass index (BMI) to 40 controls from the community. Blood samples were collected for biochemical assessment. Homeostasis model assessment adiponectin (HOMA-AD), Homeostasis model assessment insulin resistance (HOMA-IR), and adiponectin/leptin ratio (ALR) were used to identify IR. Results The median HOMA-IR values were similar between the groups. However, the HOMA-AD value was significantly lower and the ALR significantly higher in the NF1 group. Fasting blood glucose (FBG), leptin, and visfatin levels of patients with NF1 were significantly lower, although adiponectin levels were significantly higher than those in the controls. Fasting insulin and blood glucose levels 2 hours after administration of 75 g of dextrose, glycated hemoglobin, and resistin showed no significant differences between groups. The HOMA-AD correlated with BMI, FBG, blood glucose levels 2 hours after administration of 75 g of dextrose, fasting insulin, glycated hemoglobin, adiponectin, leptin, visfatin, ALR, and HOMA-IR. The ALR correlated with BMI leptin, visfatin, and adiponectin. Conclusions Lower levels of FBG, leptin, visfatin, and HOMA-AD, and higher adiponectin levels and ALR may be related to increased insulin sensitivity and lower occurrence of type 2 diabetes mellitus in patients with NF1.

Topics: Adiponectin; Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Homeostasis; Humans; Insulin Resistance; Leptin; Male; Neurofibromatosis 1

Lipodystrophies are a group of heterogeneous disorders characterized by varying degrees of body fat loss and predisposition to insulin resistance and its metabolic complications. Lipodystrophy associated metabolic abnormalities include insulin resistance, that often lead to diabetes mellitus and its complications, hypertriglyceridemia that may be severe enough to cause acute pancreatitis, and hepatic steatosis that may lead to cirrhosis. We present the case of an 18-year-old female who was hospitalized as an inaugural Diabetes Mellitus. She was diagnosed with severe hypertriglyceridemia, when she was 8 years old and was hospitalized at least three times by the Pediatric Service related to this condition. Lipodystrophy developed at the age of 11. The reason for the latest hospitalisation was hyperglycemia, hypertriglyceridemia and elevated transaminase levels. Leptin levels were very low 1.5 ug/L (ref range 4-10 ug/L in women). She was given Insulin and antihyperlipidemic therapy. However there was little improvement in laboratory results even in 2 months. A year after her hospitalisation at our clinic she started leptin therapy and her laboratory values improved. In a patient with a newly diagnosed diabetes mellitus, hypertriglyceridemia and loss of adipose tissue, lipodystrophy should be suspected.

Topics: Adolescent; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Lipodystrophy, Congenital Generalized

Obese subjects display elevated plasma levels of leptin reflecting the phenomenon of leptin resistance. Here, we aimed to determine whether leptin-reactive immunoglobulins (Ig) are present in obese and type 2 diabetes (T2D) patients and whether their plasma levels and affinity kinetics may correlate with obesity and diabetes markers. We show that leptin levels are increased in obese patients with and without T2D. Although mean plasma levels of leptin-reactive IgG were similar between study groups, IgG in obese non-diabetic patients had increased dissociation rate and lower affinity (increased dissociation equilibrium constant value; KD). In controls and diabetic patients, the association rates of leptin IgG correlated negatively with obesity and diabetes markers, respectively. In contrast, KD values correlated positively with plasma leptin levels and obesity traits in our cohort, and with diabetes markers in both the total cohort and in the obese T2D group. Taken together, our data reveal that leptin-reactive IgG are present in healthy subjects, obese, and diabetic patients but display altered affinity kinetics in obesity. Increased IgG binding to leptin in healthy subjects associated with lower body mass index (BMI) suggests an enhancing role of IgG in leptin signaling. Accordingly, a decreased affinity of IgG for leptin, found in obese patients, can be relevant to leptin resistance.

Topics: Adult; Aged; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Immunoglobulins; Leptin; Male; Middle Aged; Obesity

Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 diabetes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabetics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to diabetes. Only leptin and IL-6 had a significant association with the measured metabolites. Leptin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes.

Topics: Body Weight; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Interleukin-6; Leptin; Metabolomics; Microbiota; Obesity; Time Factors

Determine the metabolic profile and identify risk factors of women transitioning from gestational diabetes mellitus (GDM) to type 2 diabetes mellitus (T2DM).. 237 women diagnosed with GDM underwent an oral glucose tolerance test (OGTT), anthropometrics assessment, and completed lifestyle questionnaires six years after pregnancy. Blood was analysed for clinical variables (e.g., insulin, glucose, HbA1c, adiponectin, leptin, and lipid levels) and NMR metabolomics. Based on the OGTT, women were divided into three groups: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM.. Six years after GDM, 19% of subjects had T2DM and 19% IGT. After BMI adjustment, the IGT group had lower HDL, higher leptin, and higher free fatty acid (FFA) levels, and the T2DM group higher triglyceride, FFA, and C-reactive protein levels than the NGT group. IGT and T2DM groups reported lower physical activity. NMR measurements revealed that levels of branched-chain amino acids (BCAAs) and the valine metabolite 3-hydroxyisobyturate were higher in T2DM and IGT groups and correlated with measures of insulin resistance and lipid metabolism.. In addition to well-known clinical risk factors, BCAAs and 3-hydroxyisobyturate are potential markers to be evaluated as predictors of metabolic risk after pregnancy complicated by GDM.

Topics: Adiponectin; Adult; Amino Acids, Branched-Chain; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diabetes, Gestational; Disease Progression; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hydroxybutyrates; Insulin Resistance; Leptin; Pregnancy; Risk Factors

Several observational studies have shown that low serum vitamin B-12 is associated with increased body mass index (BMI) and adverse cardiometabolic outcomes. However, it is unclear if these associations reflect a causal effect of vitamin B-12 on cardiometabolic risk factors and diseases, latent confounding, or reverse causality.. The aims of this study were to investigate 1) the possible causal relation between vitamin B-12 and indicators of body fat, lipid, and glucose variables; type 2 diabetes (T2D); and cardiovascular disease by using a 2-sample Mendelian randomization (MR) method and 2) the possible pleiotropic role of fucosyltransferase 2 (FUT2).. We selected 11 single nucleotide polymorphisms (SNPs) robustly associated with serum concentrations of vitamin B-12 in a previous genomewide association study (GWAS) in 45,576 individuals. We performed 2-sample MR analyses of the relation between vitamin B-12 and cardiometabolic risk factors and diseases with the use of publicly available GWAS summary statistics for 15 outcomes in ≤339,224 individuals. The robustness of results was tested with sensitivity analyses by using MR Egger regression and weighted-median estimation, and by performing additional analyses excluding a variant in the FUT2 gene, which may be pleiotropic.. We found a suggestive causal relation between vitamin B-12 and fasting glucose and β cell function [homeostatic model assessment (HOMA) of β cell function (HOMA-B)]. However, we found no evidence that serum concentrations of vitamin B-12 were causally related to BMI, waist-to-hip ratio, plasma leptin, body fat, fasting insulin, insulin resistance (from HOMA of insulin resistance), glycated hemoglobin, triglycerides, T2D, coronary artery disease, or HDL, LDL, or total cholesterol.. We found no evidence that serum concentrations of vitamin B-12 are causally related to body weight or the majority of cardiometabolic outcomes investigated. However, vitamin B-12 may have a causal effect on fasting glucose and HOMA-B, although these results will require replication in large independent data sets. This trialwas registered at http://www.isrctn.com/ISRCTN47414943 as ISRCTN47414943.

Topics: Blood Glucose; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fucosyltransferases; Galactoside 2-alpha-L-fucosyltransferase; Genome-Wide Association Study; Humans; Insulin Resistance; Leptin; Lipids; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors; Vitamin B 12

Oxidative stress (OS) plays an important role in type 2 diabetes (T2D) pathogenesis and its complications. New therapies target natural antioxidants as an alternative and/or supplemental strategy to prevent and control them. Our previous chemical and biological studies highlighted the important antioxidant activities of cherries, among other fruits and vegetables, thus we aimed to determine in vivo effects of 2-month long cherry consumption using a high-fat/high-fructose (HFHF) model of diabetic-rats (Lozano et al. in Nutr Metab 13:15, 2016).. After 2 months of HFHF, male Wistar rats were divided into: HFHF and HFHF enriched in cherry (nutritional approach) or standard diet ND (lifestyle measures) and ND plus cherry during 2 months. Metabolic, lipidic, oxidative parameters were quantified. Tissues (liver, pancreas and vessels) OS were assessed and hepatic (steatosis, fibrosis, inflammation) and vascular (endothelial dysfunction) complications were characterized.. T2D was induced after 2 months of HFHF diet, characterized by systemic hyperglycaemia, hyperinsulinemia, glucose intolerance, dyslipidaemia, hyperleptinemia, and oxidative stress associated with endothelial dysfunction and hepatic complications. Cherry consumption for 2 months, in addition to lifestyle measures, in T2D-rats decreased and normalized the systemic disturbances, including oxidative stress complications. Moreover, in the vessel, cherry consumption decreased oxidative stress and increased endothelial nitric oxide (NO) synthase levels, thus increasing NO bioavailability, ensuring vascular homeostasis. In the liver, cherry consumption decreased oxidative stress by inhibiting NADPH oxidase subunit p22phox expression, nuclear factor erythroid-2 related factor 2 (Nrf2) degradation and the formation of reactive oxygen species. It inhibited the activation of sterol regulatory element-binding proteins (1c and 2) and carbohydrate-responsive element-binding protein, and thus decreased steatosis as observed in T2D rats. This led to the improvement of metabolic profiles, together with endothelial and hepatic function improvements.. Cherry consumption normalized vascular function and controlled hepatic complications, thus reduced the risk of diabetic metabolic disorders. These results demonstrate that a nutritional intervention with a focus on OS could prevent and/or delay the onset of vascular and hepatic complications related to T2D.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, High-Fat; Endothelium, Vascular; Energy Metabolism; Fructose; Fruit; Insulin; Leptin; Lipids; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Pancreas; Prunus avium; Rats, Wistar; Signal Transduction; Time Factors

Leptin/leptin resistance has been suggested to play a role in nonalcoholic fatty liver disease (NAFLD), and therefore we investigated the correlation of leptin/leptin-receptor system with markers of hepatic steatosis (HS) and fibrosis (HF) in patients with type 2 diabetes (T2D).. In 159 T2D subjects with disease duration of 6.0 (0.0-27.0) years, HS was evaluated by semi-quantitative ultrasonographic scores and by clinical/biochemical variables: Fatty liver index and Hepatic steatosis index. HF was evaluated by NAFLD fibrosis score (NAFLD-FS). Serum leptin and leptin receptor (sObR) concentrations were measured and leptin resistance estimated by Free Leptin Index (FLpI). Both simple and multiple correlations between the HS and HF with the three parameters of interest were examined.. Leptin levels and FLpI correlated with diabetes duration (0.25 [95%CI: 0.09-0.39] and 0.24 [95%CI: 0.08-0.39]; P < 0.01 for both). 76.1% of T2D patients had HS and 29% had HF. The univariate analysis indicated positive correlations of HS indexes with serum leptin, FLpI, and negative correlations with serum sObR (P < 0.0001 for all). In the multiple regression analysis leptin, sObR, FLpI, waist-to-hip ratio, HbA1c, lipids, and HOMA-IR correlated independently with HS (P < 0.0001 for all). Although the univariate analyses indicated weak correlations of NAFLD-FS with leptin, sObR, and FLpI, in the multiple regression analyses, only age and waist independently predicted HF.. In patients with T2D, HS correlated positively with serum leptin and leptin resistance, and negatively with sObR, along with variables of adiposity and metabolic control, but neither of them made a significant contribution to HF.

Topics: Adult; Aged; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Drug Resistance; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity

The aimed of this research is to evaluate the effects of clove and fermented ginger supplements on blood glucose,serum insulin, insulin receptor and Leptin levels of high fat diet-induced type 2 diabetes mellitus in rabbits. Clove and gingerare spices with records of medicinal value over decades. Thirty males rabbits weighing, 1-1.5kg were used for the research.Type 2 diabetes was induced by feeding the animals with a high fat diet for a period of eight weeks. Blood glucose levelswere determined after the induction period and rabbits having 140 mg/dL and above were selected for the study. The animalswere grouped into six groups with five (n=5) rabbits in each group: Group 1 (Normoglycemic control group.) received normalfeed and distilled water ad libitum for six weeks; Group 2 (Diabetic negative control group.) received normal feed anddistilled water ad libitum for six weeks; Groups 3 (Diabetic positive control.) received cholestran 0.26g/kg and normal feedfor a period of six weeks; Group 4 and 5 (diabetic rabbits) were fed on 12.5%, clove and 12.5% fermented gingerrespectively for a period of six weeks; while Group 6 were co-fed on 12.5% clove and 12.5% fermented ginger for a periodof six weeks. Fasting blood glucose levels were determined at weekly interval during the treatment period. At the end of theexperiment, the rabbits were euthanized by cervical dislocation and blood samples were collected for the determination ofinsulin, insulin receptor and leptin levels. A significantly (P<0.05) decrease in blood glucose levels was recorded in thesupplements treated groups compared to diabetic control group. Clove supplement been most effective and sustaining inantihyperglycemic activity, also appears with a significant decreasing effect on leptin levels compared to diabetic controlgroup. A significant increase in insulin levels was also noted in the fermented ginger treated group along with higher levelsof Leptin compared as compared to control group. In conclusion the result of the study show that clove and fermented gingersupplementation possesses anti-diabetic properties and may help in the control of hyperleptinaemia in type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Hypoglycemic Agents; Insulin; Leptin; Male; Rabbits; Receptor, Insulin; Syzygium; Zingiber officinale

Apart from the primary metabolic symptoms of obesity and/or diabetes, there are numerous secondary problems, including disruptions of the reproductive system. The KNDy neurones, which express kisspeptin, neurokinin B and dynorphin A and are located in the arcuate nucleus of the hypothalamus (ARC), are important regulators of reproduction. Their functions are highly influenced by metabolic and hormonal status. We have previously shown that, in male rats with experimentally-induced diabetes type 2 (but not with high-fat diet-induced obesity), there are alterations in the number of these cells. In the present study, we hypothesised that a high-fat diet (HFD) and/or diabetes type 2 (DM2) in female rats affect the oestrous cycle, hormonal profiles and the number of kisspeptin-immunoreactive, neurokinin B-immunoreactive and/or dynorphin A-immunoreactive neurones in the ARC. Rats were assigned to one of three groups: a control group fed a regular chow diet, a high-fat diet group (HFD) and a diabetic group (DM2), with both of the latter two groups receiving a high calorie diet (50% of energy from lard). The third group was additionally treated with streptozotocin to induce DM2. Their oestrous cycles was monitored and their metabolic and hormonal status were assessed. We found that HFD and DM2 female rats, despite having significant alterations in their metabolic and hormonal profiles, as well as disruptions of the oestrous cycle, showed no changes in the number of the kisspeptin-immunoreactive, neurokinin B-immunoreactive and/or dynorphin A-immunoreactive neurones in the ARC. However, slight differences in the rostrocaudal distribution of these neurones among groups were reported. In conclusion, the data from the present study, together with our previously published results in males, indicate sex differences in the response of KNDy neurones to DM2 but not to HFD conditions.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus, Type 2; Diet, High-Fat; Dynorphins; Estrous Cycle; Female; Insulin; Kisspeptins; Leptin; Neurokinin B; Neurons; Neuropeptides; Peptide Hormones; Rats, Wistar

A soluble form of the leptin receptor (soluble Ob-R) in the circulation regulates leptin's bioactivity, and is inversely associated with body adiposity and circulating leptin levels. However, no study has examined the clinical impact of soluble Ob-R on glucose metabolism in diabetes. The present study aimed to investigate the association of plasma soluble Ob-R levels with insulin resistance and pancreatic β-cell function in patients with type 2 diabetes.. A total of 289 Japanese patients with type 2 diabetes were included in the present study. Fasting plasma soluble Ob-R levels and plasma leptin levels were measured by enzyme-linked immunosorbent assay. Insulin resistance and pancreatic β-cell function were estimated by homeostasis model assessment of insulin resistance, homeostasis model assessment of β-cell function and fasting C-peptide index.. The median plasma soluble Ob-R level and plasma leptin level were 3.4 ng/mL and 23.6 ng/mL, respectively. Plasma soluble Ob-R levels were negatively correlated with homeostasis model assessment of insulin resistance, homeostasis model assessment of β-cell function and the C-peptide index, whereas plasma leptin levels were positively correlated with each index in univariate analyses. Multivariate analyses including plasma soluble Ob-R levels, plasma leptin levels and use of sulfonylureas, along with age, sex, body mass index and other covariates, showed that soluble Ob-R levels were independently and negatively associated with homeostasis model assessment of β-cell function and the C-peptide index, but not significantly associated with homeostasis model assessment of insulin resistance.. Plasma soluble Ob-R levels are independently associated with pancreatic β-cell function, but not with insulin resistance, in patients with type 2 diabetes. The present study implicates the role of soluble Ob-R in pancreatic β-cell dysfunction in type 2 diabetes.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Male; Middle Aged; Receptors, Leptin

Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin.. Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin.. Prospective, single-arm, open-label studies with continuous enrollment since 2000.. National Institutes of Health, Bethesda, Maryland.. Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia).. Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d).. Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment.. After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty.. Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Body Height; Child; Child, Preschool; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Infant; Insulin Resistance; Leptin; Lipodystrophy; Liver; Male; Non-alcoholic Fatty Liver Disease; Prospective Studies; Puberty; Triglycerides

Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive syndrome characterized by a difficulty in storing lipids in adipocytes, low body fat mass, hypoleptinemia, and hyperinsulinemia. Sclerostin is a product of SOST gene that blocks the Wnt/β-catenin pathway, decreasing bone formation and enhancing adipogenesis. There are no data about sclerostin in people with BSCL.. We aimed to evaluate serum sclerostin, bone mineral density (BMD), and L1-L4 Trabecular Bone Score (TBS) in BSCL patients, generating new knowledge about potential mechanisms involved in the bone alterations of these patients.. In this cross-sectional study, we included 11 diabetic patients with BSCL (age 24.7±8.1years; 6 females). Sclerostin, leptin, L1-L4 TBS, BMD were measured. Potential pathophysiological mechanisms have been suggested.. Mean serum sclerostin was elevated (44.7±13.4pmol/L) and was higher in men than women (55.3±9.0 vs. 35.1±8.4pmol/L, p=0.004). Median of serum leptin was low [0.9ng/mL (0.5-1.9)]. Seven out of 11 patients had normal BMD, while four patients had high bone mass (defined as Z-score>+2.5SD). Patients on insulin had lower sclerostin (37.3±9.2 vs. 52.6±13.4pmol/L, p=0.05). The mean TBS was 1.402±0.106, and it was higher than 1.300 in nine patients.. Patients with lipoatrophic diabetes (BSCL) have high serum concentrations of sclerostin, normal or high BMD, and reasonable trabecular bone mass measured by TBS. This is the first report of high sclerostin and good bone microarchitecture (TBS) in BSCL patients.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Bone Density; Bone Morphogenetic Proteins; Cancellous Bone; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Genetic Markers; Humans; Hyperinsulinism; Hypertrophy; Insulin; Leptin; Lipodystrophy, Congenital Generalized; Male; Muscular Diseases; Young Adult

Compared to O-BP, we found elevated plasma leptin and resistin levels in O-T1DM, decreased gene expression of all adipokines in O-GDM, decreased. In conclusion, offspring of women with diabetes in pregnancy exhibit increased

Topics: Adiponectin; Adult Children; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; DNA Methylation; Epigenesis, Genetic; Female; Follow-Up Studies; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Leptin; Maternal Exposure; Pregnancy; Resistin; Subcutaneous Fat

This study aimed to measure salivary levels of leptin and nerve growth factor (NGF) in patients with type 2 diabetes (T2D) and to compare with healthy subjects. In addition, markers previously evaluated in diabetes, including insulin, hepatocyte growth factor (HGF), and monocyte chemoattractant protein-1 (MCP-1), and markers of inflammation interleukin ([IL]-1b, IL-6, IL-8, Tumor necrosis factor alpha [TNF-α]), were also measured in saliva to evaluate possible relationship of these markers with the new analytes evaluated in the study.. Unstimulated whole saliva was collected by passive drooling from a total of 65 individuals (34 controls and 31 with T2D) and used for leptin, NGF, HGF, MCP-1, insulin, IL-1b, IL-6, IL-8, and TNF-α determination.. Salivary leptin was 2.1 higher in T2D than in healthy controls (P<.001), while no statistically significant differences were detected between the two groups in salivary concentrations of NGF. Salivary IL-6, TNF-α, insulin, and MCP-1 were higher in DM in comparison with controls (P<.05 in all cases). Leptin showed positive significant correlations with MCP-1, IL-6, TNF-α, and insulin, while NGF positively correlated with HGF, MCP-1, IL-1 β, IL-6, and TNF-α.. This pilot study indicates that salivary leptin is increased in patients with T2D being positively correlated with insulin and pro-inflammatory cytokines and should be further explored as a non-invasive biomarker of T2D. In addition, salivary NGF was positively correlated with pro-inflammatory cytokines and further studies should be performed to evaluate whether it could be useful to detect diabetic neuropathy in T2D patients.

Topics: Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Nerve Growth Factor; Pilot Projects; Saliva

Branched chain amino acids (BCAA) may be involved in the pathogenesis of insulin resistance and are associated with type 2 diabetes mellitus (T2DM) development. Adipokines such as leptin and adiponectin influence insulin resistance and reflect adipocyte dysfunction. We examined the extent to which the association of BCAA with insulin resistance is attributable to altered leptin and adiponectin levels in individuals with varying degrees of glucose tolerance.. BCAA were measured by nuclear magnetic resonance, whereas leptin and adiponectin were measured by immunoassay, in subjects with normal fasting glucose (n = 30), impaired fasting glucose (n = 25), and T2DM (n = 15). Insulin resistance was estimated by homeostasis model assessment (HOMAir).. BCAA were higher in men than in women (P < 0.001) and tended to be higher in T2DM subjects (P = 0.10) compared to subjects with normal or impaired fasting glucose. In univariate regression analysis, BCAA were correlated with HOMAir (r = 0.46; P < 0.001) and inversely with adiponectin (r = -0.53; P < 0.001) but not with leptin (r = -0.08; P > 0.05). Multivariable linear regression analysis, adjusting for age, sex, T2DM, and body mass index (BMI), demonstrated that BCAA were positively associated with HOMAir (β = 0.242, P = 0.023). When BCAA, leptin, and adiponectin were included together, the positive relationship of HOMAir with BCAA (β = 0.275, P = 0.012) remained significant.. Insulin resistance was associated with BCAA. This association remained after adjusting for age, sex, T2DM, BMI, as well as leptin and adiponectin. It is unlikely that the relationship of insulin resistance with BCAA is to a major extent attributable to effects of leptin and adiponectin.

Topics: Adiponectin; Adult; Aged; Amino Acids, Branched-Chain; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin Resistance; Leptin; Magnetic Resonance Spectroscopy; Male; Middle Aged; Sex Characteristics

Type 2 diabetes presents with numerous macrovascular and microvascular impairments, which in turn lead to various co-morbidities. Vascular co-morbidities can be seen when examining arterial stiffness (AS), which is a predictor for endothelial health and cardiovascular disease risk. Pulse wave analysis (PWA) and pulse wave velocity (PWV) are two tests that are commonly used to measure AS. Currently, disease states and progression are tracked via blood biochemistry. These gold standards in monitoring diabetes are expensive and need optimization.. To investigate which biophysical and biochemical parameters correlated best with AS, which may reduce the number of biochemical tests and biophysical parameter measurements needed to track disease progression.. Data from 42 subjects with type 2 diabetes mellitus for ≤10 years, aged 40-70 years, were analyzed at a single time point. We investigated various blood biochemistry, body composition, and AS parameters.. A combination of fat mass and fat-free mass was most associated with PWA over any other parameters. Leptin and high-sensitivity C-reactive protein seem to be the next two parameters that correlate with augmentation index. No other parameters had strong correlations to either PWA or PWV values.. Body composition methods seemed to be better predictors of type 2 diabetes mellitus patient's vascular disease progression. Our study indicates that body composition measurements may help replace expensive tests. This may have public health and health surveillance implications in countries facing financial challenges.

Topics: Adipose Tissue; Adult; Aged; Blood; Blood Chemical Analysis; Body Composition; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Disease Progression; Female; Humans; Leptin; Male; Middle Aged; Predictive Value of Tests; Public Health Surveillance; Pulse Wave Analysis; Vascular Stiffness

The coincidences between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are so compelling that it is attractive to speculate that diabetic conditions might aggravate AD pathologies by calcium dysfunction, although the understanding of the molecular mechanisms involved remains elusive. The present work was undertaken to investigate whether calcium dyshomeostasis is associated with the exacerbated Alzheimer-like cognitive dysfunction observed in diabetic conditions in APP/PS1-ob/ob mice, which were generated by crossing ob/ob mice with APP/PS1 mice. We confirmed that the diabetic condition can aggravate not only Aβ deposition but also tau phosphorylation, synaptic loss, neuronal death, and inflammation, exacerbating cognitive impairment in AD mice. More importantly, we found that the diabetic condition dramatically elevated calcium levels in APP/PS1 mice, thereby stimulating the phosphorylation of the calcium-dependent kinases. Our findings suggest that controlling over-elevation of intracellular calcium may provide novel insights for approaching AD in diabetic patients and delaying AD progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Calcium Signaling; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Inflammation; Leptin; Male; Memory Disorders; Mice; Mice, Transgenic; Phosphorylation; Protein Aggregation, Pathological; Signal Transduction; Synapses; tau Proteins

The antidiabetic effect of Lactobacillus is increasingly recognized worldwide. In this research, the hypoglycemic activity of Lactobacillus casei CCFM419 was investigated in mice with high-fat and low-dose streptozotocin induced type 2 diabetes. Oral L. casei CCFM419 administration favourably regulated blood glucose balance, increased glucose tolerance and protected islets in the diabetic mice, accompanied by an improvement in lipid metabolism. The homeostasis model of insulin resistance, insulin level and insulin tolerance test and mRNA expression of PI3K/Akt signalling pathway indexes revealed that L. casei CCFM419 had a positive effect on insulin resistance. Furthermore, treatment with L. casei CCFM419 recovered the level of short-chain fatty acids and increased the abundance of butyrate-producing bacteria, such as Allobaculum and Bacteriodes. These results demonstrated that L. casei CCFM419 had the potential ability to ameliorate insulin resistance and hyperglycaemic in type 2 diabetic mice through underlying PI3K/Akt signalling pathway and short-chain fatty acids/gut microbiota pathways.

Topics: Animals; Bacteroides; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Gastrointestinal Microbiome; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Lacticaseibacillus casei; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Pioglitazone; Probiotics; Proto-Oncogene Proteins c-akt; Streptozocin; Thiazolidinediones

Low physical fitness (PF) is a risk factor for type 2 diabetes mellitus (T2D). Women with a history of gestational diabetes (GDM) are at risk for T2D at a young age, but the role of PF in this population is not clear. PF has also been found to correlate inversely with plasma leptin in previous studies. Here, we examine whether women who had GDM have lower PF than women after a normoglycemic pregnancy and, second, whether PF is associated with plasma leptin, independently of body fat mass.. Cross-sectional analysis of 236 participants in the PPSDiab Study (cohort study of women 3-16 months after delivery, 152 after gestational diabetes (pGDM), 84 after normoglycemic pregnancy (control subjects); consecutively recruited 2011-16); medical history, physical examination with bioelectrical impedance analysis (BIA), whole body magnetic resonance imaging (MRI) (n = 154), 5-point oral glucose tolerance test, cardiopulmonary exercise testing, clinical chemistry including fasting plasma leptin; statistical analysis with Mann-Whitney U and t -test, Spearman correlation coefficient, multiple linear regression.. Women pGDM had lower maximally achieved oxygen uptake (VO2peak/kg: 25.7(21.3-29.9) vs. 30.0(26.6-34.1)ml/min/kg; total VO2peak: 1733(1552-2005) vs. 1970(1767-2238)ml/min; p<0.0001 for both), and maximum workload (122.5(105.5-136.5) vs. 141.0(128.5-159.5)W; p<0.0001). Fasting plasma leptin correlated inversely with PF (VO2peak/kg ρ = -0.72 p<0.0001; VO2peak ρ = -0.16 p = 0.015; max. load ρ = -0.35 p<0.0001). These associations remained significant with adjustment for body mass index, or for body fat mass (BIA and MRI).. Women with a recent history of GDM were less fit than control subjects. Low PF may therefore contribute to the risk for T2D after GDM. This should be tested in intervention studies. Low PF also associated with increased leptin levels-independently of body fat. PF may therefore influence leptin levels and signaling. This hypothesis requires further investigation.

Topics: Adult; Blood Glucose; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose Tolerance Test; Humans; Leptin; Linear Models; Oxygen Consumption; Physical Fitness; Pregnancy; Prospective Studies; Risk Factors

Topics: Adiponectin; Adult; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-6; Leptin; Metabolic Syndrome; MicroRNAs; Obesity; Risk Factors

Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Eating; Insulin; Leptin; Male; Mice; Obesity; Pancreas

Excessive glucocorticoid (GC) in type 2 diabetes mellitus (T2DM) reduces insulin sensitivity, impairs β-cell function, increases gluconeogenesis and glycogenolysis, impairs glucose uptake and metabolism, and reduces the insulinotropic effects of glucagon-like peptide 1. Melatonin, which serves as a physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis, has been suggested to have anti-diabetic effects. The objective of the present study was to investigate the effect of the MT1/MT2 melatonin agonist Neu-P11 on glucose and lipid metabolism in T2DM rats induced by a high fat diet combined with low doses of streptozotocin. T2DM rats were intragastrically administered melatonin (20mg/kg), Neu-P11 (20, 10, 5mg/kg), or a vehicle for 4 weeks. The results showed that the increased food intake, water consumption, hyperglycemia, glucose intolerance, and insulin resistance in T2DM rats were all improved by Neu-P11 treatment. Neu-P11 increased GC receptor expression and suppressed 11β-hydroxysteroid dehydrogenase 1 activity in the hippocampus by enhancing GC sensitivity and HPA feedback, thus decreasing the high GC levels. Transcript levels of the glucose metabolism-related genes peroxisome proliferator-activated receptor-γ, glucose transporter type-4, and adiponectin in adipose tissue were significantly increased after Neu-P11 treatment, while leptin mRNA was significantly decreased. Furthermore, MT1 and MT2 protein levels were enhanced by Neu-P11. These data suggest that normalization of the hyperactivated HPA axis by melatonin and Neu-P11 in T2DM regulates metabolic profiles and insulin sensitivity, which may attenuate insulin resistance and glucose homeostasis. Because Neu-P11 has superior pharmacokinetics and a longer half-life than melatonin, it might be beneficial in treating obesity and T2DM.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; Drinking; Fasting; Female; Gene Expression Regulation, Enzymologic; Glucose Transporter Type 4; Hippocampus; Hypothalamus; Indoles; Insulin Resistance; Leptin; Pituitary-Adrenal System; PPAR gamma; Pyrans; Rats; Rats, Wistar; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; RNA, Messenger

We aimed at investigating whether the acute abrogation of leptin after bariatric surgery is able to reduce neutrophil activation and potentially affect type 2 diabetes mellitus (T2DM) remission.. Metabolic and inflammatory parameters (i.e. leptin, IL-6 and neutrophil products) were compared at baseline (before bariatric surgery), one month, one and three years after surgery in morbid obese (MOB) T2DM patients (n=12) and non-MOB controls (n=32). In vitro, the effects of leptin on Il-6-induced human neutrophil degranulation and integrin upregulation were assessed.. At baseline, MOB T2DM patients had a similar demographic, lipid and glycemic profiles than non-MOB T2DM controls, but higher levels of inflammatory mediators, such as CRP, fibrinogen, neutrophil-to-lymphocyte ratio (NLR), matrix metalloproteinase (MMP)-8 and leptin. One month after surgery, CRP, fibrinogen and MMP-8 were reduced only in MOB T2DM patients, while serum leptin was reduced in both groups. In the overall cohort, leptin and MMP-8 drops from baseline to one month post-surgery were positively correlated (Δleptin vs. ΔMMP8: r=0.391, p=0.025). Moreover, ΔMMP8 inversely correlated with fasting glucose levels at one-year follow-up and with glycated hemoglobin at both one- and three-year. At the cut-off point identified by ROC curve analysis (>0ng/mL), ΔMMP8 predicted complete T2DM remission at 3-year follow-up. In vitro, leptin increased IL-6-induced MMP-8 release and abrogated CD18 up-regulation.. Bariatric surgery is associated to an acute abrogation of leptin that could affect MMP-8 levels, particularly in MOB T2DM patients. This beneficial event is associated with T2DM remission at 3-year follow-up.

Topics: Bariatric Surgery; Biomarkers; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Leptin; Male; Matrix Metalloproteinase 8; Middle Aged; Pilot Projects; Predictive Value of Tests; Remission Induction; Retrospective Studies

Over the past 2 decades, the incidence of childhood obesity has risen dramatically. This recent rise in childhood obesity is particularly concerning as adults who were obese during childhood develop type II diabetes that is intractable to current forms of treatment compared with individuals who develop obesity in adulthood. While the mechanisms responsible for the exacerbated diabetic phenotype associated with childhood obesity is not clear, it is well known that childhood is an important time period for the establishment of normal white adipose tissue in humans. This association suggests that exposure to obesogenic stimuli during adipose development may have detrimental effects on adipose function and metabolic homeostasis. In this study, we identify the period of development associated with puberty, postnatal days 18-34, as critical for the establishment of normal adipose mass in mice. Exposure of mice to high fat diet only during this time period results in metabolic dysfunction, increased leptin expression, and increased adipocyte size in adulthood in the absence of sustained increased fat mass or body weight. These findings indicate that exposure to obesogenic stimuli during critical developmental periods have prolonged effects on adipose tissue function that may contribute to the exacerbated metabolic dysfunctions associated with childhood obesity.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, White; Adiposity; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Female; Homeostasis; Humans; Leptin; Male; Mice; Obesity; Puberty

The objective of the present study was to observe the effect of sitagliptin on obese patients with insulin treatment-induced diabetes mellitus.. A total of 120 obese patients with insulin treatment-induced diabetes mellitus were consecutively selected and divided into the control group (n=35), observation group 1 (n=40), and observation group 2 (n=45). The control group received different types or doses of insulin, observation group 1 received insulin combined with metformin, and observation group 2 received insulin combined with sitagliptin. The therapeutic effects were compared at the 6-month follow-up visit.. Body mass index (BMI) was lower in observation group 1 and observation group 2, and higher in the control group compared with before treatment; the occurrence of hypoglycemia in observation group 2 was lower than in the other two groups, and the differences were statistically significant (p<0.05). After treatment, the fasting insulin (FINS) and homeostatic model assessment insulin-resistance (HOMA-IR) in observation group 2 were significantly lower than in the other two groups (p<0.05). Adiponectin levels were increased and leptin and visfatin levels were decreased in observation group 2 after treatment, and the differences were statistically significant (p<0.05). The levels of fasting blood glucose, hemoglobin A1c, total cholesterol, triglyceride, and low-density lipoprotein in the three groups were not significantly different (p>0.05).. Sitagliptin can reduce BMI and the occurrence of hypoglycemia in obese patients with insulin treatment-induced diabetes mellitus, and the effect may be related to decreased HOMA-IR, decreased leptin and visfatin levels, and increased adiponectin levels.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Sitagliptin Phosphate; Triglycerides

Impaired glucose regulation (IGR) patients have increased risk of type 2 diabetes mellitus (T2DM). Identifying relevant risk factors in IGR subjects could facilitate early detection and prevention of IGR progression to diabetes. This study investigated the association between Traditional Chinese Medicine (TCM) body constitution and serum cytokines, and whether body constitution could independently predict diabetes in IGR subjects.. Patients with IGR (n = 306) received a blood test and their body constitution type was assessed using a body constitution questionnaire (BCQ). Serum levels of cytokines were measured by ELISA. Patients were followed up for at least three years, and their status of diabetes were recorded. Multivariate logistic regression was used to estimate odds ratios (ORs) of diabetes for body constitution.. Phlegm-damp, Damp-heat and Qi-deficiency were three most common unbanlenced constitutions among IGR subjects. Phlegm-damp and Damp-heat constitution subjects showed higher serum levels of interleukin 6 (IL-6), tumour necrosis factor-α (TNF-α), leptin and lower serum levels of adiponectin (P<0.05). Qi-deficiency constitution subjects showed higher serum levels of leptin and lower serum levels of adiponectin, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) (P<0.05). Subjects with Phlegm-damp or Damp-heat constitution demonstrated a significantly higher risk of diabetes (P<0.05).. Phlegm-damp and Damp-heat TCM body constitution are strongly associated with abnormal serum cytokines, and could potentially serve as a predictor of diabetes in IGR subjects. Body constitution can help to identify IGR subjects who are at a high risk of progression to diabetes.

Topics: Adiponectin; Cytokines; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Leptin; Male; Medicine, Chinese Traditional; Middle Aged; Prospective Studies; Surveys and Questionnaires

This study explores the determinants of sex hormone binding globulin (SHBG) and associations with categories of glucose intolerance and undiagnosed diabetes in first-degree relatives (FDR) of patients with Type 2 Diabetes Mellitus (T2D).. Anthropometric indices, fasting lipids, glucose, insulin, adiponectin, leptin, SHBG, estradiol (E2), testosterone (TT), androstenedione (AND), dehydroepiandrosterone sulphate (DHEA-S), high-sensitivity C-reactive protein (hs-CRP) and alanine aminotransferase (ALT) were measured in 584 FDR. Homeostasis model assessment-estimate of insulin resistance (HOMA-IR), beta cell function (%B), insulin sensitivity (%S) and free androgen index (FAI) were calculated.. 266 subjects were normoglycemic; 237 had prediabetes and 81 had undiagnosed diabetes. SHBG decreased stepwise with worsening categories of glucose intolerance in females whereas FAI decreased stepwise with worsening categories in males only. SHBG showed significant positive correlations with adiponectin, and HDL-C and significant negative correlations with body mass index (BMI), waist circumference (WC), Waist:hip ratio (WHR), ALT, triglycerides (TG), %B, leptin and FAI. After adjustment for WHR, only HDL-C and FAI in men and FAI and HbA1c in females remained significantly associated with SHBG. Receiver Operating Characteristic (ROC) curve analysis for detection of diabetes showed that areas under the curve for FAI and SHBG were 0.711 and 0.386 for males and 0.430 and 0.660 for females respectively.. Associations of SHBG with some anthropometric and metabolic variables in FDR suggests that lower levels is a marker for risk of developing T2D through obesity dependent metabolic pathways but low FAI is a better marker of state of diabetes in males.

Topics: Adiponectin; Adult; Biomarkers; Body Mass Index; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Prediabetic State; ROC Curve; Sex Hormone-Binding Globulin; Triglycerides; Waist Circumference; Young Adult

BACKGROUND The fast pace of life, promoting fast food consumption and low physical activity, has resulted in obesity and/or diabetes as being serious social problems. The aim of the present study was to evaluate concentrations of selected adipokines (leptin, adiponectin, resistin, and visfatin) and to assess the leptin/adiponectin ratio in plasma of type 2 diabetes (T2D) patients in relation to degree of obesity. MATERIAL AND METHODS The study comprised 92 T2D subjects divided into 4 groups according to BMI value - I (normal body weight), II (overweight), III (obesity), and IV (severe obesity) - and 20 healthy volunteers (control group). Each group was divided into male and female subgroups. Plasma concentrations of adipokines were determined by enzyme-linked immunosorbent assay. RESULTS In women, leptin concentration was significantly higher in group IV, whereas in men it was higher in groups III and IV than in the control group and groups I and II. Irrespective of sex, a significant decrease in adiponectin level was observed in group III vs.. There was no significant difference in resistin levels. In women visfatin was markedly enhanced in group III, whereas in men in groups II, III and IV vs.. Leptin/adiponectin ratio was increased in groups III and IV vs. control in women, whereas in men vs. both control and group I. CONCLUSIONS The obese type 2 diabetic patients presented a disturbed adipokine profile, which seems to be an important link between obesity and T2D. The future studies concerning the question if regulating of adipokines' concentrations could be a promising approach for managing metabolic disorders seem to be well-grounded.

Topics: Adipokines; Adiponectin; Adult; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Overweight; Resistin

We previously showed the deleterious effects of increased dietary protein on renal manifestations and glucose metabolism in leptin receptor-deficient (db) mice. Here, we further examined its effects on glucose metabolism, including urinary C-peptide. We also orally administered mixtures corresponding to low- or high-protein diets to diabetic mice.. In diet experiments, under pair-feeding (equivalent energy and fat) conditions using a metabolic cage, mice were fed diets with different protein content (L diet: 12 % protein, 71 % carbohydrate, 17 % fat; H diet: 24 % protein, 59 % carbohydrate, 17 % fat) for 15 days. In oral administration experiments, the respective mixtures (L mixture: 12 % proline, 71 % maltose or starch, 17 % linoleic acid; H mixture: 24 % proline, 59 % maltose or starch, 17 % linoleic acid) were supplied to mice. Biochemical parameters related to glucose metabolism were measured.. The db-H diet mice showed significantly higher water intake, urinary volume, and glucose levels than db-L diet mice but similar levels of excreted urinary C-peptide. In contrast, control-H diet mice showed significantly higher C-peptide excretion than control-L diet mice. Both types of mice fed H diet excreted high levels of urinary albumin. When maltose mixtures were administered, db-L mixture mice showed significantly higher blood glucose after 30 min than db-H mixture mice. However, db mice administered starch-H mixture showed significantly higher blood glucose 120-300 min post-administration than db-L mixture mice, although both groups exhibited similar insulin levels.. High-protein, low-carbohydrate diets deteriorated diabetic conditions and were associated with insufficient insulin secretion in db mice. Our findings may have implications for dietary management of diabetic symptoms in human patients.

Topics: Albuminuria; Animals; Blood Glucose; Body Weight; C-Peptide; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dietary Carbohydrates; Dietary Proteins; Insulin; Insulin Secretion; Leptin; Male; Maltose; Mice; Mice, Inbred C57BL; Mice, Knockout; Starch

A number of clinical studies have demonstrated that leptin concentrations are related to the metabolic disturbances that constitute the metabolic syndrome (MetS) and to diabetes mellitus (DM).. To investigate possible determinants of leptin concentrations in a sample of patients at high cardiovascular (CV) risk carrying two or more features of the MetS and to investigate if any difference exist between at risk patients with or without DM.. Serum leptin concentrations were measured in 60 consecutive male patients affected by at least two CV risk factors which belong to the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) definition of MetS: 30 patients affected by type 2 DM (T2DM) and 30 nondiabetic patients (non-T2DM). Nineteen healthy subjects were included in the study as a control group (HC).. Leptin was significantly higher in patients carrying two or more features of the MetS compared with HC (P = 0.02). Stratifying MetS patients for DM, we found that leptin level was higher in non-T2DM patients (7.8 ng/ml), intermediate in T2DM (6.2 ng/ml), and lower in HC (4.6 ng/ml). In MetS patients, a positive correlation was found between leptin and waist, triglycerides, and number of MetS criteria. After stratification for T2DM, the correlations were still significant in the non-T2DM but not in the T2DM group.. In our sample of moderate-to-high-risk patients, leptin level is positively associated with waist circumference and triglycerides but only in non-T2DM patients. Our data suggest that diabetic subjects could modulate leptin production in a different way compared with patients carrying other MetS-related anomalies.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Risk Factors; Triglycerides; Waist Circumference

Topics: Adolescent; Adult; Aged; Biomarkers; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Leptin; Lipodystrophy; Male; Middle Aged; Proprotein Convertase 9; Young Adult

Type 2 diabetes mellitus (T2DM) is a consequence of complex interactions among multiple genetic variants and environmental risk factors. This complex disorder is also characterized by changes in various adipokines. In this study, our objective was to estimate the levels of adiponectin, leptin, and resistin (ALR) in T2DM patients, besides studying the effect of various drugs on their levels. Study participants included 400 diabetic and 300 normal patients from the Department of Endocrinology and Department of Biochemistry, Govt Medical College Srinagar. Subjects were categorized under various groups, i.e., Group 1 (metformin treated) and Group 2 (glimepiride treated), and cases were also categorized as obese with T2DM (Group A), obese without T2DM (Group B), and T2DM only (Group C). The serum ALR levels were estimated by ELISA (Alere), and biochemical parameters were also evaluated before and after treatment. Adiponectin levels were found to be significantly lower in T2DM cases as compared to controls (12 ± 5.5 versus 22.5 ± 7.9 μg/ml), while leptin and resistin levels were found to be significantly higher than controls (14.3 ± 7.4 versus 7.36 ± 3.73 ng/ml) (13.4 ± 1.56 versus 7.236 ± 2.129 pg/ml). Taking the effect of drugs into consideration, the effect on adiponectin and resistin levels was found to be highly significant in Group 2 before and after treatment (11 ± 5 versus 19.2 ± 4.5 μg/ml) (13.6 ± 2.5 versus 7.3 ± 2.9 pg/ml), while more effect was observed in leptin among Group 1 (metformin)-treated cases (27 ± 15 ng/ml versus 15 ± 15 ng/ml). Further the adiponectin levels were found to be significantly lower in Group B, while leptin and resistin levels were found to be significantly higher among obese cases when compared to T2DM cases only. Glimepiride also shows more effect on FBG, HbA1c% levels, while metformin shows more effect on Lipid profile levels. From the study, it can be concluded that ALR levels are affected by use of antidiabetic drugs among which glimepiride shows more effect on adiponectin and resistin levels, while leptin gets affected more by metformin. It can also be proposed that ALR levels are not affected by diabetes only, suggesting that their alterations in T2DM may be due to obesity as we observed more ALR changes in obese cases when compared to T2DM cases, and so there might be an important link between adiposity and insulin resistance.

Topics: Adiponectin; Adult; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Leptin; Male; Metabolic Syndrome; Metformin; Middle Aged; Resistin; Sulfonylurea Compounds

Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM. Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia. Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.

Topics: Alzheimer Disease; Animals; Body Temperature; Body Temperature Regulation; Caffeine; Central Nervous System Stimulants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hippocampus; Hypothermia; Leptin; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Phosphorylation; tau Proteins

Chemerin is associated with insulin resistance and is expressed in the liver. Nonalcoholic fatty liver disease (NAFLD) is related to impaired insulin sensitivity, but studies evaluating hepatic and serum chemerin in NAFLD resulted in discordant data.. Chemerin mRNA was determined in the liver tissue obtained from 33 controls and 76 NAFLD patients. Chemerin serum levels were measured in a different cohort of patients with ultrasound-diagnosed NAFLD and the respective controls. Hepatic stellate cells and hepatocytes were exposed to selected metabolites and nuclear receptor agonists to study the regulation of chemerin. Effect of recombinant chemerin on hepatocyte released proteins was analysed.. Hepatic chemerin expression was not related to BMI, gender, type 2 diabetes and hypertension. Chemerin mRNA did not correlate with steatosis and was negatively associated with inflammation, fibrosis and nonalcoholic steatohepatitis (NASH) score. Patients with NASH had lower chemerin mRNA compared to those with borderline NASH and controls. Factors with a role in NASH mostly did not regulate chemerin in the liver cells. Of note, liver X receptor agonist reduced chemerin protein. Serum chemerin was not changed in NAFLD. Levels positively correlated with age, waist-to-hip ratio, systolic blood pressure, serum FGF21 and lipocalin 2, and negatively with transferrin saturation. Chemerin induced FGF21 in supernatants of primary human hepatocytes. Hepcidin, a major regulator of iron homoeostasis and lipocalin 2, were not regulated by chemerin.. Chemerin mRNA is reduced in the liver of NASH patients, and liver X receptor seems to have a role herein.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Case-Control Studies; Cell Line; Cells, Cultured; Chemokines; Comorbidity; Cytokines; Diabetes Mellitus, Type 2; Female; Fibroblast Growth Factors; Hep G2 Cells; Hepatic Stellate Cells; Hepatocytes; Hepcidins; Humans; Hydrocarbons, Fluorinated; Hypertension; Hypoglycemic Agents; In Vitro Techniques; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipocalin-2; Liver; Liver X Receptors; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Rosiglitazone; Severity of Illness Index; Sulfonamides; Thiazolidinediones; Waist-Hip Ratio; Young Adult

Type-2 diabetes mellitus (T2DM) and breast cancer (BC) share common cytokine signaling changes resultant from adipose tissue dysfunction. This modified adipokine signaling was shown to be directly associated with changes in the body mass index (BMI) and diet and it is expected to also be influenced by T2DM pharmacotherapy. We evaluated the relationship between pre-existing diabetes treatment, circulating adipokine levels at cancer diagnosis, and long-term outcomes.. Insulin use is associated with elevated leptin, CRP, TNFα, and lower C-peptide and also linked to poor BC outcomes. More research is needed to verify these findings; however, we are among the first to correlate pharmacotherapy use, measures of adipose tissue dysfunction and cancer outcomes.

Topics: Adult; Aged; Breast Neoplasms; C-Peptide; C-Reactive Protein; Cytokines; Diabetes Mellitus, Type 2; Disease-Free Survival; Female; Humans; Insulin; Leptin; Middle Aged; Survival Rate

In insulin and leptin signaling pathway, Protein-Tyrosine Phosphatase 1B (PTP1B) plays a crucial controlling role as a negative regulator, which makes it an attractive therapeutic target for both Type-2 Diabetes (T2D) and obesity. In this work, we have generated classification models by using the inhibition data set of known PTP1B inhibitors to identify new inhibitors of PTP1B utilizing multiple machine learning techniques like naïve Bayesian, random forest, support vector machine and k-nearest neighbors, along with structural fingerprints and selected molecular descriptors. Several models from each algorithm have been constructed and optimized, with the different combination of molecular descriptors and structural fingerprints. For the training and test sets, most of the predictive models showed more than 90% of overall prediction accuracies. The best model was obtained with support vector machine approach and has Matthews Correlation Coefficient of 0.82 for the external test set, which was further employed for the virtual screening of Maybridge small compound database. Five compounds were subsequently selected for experimental assay. Out of these two compounds were found to inhibit PTP1B with significant inhibitory activity in in-vitro inhibition assay. The structural fragments which are important for PTP1B inhibition were identified by naïve Bayesian method and can be further exploited to design new molecules around the identified scaffolds. The descriptive and predictive modeling strategy applied in this study is capable of identifying PTP1B inhibitors from the large compound libraries.

Topics: Bayes Theorem; Diabetes Mellitus, Type 2; Humans; Insulin; Leptin; Machine Learning; Models, Molecular; Obesity; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Small Molecule Libraries

Intestinal gluconeogenesis (GNG) may play an important role in glucose homeostasis, but there is little information about the condition in humans.. To study the relationship between intestinal GNG and insulin resistance, its association with the evolution of morbidly obese patients after bariatric surgery, and the effect of insulin and or leptin.. Regional university hospital, Malaga (Spain).. Jejunal mRNA expression of genes involved in GNG was analyzed in 3 groups of morbidly obese patients who underwent Roux-en-Y gastric bypass: with low insulin resistance (MO-low-IR), with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2D). Also, intestinal epithelial cells (IEC) from MO-low-IR were incubated with different doses of insulin and or leptin.. In MO-high-IR, glutaminase, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6 Pase), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α), and sterol regulatory element-binding proteins 1 c (SREBP-1 c) expressions were significantly higher than in MO-low-IR. In MO-metf-T2 D, only PEPCK was significantly lower than in MO-high-IR. In IEC, an incubation with a high glucose and insulin dose produced an increase of PEPCK and SREBP-1 c, and a decrease of glutaminase, fructose 1,6-bisphosphatase (FBPase), and PGC-1 α expression. At high doses of leptin, G6 Pase and FBPase were significantly increased. The improvement of insulin resistance 3 months after bariatric surgery was positively associated with high G6 Pase and FBPase expression.. mRNA expression of genes involved in GNG is increased in the jejunum of MO-high-IR, and regulated by insulin and or leptin. High mRNA expression of genes involved in GNG is associated with a better evolution of insulin resistance after bariatric surgery.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Bypass; Gene Expression Regulation; Gluconeogenesis; Humans; Insulin; Insulin Resistance; Jejunum; Leptin; Male; Obesity, Morbid; Postoperative Period; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spain; Time Factors

The hypothalamic arcuate nucleus (ARC) is a major integration center for energy and glucose homeostasis that responds to leptin. Resistance to leptin in the ARC is an important component of the development of obesity and type 2 diabetes. Recently, we showed that Endospanin1 (Endo1) is a negative regulator of the leptin receptor (OBR) that interacts with OBR and retains the receptor inside the cell, leading to a decreased activation of the anorectic STAT3 pathway. Endo1 is up-regulated in the ARC of high fat diet (HFD)-fed mice, and its silencing in the ARC of lean and obese mice prevents and reverses the development of obesity.. Herein we investigated whether decreased Endo1 expression in the hypothalamic ARC, associated with reduced obesity, could also ameliorate glucose homeostasis accordingly.. We studied glucose homeostasis in lean or obese mice silenced for Endo1 in the ARC via stereotactic injection of shRNA-expressing lentiviral vectors.. We observed that despite being leaner, Endo1-silenced mice showed impaired glucose homeostasis on HFD. Mechanistically, we show that Endo1 interacts with p85, the regulatory subunit of PI3K, and mediates leptin-induced PI3K activation.. Our results thus define Endo1 as an important hypothalamic integrator of leptin signaling, and its silencing differentially regulates the OBR-dependent functions.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Carrier Proteins; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucose; Homeostasis; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

To evaluate the influence of dose and duration of risperidone treatment on cardiovascular and diabetes risk biomarkers in children and adolescents with autistic spectrum disorders (ASDs).. In this cross-sectional analysis, a total of 168 ASDs patients (89% male) treated with a risperidone-based regimen for ≥12months were included. Blood samples were analyzed for glucose and lipid metabolic markers, adiponectin, leptin, prolactin, cortisol and high sensitive C-reactive protein.. The mean concentrations of glucose, insulin, prolactin and leptin and HOMA-IR significantly rose with risperidone dosage (all P<0.025), but those of adiponectin and cortisol did not. Using regression analysis, insulin, leptin, prolactin and glucose concentrations and HOMA-IR show significant association with dosage. None of the markers except adiponectin showed dependence on duration of treatment. However, insulin and leptin concentrations and HOMA-IR clearly increased with increasing both dosage and duration. Dosage and duration of treatment had minimal effect on standard lipid profile and lipoprotein subclasses.. Risperidone treatment disturbed glucose homeostasis and endocrine regulation (particularly leptin) in children and adolescents with ASDs, in a dose- and duration-dependent manner, being suggestive of leptin and insulin resistance mechanisms. Metabolic adverse effects, especially development of type 2 diabetes mellitus should be closely monitored, particularly in individuals receiving high doses and/or long-term risperidone treatment.

Topics: Adiponectin; Adolescent; Antipsychotic Agents; Autistic Disorder; Blood Glucose; C-Reactive Protein; Child; Child, Preschool; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Hydrocortisone; Insulin; Insulin Resistance; Leptin; Male; Monitoring, Physiologic; Prolactin; Risperidone

A large number of diabetes patients suffer from major depression and are at high risk of mortality. In view of a role of leptin in diabetes, depression and energy homeostasis, the present study concerns circulating levels of leptin in different BMI groups of un-depressed and depressed diabetes patients. Six hundred thirty male and female patients with a primary diagnosis of diabetes were grouped according to BMI and with or without clinical symptoms of depression. Age matched healthy, normal weight male and female volunteers without clinical symptoms of depression or diabetes were taken as controls. Blood samples were obtained after an overnight fast of 12 h. Serum was stored for the determination of leptin and glucose. We found that there were more female than male diabetes patients with comorbid depression. Fasting leptin was higher in normal weight non-diabetes women than men; but comparable in normal weight men and women diabetes patients. Fasting glucose levels were higher in diabetes than non diabetes groups; values were comparable in men and women. Depression was associated with a decrease and increase in leptin respectively in normal-overweight and obese men and women diabetes patients. Glucose levels were also higher in obese depressed than un-depressed diabetes patients. The results suggested that the female gender is at greater risk to comorbid diabetes with depression. Adipo-insular axis plays an important role in diabetes, associated depression and in the greater risk of the female gender to comorbid diabetes with depression.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Body Composition; Body Mass Index; Depressive Disorder, Major; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Leptin; Male; Middle Aged; Obesity; Overweight; Sex Characteristics

Reduced testosterone, a recognized comorbidity of reduced insulin sensitivity (IS) and type 2 diabetes (T2D), has also been reported in adult males with type 1 diabetes (T1D). However, there are limited data on how early reduced testosterone occurs, and whether it is related to the reduced IS in T1D. Leptin, a modulator of the HPG-axis, may also influence testosterone in T1D. We hypothesized that IS and leptin would be associated with total testosterone (TT), and free androgen index (FAI) in adolescent males with T1D.. T1D (n = 35), T2D (n = 13), lean (n = 13) and obese (n = 9) adolescent males had IS measured by hyperinsulinemic-euglycemic clamps (glucose infusion rate [GIR]), in addition to leptin, sex hormone binding globulin (SHBG), TT, and FAI. The cohort was stratified into those with T1D (n = 35) and those without (n = 35).. TT and SHBG were lower in T2D boys vs. lean controls, and GIR and leptin correlated with FAI and TT in non-T1D participants. However, despite being insulin resistant, adolescent males with T1D had normal TT and FAI, unrelated to GIR. In T1D, leptin was inversely associated with TT (p = 0.005) and FAI (p = 0.01), independent of puberty, hemoglobin A1c (HbA1c), diabetes duration, body mass index (BMI) z-score and GIR.. Leptin accounted for a significant proportion of the variability of testosterone in T1D. However, despite reduced IS, there was no association between IS and testosterone in T1D adolescents. These observations suggest that the mechanisms affecting testosterone may differ between adolescent males with and without T1D.

Topics: Adolescent; Child; Cohort Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Male; Obesity; Testosterone

Adipokines have been suggested to be involved in the development of type 2 diabetes mellitus (T2DM). However, studies in humans are controversial and analyzes at the onset of disease are scarce.. We compared adiponectin and leptin levels between 74 predominately Caucasian adolescents with T2DM and 74 body mass index (BMI)-, age-, and gender-matched controls without T2DM. Adiponectin and leptin were correlated to age, BMI, hemoglobin A1c (HbA1c), blood pressure, and lipids.. Adolescents with T2DM showed significant lower leptin levels as compared with controls (18 ± 12 vs. 37 ± 23 ng/mL, p < 0.001), whereas the adiponectin levels did not differ between the adolescents with and without T2DM (5.0 ± 2.5 vs. 4.9 ± 2.5 µg/mL, p = 0.833). The associations between adiponectin and high-density lipoprotein (HDL) cholesterol (r = 0.42), systolic (r = -0.15), and diastolic blood pressure (r = -0.20) were stronger as the associations of leptin to these parameters (all r < 0.07). In multiple linear regression analysis, leptin was significantly and positively associated with BMI [β-coefficient: 1.3 (95% confidence interval (95% CI): ±0.5), p < 0.001] and female sex [β-coefficient: 9.7 (95% CI: ±6.7), p = 0.005], and negatively with age [β-coefficient: -2.3 (95% CI: ±2.1), p < 0.001] and HbA1c [β-coefficient -3.1 (95% CI: ±2.1), p = 0.011]. Adiponectin was not significantly associated with BMI, HbA1c, age, or gender in multiple linear regression analysis.. Because adiponectin levels did not differ between obese adolescents with and without T2DM, hypoadiponectinemia as observed in obesity seems not to be involved in the genesis of T2DM. The relative hypoleptinemia in obese adolescents with T2DM as compared with obese adolescents without T2DM may contribute to the development of T2DM. Future longitudinal studies in humans are necessary to prove this hypothesis.

Topics: Adiponectin; Adolescent; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Obesity; White People

Skeletal fractures are considered a chronic complication of type 2 diabetes mellitus (T2DM), but the etiology of compromised bone quality that develops over time remains uncertain. This study investigated the concurrent alterations in metabolic and skeletal changes in two mouse strains, a responsive (C57BL/6) and a relatively resistant (C3H/HeJ) strain, to high-fat diet-induced glucose intolerance. Four-week-old male C57BL/6 and C3H/HeJ mice were randomized to a control (Con = 10 % kcal fat) or high-fat (HF = 60 % kcal fat) diet for 2, 8, or 16 weeks. Metabolic changes, including blood glucose, plasma insulin and leptin, and glucose tolerance were monitored over time in conjunction with alterations in bone structure and turn over. Elevated fasting glucose occurred in both the C57BL/6 and C3H/HeJ strains on the HF diet at 2 and 8 weeks, but only in the C57BL/6 strain at 16 weeks. Both strains on the HF diet demonstrated impaired glucose tolerance at each time point. The C57BL/6 mice on the HF diet exhibited lower whole-body bone mineral density (BMD) by 8 and 16 weeks, but the C3H/HeJ strain had no evidence of bone loss until 16 weeks. Analyses of bone microarchitecture revealed that trabecular bone accrual in the distal femur metaphysis was attenuated in the C57BL/6 mice on the HF diet at 8 and 16 weeks. In contrast, the C3H/HeJ mice were protected from the deleterious effects of the HF diet on trabecular bone. Alterations in gene expression from the femur revealed that several toll-like receptor (TLR)-4 targets (Atf4, Socs3, and Tlr4) were regulated by the HF diet in the C57BL/6 strain, but not in the C3H/HeJ strain. Structural changes observed only in the C57BL/6 mice were accompanied with a decrease in osteoblastogenesis after 8 and 16 weeks on the HF diet, suggesting a TLR-4-mediated mechanism in the suppression of bone formation. Both the C57BL/6 and C3H/HeJ mice demonstrated an increase in osteoclastogenesis after 8 weeks on the HF diet; however, bone turnover was decreased in the C57BL/6 with prolonged hyperglycemia. Further investigation is needed to understand how hyperglycemia and hyperinsulinemia suppress bone turnover in the context of T2DM and the role of TLR-4 in this response.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Insulin; Insulin Resistance; Leptin; Mice; Species Specificity; Sprains and Strains; Toll-Like Receptor 4

Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Cathepsin D; Causality; Cohort Studies; Diabetes Mellitus, Type 2; Fatty Acid-Binding Proteins; Female; Hepatocyte Growth Factor; High-Throughput Screening Assays; Humans; Insulin Resistance; Interleukin 1 Receptor Antagonist Protein; Leptin; Linear Models; Longitudinal Studies; Male; Mendelian Randomization Analysis; Proportional Hazards Models; Prospective Studies; Proteomics; Renin; Risk Assessment; Sweden; Tissue Plasminogen Activator

The aim of the study was to determine the serum levels of adiponectin, leptin and IL-1 β in elderly diabetic patients with and without mild cognitive impairment (MCI) and to examine the associations of these markers with clinical and cognitive parameters. A biochemical evaluation was performed of 62 seniors with type 2 diabetes (T2DM) and MCI, and 132 seniors with T2DM but without MCI (controls). Serum leptin and IL-1 β levels were higher and adiponectin concentration was lower in MCI patients than controls. In MCI subjects, adiponectin level was negatively correlated with leptin, IL-1 β levels and BMI. Leptin concentration was correlated with IL-1 β level. Univariate logistic regression models revealed that the factors which increased the likelihood of diagnosis of MCI in elderly patients with T2DM were higher levels of HbA1c, leptin, IL-1 β and triglycerides, as well as lower levels of adiponectin and HDL cholesterol. Similarly, previous CVD, hypertension, hyperlipidemia, retinopathy, nephropathy, hypoglycemia, longer duration of diabetes, increased number of co-morbidities, older age, fewer years of formal education were found to be associated with MCI. The multivariable model indicated fewer years of formal education, previous CVD, hypertension, increased number of co-morbidities, higher HbA1c and IL-1 β levels and lower adiponectin level. Elderly diabetic patients with MCI have higher levels of leptin and IL-1 β and lower levels of adiponectin. Further prospective studies are needed to determine the role of these markers in the progression to dementia.

Topics: Adiponectin; Aged; Aged, 80 and over; Aging; Biomarkers; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-1beta; Leptin; Male; Risk Factors

Bariatric procedures that exclude the proximal small intestine lead to significant weight loss which is probably mediated by changes in hormones that alter appetite, such as peptide YY (PYY), ghrelin, cholecystokinin (CCK), and leptin. Here, the effect of the non-surgical duodenal-jejunal bypass liner (DJBL) on concentrations of hormones implicated in appetite control was investigated.. A two-center prospective study was conducted between January and December 2010. Seventeen obese subjects with type 2 diabetes were treated with the DJBL for 24 weeks. Fasting concentrations of leptin and meal responses of plasma PYY, CCK, and ghrelin were determined prior to and after implantation of the DJBL.. At baseline, subjects had an average body weight of 116.0 ± 5.8 kg. One week after implantation, subjects had lost 4.3 ± 0.6 kg (p < 0.01), which progressed to 12.7 ± 1.3 kg at week 24 (p < 0.01). Postprandial concentrations of PYY and ghrelin increased (baseline vs. week 1 vs. week 24 PYY: 2.6 ± 0.2 vs. 4.1 ± 0.4 vs. 4.1 ± 0.7 nmol/L/min and ghrelin: 7.8 ± 1.8 vs. 11.0 ± 1.8 vs. 10.6 ± 1.8 ng/mL/min, all p < 0.05). In parallel, the CCK response decreased (baseline vs. week 1 vs. week 24: 434 ± 51 vs. 229 ± 52 vs. 256 ± 51 pmol/L/min, p < 0.01). Fasting leptin concentrations also decreased (baseline vs. week 24: 98 ± 17 vs. 53 ± 10 ng/mL, p < 0.01).. DJBL treatment induces weight loss paralleled by changes in concentrations of hormones involved in appetite control.

Topics: Bariatrics; Cholecystokinin; Diabetes Mellitus, Type 2; Duodenum; Female; Ghrelin; Humans; Jejunum; Leptin; Male; Middle Aged; Obesity, Morbid; Peptide YY; Postprandial Period; Prospective Studies; Treatment Outcome

Siblings born before (BMS) and after (AMS) maternal biliopancreatic diversion (BPD) show differences in the methylome. The objective was to use a sibling-pair design to examine the effects from interpregnancy weight loss as a consequence of maternal bariatric surgery, other than BPD, on the methylome comparing BMS and AMS.. Women with at least one child born before and one after bariatric surgery were identified in Swedish national registers. Whole blood samples from BMS (N = 31) and AMS (N = 31) siblings were collected for epigenetic methylation analysis while maternal information was collected from antenatal medical records.. In total 3,074 genes, with corresponding 23,449 CpG methylation sites, were differently methylated and associated with an overrepresentation of differently methylated CpG sites in genes involved with insulin receptor signaling, type 2 diabetes signaling, and leptin signaling in obesity, while the most significant differently methylated genes were HLA-DQA1, HLA-DQB1, and TSPAN18, when comparing BMS and AMS siblings.. These results suggest that maternal bariatric surgery, with subsequent weight loss between pregnancies, is associated with alterations in the methylome of genes involved in insulin receptor signaling, type 2 diabetes signaling, and leptin signaling in obesity in a comparison of BMS and AMS siblings.

Topics: Adult; Bariatric Surgery; Biliopancreatic Diversion; Child; Child, Preschool; Diabetes Mellitus, Type 2; Diseases in Twins; DNA Methylation; Female; HLA-DQ alpha-Chains; HLA-DQ beta-Chains; Humans; Infant; Infant, Newborn; Inflammation; Leptin; Male; Obesity; Pregnancy; Sweden; Tetraspanins

Replicated evidence indicates that individuals with BD are differentially affected by metabolic comorbidities and that its occurrence is a critical mediator and/or moderator of BD outcomes. This study aimed to explore the role of adipokines on bipolar disorder (BD) course and its relationship with metabolic comorbidities (i.e. type 2 diabetes mellitus, obesity). We measured plasma levels of adiponectin and leptin, as well as anthropometric and metabolic parameters of 59 patients with BD and 28 healthy volunteers. Our results showed that, in female participants, adiponectin was lower in individuals with BD, relative to healthy controls (p = 0.017). In the BD population, adiponectin levels were correlated with fasting glucose (r = -0.291, p = 0.047), fasting insulin (r = -0.332, p = 0.023), C-peptide (r = 0.040, p = 0.040), homeostatic model assessment-insulin resistance (r = -0.411, p = 0.004), HDL (r = 0.508, p < 0.001), VLDL (r = -0.395, p = 0.005) and triglycerides (r = -0.310, p = 0.030). After adjustment for age, gender and BMI, individuals with BD and low adiponectin levels (i.e. < 7.5 μg/ml), had a higher number of mood episodes (p < 0.001), lower number of psychiatric hospitalizations (p = 0.007), higher depressive symptoms (p < 0.001) and lower levels of functioning (p = 0.020). In conclusion, adiponectin levels, either directly or as a proxy of metabolic dysfunction, is independently associated with an unfavorable course of illness in BD.

Topics: Adiponectin; Adult; Bipolar Disorder; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity

Type 2 diabetes mellitus (T2DM) is recognized as major risk factor for the progress of active pulmonary tuberculosis (PTB), although the mechanistic link between diabetes and tuberculosis remains poorly characterized. Moreover, the influence of poorly controlled diabetes on the baseline levels of adipocytokines in the context of tuberculosis has not been explored in detail. To characterize the influence of coexistent DM on adipocytokine levels in pulmonary or latent TB (LTB), we examined circulating levels of adipocytokines in the plasma of individuals with PTB-DM or LTB-DM and compared them with those without DM (PTB or LTB). PTB-DM or LTB-DM is characterized by diminished circulating levels of adiponectin and adipsin and/or heightened circulating levels of leptin, visfatin and PAI-1. In addition, adiponectin and adipsin exhibit a significant negative correlation, whereas leptin, visfatin and PAI-1 display a significant positive correlation with HbA1C levels and random blood glucose levels. Therefore, our data reveal that PTB-DM or LTB-DM is characterized by alterations in the systemic levels of adipocytokines, indicating that altered adipose tissue inflammation underlying Type 2 diabetes potentially contributes to pathogenesis of TB disease.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Blood Glucose; Complement Factor D; Cytokines; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Inflammation; Latent Tuberculosis; Leptin; Male; Middle Aged; Mycobacterium tuberculosis; Nicotinamide Phosphoribosyltransferase; Plasminogen Activator Inhibitor 1; Tuberculosis, Pulmonary

Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD.

Topics: Aging; Analysis of Variance; Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Glycemic Index; Hypothermia, Induced; Insulin Resistance; Leptin; Male; MAP Kinase Kinase 4; Mice; Mice, Mutant Strains; Phosphorylation; Signal Transduction; tau Proteins

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.

Topics: Adipose Tissue; Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Energy Intake; Epididymis; Glucose; Glucosides; Humans; Hyperphagia; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Weight Loss

A deranged adipokine system is implicated in obesity and in type 2 diabetes mellitus (T2DM), and the lack of remission of T2DM after bariatric surgery could be also accounted for by the postoperative persistence of this condition.. Thirty T2DM patients undergoing biliopancreatic diversion (BPD) with a wide range of baseline body mass index (BMI) were evaluated prior to and at 1 and 5 years following BPD. Besides the usual clinical evaluations, acute insulin response (AIR) to intravenous glucose load as a parameter of insulin secretion and the serum leptin and adiponectin concentration were measured throughout the follow-up period in all patients.. A long-term T2DM remission was observed in 21 patients (70 %). Serum leptin level reduced at the first year and remained substantially unchanged at a long term in both the remitter and non-remitter patients, while following the operation, a progressive significant increase of serum adiponectin level was observed only in remitter patients (from 9.2 to 12.3 μg/mL at 1 year and to 15.18 μg/mL at 5 years in the remitters and from 8.8 to 8.75 μg/mL at 1 year and to 11.8 μg/mL at 5 years in the non-remitters). Serum leptin mean values were positively associated with the BMI ones both prior to and following BPD (p < 0.005), while serum adiponectin values were positively related (p < 0.04) to the postoperative AIR data.. The improvement of the pattern of cytokine production, as evidenced by postoperative rise in serum adiponectin concentration, might play a role in T2DM remission after bariatric surgery.

Topics: Adiponectin; Adult; Aged; Biliopancreatic Diversion; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Postoperative Period; Time Factors

To analyze inflammatory markers, adipokines, and hepatokines in obese adolescents with and without type 2 diabetes mellitus (T2DM).. We studied high sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-α, interleukin-1β, and interferon-γ, the hepatokines (fetuin-A and fibroblast growth factor [FGF]-21), and the adipokines (adiponectin and leptin) in a cross-sectional study of 74 predominately Caucasian adolescents with T2DM aged 12-18 years and in 74 body mass index (BMI)-, age-, and sex-matched controls.. Adolescents with T2DM had significantly higher concentrations of hsCRP, TNF-α, and interleukin-1β compared with obese controls without T2DM. Interferon-γ was not detectable in obese adolescents with or without T2DM. In multiple linear regression analysis, hsCRP was significantly associated with FGF-21 and BMI, but not with hemoglobin A1c, adiponectin, leptin, fetuin-A, sex, or age. TNF-α was significantly related negatively to leptin, positively to BMI, but not to hemoglobin A1c, adiponectin, fetuin-A, FGF-21 sex, or age in multiple linear regression analysis.. Increased inflammatory markers are associated with T2DM in adolescents. Because hsCRP was related to FGF-21 and TNF-α was associated with leptin, these findings suggest a link between increased levels of these adipokines and hepatokines and chronic inflammation. Future longitudinal studies in humans are necessary to confirm these hypotheses.

Topics: Adiponectin; Adolescent; alpha-2-HS-Glycoprotein; Biomarkers; Body Mass Index; C-Reactive Protein; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Fibroblast Growth Factors; Humans; Interleukin-1beta; Leptin; Male; Obesity; Tumor Necrosis Factor-alpha

The leptin (LEP G2548A) and leptin receptor (LEPR Q223R) gene polymorphisms have been variably associated with type 2 diabetes (T2D) in different populations. In this study we hypothesized that these variants might be associated with T2D and related metabolic traits in an Iranian population.. The LEP G2548A and LEPR Q223R genotypes were determined by PCR-RFLP in 378 normoglycemic controls and 154 T2D patients. Bonferroni correction was applied for the correction of multiple testing.. The A allele of the LEP G2548A polymorphism was more prevalent in females of the T2D group than the controls (p = 0.009). In a recessive model (GG+GA vs. AA), the frequency of the AA genotype was higher in female patients compared to normoglycemic subjects 134.9% vs. 19.3%, OR 2.60 (1.27-5.31), p = 0.0091. Multivariate logistic regression analysis also showed that the AA genotype of the LEP G2548A polymorphism is an independent risk factor for T2D in females. No significant association was found between the allele and genotype frequencies of the LEPR Q223R variant with T2D in female and male groups. In addition, no significant difference in anthropometrical and biochemical parameters was observed between the genotypes of LEP and LEPR variants in gender-specific groups in both non-diabetic and diabetic subjects.. Our results suggest that the LEP G2548A polymorphisms might associate with T2D among Iranian female subjects, whereas the LEPR Q223R variant is not associated with T2D and its related metabolic traits in this population.

Topics: Adult; Aged; Asian People; Biomarkers; Blood Glucose; Case-Control Studies; Chi-Square Distribution; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Insulin; Iran; Leptin; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Phenotype; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Leptin; Risk Factors; Young Adult

Adults with metabolic syndrome from different race/ethnicities are often predisposed to developing type 2 diabetes (T2D); however, growing evidence suggests that healthy diets and lifestyle choices can significantly slow or prevent progression to T2D. This poorly understood relationship to healthy dietary patterns and prevention of T2D motivated us to conduct a retrospective analysis to determine the potential impact of a minor dietary lifestyle change (daily mushroom consumption) on known T2D risk factors in racially diverse adults with confirmed features of the metabolic syndrome. Retrospectively, we studied 37 subjects who had participated in a dietary intervention focused on vitamin D bioavailability from white button mushrooms (WBM). All 37 had previously completed a 16-week study where they consumed 100 g of WBM daily and were then followed-up for one month during which no mushrooms were consumed. We analyzed differences in serum risk factors from baseline to 16-week, and from baseline to one-month follow-up. Measurement of serum diabetic risk factors included inflammatory and oxidative stress markers and the antioxidant component naturally rich in mushrooms, ergothioneine. Significant beneficial health effects were observed at 16-week with the doubling of ergothioneine from baseline, increases in the antioxidant marker ORAC (oxygen radical absorption capacity) and anti-inflammatory hormone, adiponectin and significant decreases in serum oxidative stress inducing factors, carboxymethyllysine (CML) and methylglyoxal (MG), but no change in the lipid oxidative stress marker 8-isoprostane, leptin or measures of insulin resistance or glucose metabolism. We conclude that WBM contain a variety of compounds with potential anti-inflammatory and antioxidant health benefits that can occur with frequent consumption over time in adults predisposed to T2D. Well-controlled studies are needed to confirm these findings and identify the specific mushroom components beneficial to health.

Topics: Adiponectin; Adult; Agaricus; Antioxidants; beta-Glucans; Biomarkers; Body Mass Index; Chitin; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diet; Dinoprost; Ergothioneine; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Linear Models; Lysine; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Oxidative Stress; Polyphenols; Pyruvaldehyde; Retrospective Studies; Risk Factors; Triglycerides; Vitamin D

Sleep disturbances and alterations of diurnal endocrine rhythms are associated with increased risk of type 2 diabetes (T2D). We previously showed that young men born small for gestational age (SGA) and with increased risk of T2D have elevated fat and decreased glucose oxidation rates during nighttime. In this study, we investigated whether SGA men have an altered diurnal profile of hormones, substrates and inflammatory markers implicated in T2D pathophysiology compared with matched individuals born appropriate for gestational age (AGA).. We collected hourly blood samples for 24 h, to measure levels of glucose, free fatty acids (FFA), triglycerides (TG), insulin, C-peptide, leptin, resistin, ghrelin, plasminogen activator inhibitor-1 (PAI-1), incretins (GLP-1 and GIP), and inflammatory markers (TNF-α and IL-6) in 13 young men born SGA and 11 young men born AGA.. Repeated measurements analyses were used to analyze the diurnal variations and differences between groups. The SGA subjects had increased 24-h glucose (P=0.03), glucagon (P=0.03) and resistin (P=0.003) levels with no difference in diurnal rhythms compared with AGA controls. We found significant diurnal variations in levels of blood glucose, plasma TG, FFA, insulin, C-peptide, GLP-1, GIP, leptin, visfatin, TNF-α, IL-6 and PAI-1. The variation in FFA levels differed between the groups during the evening. Plasma ghrelin and glucagon levels did not display diurnal variations.. Young men born SGA exhibit elevated 24-h blood glucose, and plasma glucagon and resistin levels with no major differences in diurnal rhythms of these or other key metabolic hormones, substrates or inflammatory markers implicated in the origin of adiposity and T2D.

Topics: Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Gestational Age; Ghrelin; Glucagon-Like Peptide 1; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin; Interleukin-6; Leptin; Male; Resistin; Triglycerides; Tumor Necrosis Factor-alpha; Young Adult

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Leptin; Mice; Obesity

In the present study, male diabetic KK-A(y) mice were used to investigate the antidiabetic effect of bayberry fruit extract (BFE, 200 mg kg(-1)) by gavage for 5 weeks. BFE significantly lowered fasting blood glucose, improved glucose tolerance and insulin sensitivity in KK-A(y) mice. It significantly reduced serum concentrations of glucose, lipids, inflammation, and liver function markers, including insulin, glucagon, leptin, total cholesterol, triglycerides, low density lipoprotein, interleukin-1β, and alanine transferase in KK-A(y) mice. Liver weight and liver lipid accumulation were also markedly reduced by BFE in mice. The hypoglycemic effect of BFE appeared to be partially mediated through the inhibition of hepatic gluconeogenesis, which was supported by the reduced PPARγ coactivator 1-alpha (PGC-1α) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expressions in the liver of KK-A(y) mice and by the decreased glucose production, increased glycolysis as well as the reduced gene expression levels of PGC-1α, PEPCK, and glucose-6-phosphatase (G6Pase) in HepG2 cells. Gene expressions of hepatic lipid metabolism and inflammatory markers were also down-regulated by BFE in the liver of KK-A(y) mice. Furthermore, BFE promoted hepatic phosphorylation of AMPKα (Thr172) both in vivo and in vitro. Therefore, the activation of the AMPK pathway may play an important role in the antidiabetic effects of BFE, and red Chinese bayberry fruits may be an effective dietary food for the management of type 2 diabetes and its complications.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Flavonoids; Fruit; Glucagon; Glucose-6-Phosphatase; Glutathione Peroxidase; Hep G2 Cells; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Liver; Mice; Myrica; Organ Size; Plant Extracts; Transcription Factors

The rupture of unstable carotid atherosclerotic plaques is one of the main causes of cerebrovascular ischemic events. There is need for circulating markers that can predict plaque instability and risk of stroke. Proinflammatory chemerin, leptin, and resistin, along with anti-inflammatory adiponectin, are adipokines with direct influence on vascular function. We investigated the association of circulating adipokines with carotid plaque instability and cerebrovascular symptomatology.. Neurologically symptomatic and asymptomatic patients (n=165) scheduled for carotid endarterectomy were recruited. Fasting blood samples were collected preoperatively; adiponectin and leptin levels were determined by radioimmunoassay; and chemerin and resistin levels were measured by enzyme-linked immunosorbent assays. The instability of plaque specimens was assessed using gold-standard histological classifications. Chemerin was significantly associated with plaque instability. The fully adjusted model, accounting for age, sex, body mass index, high-sensitivity C-reactive protein, type 2 diabetes mellitus, and circulating adiponectin, leptin, and resistin, yielded an odds ratio of 0.991 (95% confidence interval 0.985-0.998) for plaque instability per unit increase in chemerin. High leptin levels were significantly associated with presence of specific features of plaque instability. In subjects with type 2 diabetes mellitus, resistin levels were significantly elevated in symptomatic when compared with asymptomatic subjects (P=0.001) and increased the risk of cerebrovascular symptomatology (adjusted odds ratio 1.264, 95% confidence interval 1.004-1.594).. Low chemerin and high resistin levels were associated with carotid disease severity, suggesting that these adipokines may act as potential markers for plaque instability and stroke risk. Future studies are needed to assess causation between circulating adipokines and plaque instability.

Topics: Adiponectin; Aged; Biomarkers; Carotid Stenosis; Cerebrovascular Disorders; Chemokines; Chi-Square Distribution; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Resistin; Risk Assessment; Risk Factors; Rupture, Spontaneous; Severity of Illness Index

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Leptin; Male; Middle Aged

There is a growing number of patients with type 2 diabetes mellitus. As a component of the metabolic syndrome, type 2 diabetes is often associated with hyperuricemia and gout. These diseases worsen prognosis of concomitant cardiovascular disorders.. To assess the relationship between adiponectin and leptin levels and echocardiographic parameters in patients with type 2 diabetes mellitus, gout, and a combination thereof.. The study involved 30 men aged 41 to 70 years divided into 3 groups. The first group included 10 patients with type 2 diabetes, the second one 10 patients with gout, and the third group consisted of 10 men with a combination of type 2 diabetes and gout. In all patients the levels of glucose, immunoreactive insulin, HOMA-IR, adiponectin, and leptin were measured. All patients underwent echocardiography.. The study revealed hyperglycemia in patients with type 2 diabetes and its combination with gout. Patients of all three groups had increased insulin resistance, insulin and leptin levels, decreased concentration of adiponectin. The thickness of interventricular sepum in systole and diastole, posterior wall of the left ventricle in diastole, myocarduial mass of the left ventricle, the size of the left atrium and the right ventricle increased in patients of all three groups.. The study demonstrated compensatory hyperinsulinemia and insulin resistance, hypoadiponectinemia, hyperleptinemia, left ventricular hypertrophy, diastolic dysfunction, and intact ventricular contractility in patients with type 2 diabetes, gout, and their combination. Hypoadiponectinemia and hyperleptinemia play a role in remodeling of myocardium in these patients.

Topics: Adiponectin; Adult; Aged; Comorbidity; Diabetes Mellitus, Type 2; Electrocardiography; Gout; Humans; Hypertrophy, Left Ventricular; Leptin; Male; Middle Aged

The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Liver; Fluorescent Antibody Technique; Glucose Tolerance Test; Hypothalamus; Immunohistochemistry; Leptin; Liver; Mice; Mice, Obese; Obesity; Pentacyclic Triterpenes; Real-Time Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Triterpenes; Withanolides

Maternal obesity (MO) is a deleterious condition that enhances susceptibility of adult offspring to metabolic diseases such as type 2 diabetes. The objective is to study the effect of MO on in vitro insulin secretion and pancreatic cellular population in offspring. We hypothesize that a harmful antenatal metabolic environment due to MO diminishes the basal glucose-responsive secretory function of pancreatic beta cells in offspring. Mothers were fed a control (C) or high-fat diet from weaning through pregnancy (120 days) and lactation. At postnatal days (PNDs) 36 and 110, pups were killed, peripheral blood was collected and pancreatic islets were isolated. Basal insulin secretion was measured in vitro in islets for 60 min. It was found that blood insulin, glucose and homeostasis model assessment (HOMA) index were unaffected by maternal diet and age in females. However, male MO offspring at PND 110 showed hyperinsulinemia and insulin resistance compared with C. Body weight was not modified by MO, but fat content was higher in MO pups compared with C pups. Triglycerides and leptin concentrations were higher in MO than in C offspring in all groups except in females at PND 36. Pancreatic islet cytoarchitecture was unaffected by MO. At PND 36, islets of male and female C and MO offspring responded similarly to glucose, but at PND 110, male and female MO offspring islets showed a 50% decrease in insulin secretion. It was concluded that MO impairs basal insulin secretion of offspring with a greater impact on males than females, and this effect mainly manifests in adulthood.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Female; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Triglycerides

Epidemiological evidence suggests that adipokines may be associated with the onset of type 2 diabetes, but the evidence to date is limited and inconclusive. This study examined the association between adiponectin and leptin and the subsequent diagnosis of type 2 diabetes in a UK population based cohort of non-diabetic middle-aged men.. Baseline serum levels of leptin and adiponectin were measured in 1839 non-diabetic men aged 50-60years who were participating in the prospective population-based PRIME study. Over a mean follow-up of 14.7years, new cases of type 2 diabetes were determined from self-reported clinical information with subsequent validation by general practitioners.. 151 Participants developed type 2 diabetes during follow-up. In Cox regression models adjusted for age, men in the top third of the leptin distribution were at increased risk (hazard ratio (HR) 4.27, 95% CI 2.67-6.83) and men in the top third of the adiponectin distribution at reduced risk (HR 0.24, 95% CI 0.14-0.42) relative to men in the bottom third. However, significance was lost for leptin after additional adjustment for BMI, waist to hip ratio, lifestyle factors and biological risk factors, including C-reactive protein (CRP). Further adjustment for HOMA-IR also resulted in loss of significance for adiponectin.. This study provides evidence that adipokines are associated with men's future type 2 diabetes risk but not independently of other risk factors.

Topics: Adiponectin; Biomarkers; C-Reactive Protein; Diabetes Mellitus, Type 2; Humans; Incidence; Leptin; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Risk Factors; United Kingdom

Gastrointestinal complications in diabetes may affect glucose and endocrine homeostasis. Glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and leptin regulate glucose homeostasis, food intake, and gastric emptying.. The aim was to investigate associations between diabetes complications and glucose homeostasis and plasma levels of GIP, GLP-1, and leptin.. Sixteen diabetes patients (seven men) were examined with gastric emptying scintigraphy and 72-h continuous subcutaneous glucose monitoring, 14 with the deep-breathing test, and 12 with esophageal manometry. A fiber-rich breakfast was given during the second day of glucose registration. Blood samples were taken 10 min and right before a fat-rich breakfast, as well as 10, 20, 30, 45, 60, 90, 120, 150, and 180 min afterwards. 20 healthy volunteers acted as controls. Plasma was analyzed regarding GIP, GLP-1, and leptin by Luminex.. Gastroparesis lowered maximal concentration (c-max) (p = 0.003) and total area under the curve (tAUC) (p = 0.019) of glucose levels as well as d-min (p = 0.043) of leptin levels. It tended to lower baseline (p = 0.073), c-max (p = 0.066), change from baseline (d-max) (p = 0.073), and tAUC (p = 0.093) of GLP-1 concentrations. Esophageal dysmotility tended to lower tAUC of glucose levels (p = 0.063), and c-min (p = 0.065) and tAUC (p = 0.063) of leptin levels. Diabetes patients had a higher baseline concentration of glucose (p = 0.013), GIP (p = 0.023), and leptin (p = 0.019) compared with healthy subjects.. Gastric and esophageal dysmotility are associated with both lesser increases in postprandial glucose elevations and decreased postprandial changes in GLP-1 and leptin.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Esophageal Motility Disorders; Female; Gastric Inhibitory Polypeptide; Gastroparesis; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Male; Middle Aged; Postprandial Period

Statistical models to predict incident diabetes are often based on limited variables. Here we pursued two main goals: 1) investigate the relative performance of a machine learning method such as Random Forests (RF) for detecting incident diabetes in a high-dimensional setting defined by a large set of observational data, and 2) uncover potential predictors of diabetes. The Jackson Heart Study collected data at baseline and in two follow-up visits from 5,301 African Americans. We excluded those with baseline diabetes and no follow-up, leaving 3,633 individuals for analyses. Over a mean 8-year follow-up, 584 participants developed diabetes. The full RF model evaluated 93 variables including demographic, anthropometric, blood biomarker, medical history, and echocardiogram data. We also used RF metrics of variable importance to rank variables according to their contribution to diabetes prediction. We implemented other models based on logistic regression and RF where features were preselected. The RF full model performance was similar (AUC = 0.82) to those more parsimonious models. The top-ranked variables according to RF included hemoglobin A1C, fasting plasma glucose, waist circumference, adiponectin, c-reactive protein, triglycerides, leptin, left ventricular mass, high-density lipoprotein cholesterol, and aldosterone. This work shows the potential of RF for incident diabetes prediction while dealing with high-dimensional data.

Topics: Adiponectin; Adult; Aged; Anthropometry; Biomarkers; Black or African American; Blood Glucose; C-Reactive Protein; Cholesterol, HDL; Demography; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Incidence; Leptin; Machine Learning; Male; Middle Aged; Models, Theoretical; Triglycerides; Waist Circumference

We aimed to determine leptin level in patients with type 2 diabetes mellitus after fetal pancreatic stem cell transplant.. We examined 14 patients (aged 43-63 years old) with type 2 diabetes mellitus, which we subsequently divided into 2 groups and examined. Group 1 comprised 8 patients who received fetal pancreatic stem cell transplant (cells were 16-18 wk gestation) performed by intravenous infusion; group 2 comprised 6 patients in the control group who were on hypoglycemic tablet therapy or insulin therapy. The quantity of fetal stem cells infused was 5 to 6 × 106. We analyzed leptin and C-peptide levels in patients both before and 3 months after the fetal pancreatic stem cell transplant procedure.. In patients with type 2 diabetes mellitus, fetal pancreatic stem cell transplant led to a significant increase in leptin levels, from 11.01 ng/mL to 16.29 ng/mL, after 3 months (P < .05).. Leptin level increase significantly within 3 months after fetal pancreatic stem cell transplant in patients with type 2 diabetes mellitus.

Topics: Adult; Biomarkers; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Fetal Stem Cells; Humans; Hypoglycemic Agents; Leptin; Male; Middle Aged; Pancreas Transplantation; Prospective Studies; Time Factors; Treatment Outcome; Up-Regulation

Type 2 diabetes is a metabolic syndrome characterized by insulin resistance and relative insulin deficiency. In this study, the anti-diabetic effects of live and dead multi-strain probiotics were explored and compared in a high-fat and streptozotocin-induced model of type 2 diabetes in mice. Either live or dead probiotics were daily administered orally to the mice over 10 weeks. Both live and dead multi-strain probiotics reduced HbA1C and leptin levels, improved glucose tolerance, and protected against the impairment of the pancreas, while the live probiotic showed a greater ability to reduce fasting and postprandial blood glucose levels. In addition, the live multi-strain probiotic exerted the beneficial effect of ameliorating insulin resistance. This effect was associated with the gut microbiota, butyrate production, and the inflammatory response, and was more effective for the live probiotic than the dead probiotic. These findings showed that the viable probiotic more effectively relieved hypoglycemic symptoms in the host by ameliorating insulin resistance. Furthermore, a pathway related to insulin resistance, i.e., the gut microbiota-butyrate-inflammatory axis, provided a promising rationale for further research into preventing or treating type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Glycated Hemoglobin; Interleukin-10; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Probiotics; Tumor Necrosis Factor-alpha

We have reported a correlation between hypothalamic expression of Creb-binding protein (Cbp) and lifespan, and that inhibition of Cbp prevents protective effects of dietary restriction during aging, suggesting that hypothalamic Cbp plays a role in responses to nutritional status and energy balance. Recent GWAS and network analyses have also implicated Cbp as the most connected gene in protein-protein interactions in human Type 2 diabetes. The present studies address mechanisms mediating the role of Cbp in diabetes by inhibiting hypothalamic Cbp using a Cre-lox strategy. Inhibition of hypothalamic Cbp results in profound obesity and impaired glucose homeostasis, increased food intake, and decreased body temperature. In addition, these changes are accompanied by molecular evidence in the hypothalamus for impaired leptin and insulin signaling, a shift from glucose to lipid metabolism, and decreased Pomc mRNA, with no effect on locomotion. Further assessment of the significance of the metabolic switch demonstrated that enhanced expression of hypothalamic Cpt1a, which promotes lipid metabolism, similarly resulted in increased body weight and reduced Pomc mRNA.

Topics: Animals; Body Temperature; Brain-Derived Neurotrophic Factor; Carnitine O-Palmitoyltransferase; CREB-Binding Protein; Diabetes Mellitus, Type 2; Down-Regulation; Eating; Energy Metabolism; Female; Gene Expression Regulation; Glucose; Humans; Hypothalamus; Insulin; Leptin; Lipid Metabolism; Male; Mice; Obesity; Pro-Opiomelanocortin; Signal Transduction; Weight Gain

To investigate effects of falciparum malaria on circulating levels of leptin and adiponectin in type 2 diabetes mellitus (T2DM) and non-diabetic controls in relation to measures of adiposity.. Levels of leptin and adiponectin were measured in 100 type 2 diabetics and 100 age-matched controls before and during falciparum malaria in a 2-year prospective study. Also, waist circumference (WC), weight, height and hip circumference were measured. Body mass index (BMI) and waist-to-hip ratio (WHR) were computed.. At baseline, diabetics had significantly (p < 0.05) higher WC and BMI but lower WHR, leptin and adiponectin levels. Baseline leptin correlated positively with WC (r = 0.633; p < 0.001) and BMI (r = 0.63; p < 0.001) in diabetics but only BMI (0.562; p < 0.001) in non-diabetic controls. Baseline leptin and adiponectin correlated positively (r = 0.249; p = 0.029) in non-diabetic respondents only. Adiponectin correlated negatively with WC (r = -0.58; p = 0.006) in diabetic males only. During malaria, mean levels of leptin and adiponectin were comparable (p > 0.05) between diabetics and controls. However, compared to baseline levels, significant (p < 0.001) elevation of adiponectin was found in both study groups. In respect of leptin, significant (p < 0.001) rise but decline was observed in diabetics and controls respectively. Malaria-induced leptin correlated negatively with adiponectin (r = -0.694; p < 0.001) in non-diabetic controls only.. Diabetics and controls exhibited increased adiponectin levels due to falciparum malaria but differed in response in terms of leptin levels.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Humans; Leptin; Malaria; Prospective Studies

Inositol hexakisphosphate (IP6) and inositol both regulate insulin secretion, but their combined use in the management of diabetes deserves investigation. The combined effects of IP6 and inositol supplementation were investigated in streptozotocin-induced type 2 diabetic rats. The following groups of rats were studied for 8 weeks: non-diabetic control, non-diabetic high-fat diet control, diabetic untreated, diabetic rats treated with the combination of IP6 and inositol (650 mg/kg bw) and diabetic rats treated with glibenclamide (10 mg/kg bw). High-fat diet and streptozotocin were used to induce type 2 diabetes mellitus in Sprague-Dawley rats. Body weight, blood glucose, glycated haemoglobin, insulin, serum leptin, HOMA-insulin resistance scores, intestinal amylase activity, serum and faecal lipids and food and fluid consumption were measured. Treatment with the combination significantly reduced blood glucose (306 ± 53 mg/dl) and insulin resistance score (1.93 ± 0.45) compared with diabetic controls (522 ± 24 mg/dl and 5.1 ± 0.69 respectively). Serum leptin (2.8 ± 0.6 ng/dl) and faecal triglycerides (108 ± 8 mg/dl) were significantly increased in rats treated with the combination compared with the diabetic control (1.8 ± 0.06 ng/dl and 86 ± 4 mg/dl). Serum triglyceride (47 ± 5.1 mg/dl), total cholesterol (98 ± 3.2 mg/dl) and food intake (26 ± 0.3 g) were significantly reduced by 45%, 25% and 25%, respectively, in rats treated with the combination compared with the diabetic control. Inositol and IP6 combined supplementation may be effective in the management of type 2 diabetes mellitus and related metabolic disorders by regulating some aspects of lipid and carbohydrate metabolism.

Topics: Amylases; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Drinking; Drug Evaluation, Preclinical; Drug Therapy, Combination; Eating; Feces; Hypoglycemic Agents; Inositol; Intestines; Leptin; Lipid Metabolism; Lipids; Male; Phytic Acid; Rats, Sprague-Dawley

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Fatty Liver; Gene Expression; Glycated Hemoglobin; Humans; Leptin; Liver; Mice; Mice, Obese; Mutation; NF-kappaB-Inducing Kinase; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Hormones; Protein Serine-Threonine Kinases; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Transcription Factors

In addition to the amount of ingested calories, both timing of food intake and meal composition are determinants of body weight gain. However, at present, it is unknown if the inappropriate timing of diet components is responsible for body weight gain. In the present study, we therefore studied a time-dependent effect of the diet composition on energy homeostasis. Male Wistar rats were subjected to chow ad libitum (chow group) or a choice diet with saturated fat, a 30% sugar solution, chow and tap water. The choice diet was provided either with all components ad libitum (AL), with ad libitum access to chow, tap water and a 30% sugar solution, but with access to saturated fat only during the light period (LF), or with ad libitum access to chow, tap water and saturated fat, but access to a 30% sugar solution only during the light period (LS). Caloric intake and body weight gain were monitored during 31 days. Energy expenditure was measured in the third week in calorimetric cages. All rats on a choice diet showed hyperphagia and gained more body weight compared to the chow group. Within the choice diet groups, rats on the LS diet were most food efficient (i.e. gained most body weight per ingested calorie) and showed a lower respiratory exchange ratio (RER) with an anti-phasic pattern, whereas no differences in locomotor activity or heat production were found. Collectively these data indicate that the timing of the diet composition affects food efficiency, most likely due to a shifted oxidation pattern, which can predispose for obesity. Further studies are underway to assess putative mechanisms involved in this dysregulation.

Topics: Animals; Body Composition; Body Weight; Calorimetry; Circadian Rhythm; Diabetes Mellitus, Type 2; Diet; Dietary Fats; Dietary Sucrose; Disease Models, Animal; Eating; Energy Intake; Feeding Behavior; Homeostasis; Leptin; Light; Male; Obesity; Oxygen; Rats; Rats, Wistar; Time Factors; Weight Gain

White rice (WR) is a major staple food for people in developing countries and it may be responsible for the growing incidence of type 2 diabetes. Nonpregnant Female Sprague Dawley rats fed with WR or brown rice (BR) for 8 weeks were mated with age-matched male rats maintained on normal pellet over the same period. Offsprings were fed normal pellet after weaning until 8 weeks postdelivery. Rats fed with WR and their offsprings showed worsened oral glucose tolerance test, lower serum adiponectin levels, and higher weights, homeostatic model assessment of insulin resistance, serum retinol binding protein-4 levels, and leptin levels, compared with the normal and BR groups, suggesting an increased risk of insulin resistance. Furthermore, transcriptional levels of genes involved in insulin signaling showed different expression patterns in the liver, muscle, and adipose tissues of mothers and offsprings in both WR and BR groups. The results propose that the cycle of WR-induced insulin resistance in offsprings due to prenatal exposure, followed by their consumption of WR later in life may contribute to diabetes incidents. These findings are worth studying further.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Liver; Male; Maternal Exposure; Muscle, Skeletal; Oryza; Pregnancy; Rats; Rats, Sprague-Dawley

Diabetes is a growing health care issue, and prediabetes has been established as a risk factor for type 2 diabetes. Prediabetes is characterized by deregulated glucose control, and elucidating pathways which govern this process is critical. We have identified the wild-type (WT) p53-inducible phosphatase (WIP1) phosphatase as a regulator of glucose homeostasis. Initial characterization of insulin signaling in WIP1 knockout (WIP1(KO)) murine embryo fibroblasts demonstrated reduced insulin-mediated Ak mouse transforming activation. In order to assess the role of WIP1 in glucose homeostasis, we performed metabolic analysis on mice on a low-fat chow diet (LFD) and high fat diet (HFD). We observed increased expression of proinflammatory cytokines in WIP1(KO) murine embryo fibroblasts, and WIP1(KO) mice fed a LFD and a HFD. WIP1(KO) mice exhibited glucose intolerance and insulin intolerance on a LFD and HFD. However, the effects of WIP1 deficiency cause different metabolic defects in mice on a LFD and a HFD. WIP1(KO) mice on a LFD develop hepatic insulin resistance, whereas this is not observed in HFD-fed mice. Mouse body weights and food consumption increase slightly over time in LFD-fed WT and WIP1(KO) mice. Leptin levels are increased in LFD-fed WIP1(KO) mice, compared with WT. In contrast, HFD-fed WIP1(KO) mice are resistant to HFD-induced obesity, have decreased levels of food consumption, and decreased leptin levels compared with HFD-WT mice. WIP1 has been shown to regulate the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, loss of which leads to increased inflammation. We propose that this increased inflammation triggers insulin resistance in WIP1(KO) mice on LFD and HFD.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Fibroblasts; Genetic Predisposition to Disease; Glucose; Glucose Intolerance; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phosphoprotein Phosphatases; Prediabetic State; Primary Cell Culture; Protein Phosphatase 2C; Signal Transduction; Tumor Necrosis Factor-alpha

Although the association between cigarette smoking and risk of type 2 diabetes is well established, its mechanisms are yet to be clarified. This study examined the possible mediating effects of adiponectin, leptin, and C-reactive protein (CRP) concentrations on the smoking-diabetes association.. Between 2002 and 2011, we followed 3338 Japanese workers, aged 35-66 years, who were enrolled in the second Aichi workers' cohort study. We used multivariable-adjusted Cox regression models to determine the hazard ratios and respective 95% confidence intervals (CIs) of the association between smoking status and risk of diabetes. A multiple mediation model with bootstrapping was used to estimate the magnitude and the respective bias-corrected (BC) 95% CIs of the indirect effects of smoking on diabetes through the three biomarkers.. Relative to never smokers, the risk of diabetes was significantly elevated in current (hazard ratio 1.75, 95% CI 1.25-2.46) and ex-smokers (hazard ratio 1.54, 95% CI 1.07-2.22). The indirect effects of smoking on diabetes through adiponectin levels were statistically significant among light (point estimate 0.033, BC 95% CI 0.005-0.082), moderate (point estimate 0.044, BC 95% CI 0.010-0.094), and heavy smokers (point estimate 0.054, BC 95% CI 0.013-0.113). In contrast, neither the indirect effects of smoking on diabetes through leptin nor CRP levels were significant, as the corresponding BC 95% CIs included zero.. In our analysis, adiponectin concentration appeared to partially mediate the effect of smoking on diabetes, while leptin and CRP levels did not.

Topics: Adiponectin; Adult; Aged; Biomarkers; C-Reactive Protein; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Japan; Leptin; Male; Middle Aged; Smoking

We have investigated the differences between metabolically "healthy" morbidly obese patients and those with comorbidities.. Thirty-two morbidly obese patients were divided by the absence ("healthy": DM-DL-) or presence of comorbidities (dyslipidemic: DM-DL+, or dyslipidemic and with type 2 diabetes: DM+DL+). We have studied various plasma parameters and gene expression adipose tissue, before and after gastric bypass.. The group DM+DL+ tends to have lower values than the other two groups for anthropometric parameters. Regarding the satiety parameters, only leptin (p = 0.0024) showed a significant increase with comorbidities. Lipid parameters showed significant differences among groups, except for phospholipids and NEFA. For insulin resistance parameters, only glucose (p < 0.0001) was higher in DM+DL+ patients, but not insulin or homeostasis model assessment of insulin resistance (HOMA-IR). The gene expression of adiponectin, insulin receptor (INSR) and glucose receptor-4 (GLUT4), in the subcutaneous fat, decreased in all groups vs. a non-obese control. Interleukin-6 (IL6) and the inhibitor of plasminogen activator type 1 (PAI-1) genes decreased only in DM-DL+ and DM+DL+, but not in "healthy" patients. Leptin increased in all groups vs. the non-obese control. The visceral fat from DM+DL+ patients showed a sharp decrease in adiponectin, GLUT4, IL6 and PAI-1. All parameters mentioned above improved very significantly by surgery, independent of the occurrence of comorbidities.. The morbidly obese "healthy" individual is not really metabolically healthy, but morbidly obese individuals with diabetes and dyslipidemia are more metabolically imbalanced.

Topics: Adiponectin; Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Gastric Bypass; Glucose Transporter Type 4; Humans; Insulin; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Obesity, Metabolically Benign; Obesity, Morbid; Plasminogen Activator Inhibitor 1; Subcutaneous Fat; Young Adult

Studies in vitro have highlighted the potential involvement of neuregulin 1 (NRG1) in the regulation of energy metabolism. This effect has also been suggested in vivo, as intracerebroventricular injection of NRG1 reduces food intakes and weight gain in rodents. Thus, it was hypothesised that NRG1 might affect serum leptin levels in mice.. Weight, food intakes, energy expenditure, spontaneous physical activity and serum leptin levels were evaluated in normal-weight C57BL/6JRJ mice following intraperitoneal administration of NRG1 (50 μg/kg, three times/week) or saline for 8 weeks. Based on the results of this first experiment, leptin-resistant obese db/db mice were then given NRG1 for 8 weeks.. Leptin serum concentrations were six times higher in C57BL/6JRJ mice treated with NRG1 than in the animals given saline. NRG1 treatment also reduced weight gain by 10% and food intakes by 15% compared with saline treatment, while energy expenditure remained unchanged. In db/db mice, serum leptin concentrations, weight gain, food intakes, energy expenditure and spontaneous physical activity were not altered by NRG1 treatment.. The decrease in food intakes and weight gain associated with NRG1 treatment in C57BL/6JRJ mice may be partly explained by increased leptin levels, whereas db/db mice were not affected by the treatment, suggesting resistance to NRG1 in this pathological state.

Topics: Animals; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Insulin; Leptin; Mice; Mice, Obese; Neuregulin-1; Weight Gain

Moringa oleifera (moringa) is tropical plant traditionally used as an antidiabetic food. It produces structurally unique and chemically stable moringa isothiocyanates (MICs) that were evaluated for their therapeutic use in vivo.. C57BL/6L mice fed very high fat diet (VHFD) supplemented with 5% moringa concentrate (MC, delivering 66 mg/kg/d of MICs) accumulated fat mass, had improved glucose tolerance and insulin signaling, and did not develop fatty liver disease compared to VHFD-fed mice. MC-fed group also had reduced plasma insulin, leptin, resistin, cholesterol, IL-1β, TNFα, and lower hepatic glucose-6-phosphatase (G6P) expression. In hepatoma cells, MC and MICs at low micromolar concentrations inhibited gluconeogenesis and G6P expression. MICs and MC effects on lipolysis in vitro and on thermogenic and lipolytic genes in adipose tissue in vivo argued these are not likely primary targets for the anti-obesity and anti-diabetic effects observed.. Data suggest that MICs are the main anti-obesity and anti-diabetic bioactives of MC, and that they exert their effects by inhibiting rate-limiting steps in liver gluconeogenesis resulting in direct or indirect increase in insulin signaling and sensitivity. These conclusions suggest that MC may be an effective dietary food for the prevention and treatment of obesity and type 2 diabetes.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Composition; Cholesterol; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Liver; Gluconeogenesis; Glucose-6-Phosphatase; Hypoglycemic Agents; Insulin; Insulin Resistance; Interleukin-1beta; Isothiocyanates; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Moringa oleifera; Obesity; Plant Extracts; Resistin; Tumor Necrosis Factor-alpha; Weight Gain

Clinical studies suggest that short-term insulin treatment in new-onset type 2 diabetes (T2DM) can promote prolonged glycemic control. The purpose of this study was to establish an animal model to examine such a "legacy" effect of early insulin therapy (EIT) in long-term glycemic control in new-onset T2DM. The objective of the study was to investigate the role of diet following onset of diabetes in the favorable outcomes of EIT.. As such, C57BL6/J male mice were fed a high-fat diet (HFD) for 21 weeks to induce diabetes and then received 4 weeks of daily insulin glargine or sham subcutaneous injections. Subsequently, mice were either kept on the HFD or switched to a low-fat diet (LFD) for 4 additional weeks.. Mice fed a HFD gained significant fat mass and displayed increased leptin levels, increasing insulin resistance (poor HOMA-IR) and worse glucose tolerance test (GTT) performance in comparison to mice fed a LFD, as expected. Insulin-treated diabetic mice but maintained on the HFD demonstrated even greater weight gain and insulin resistance compared to sham-treated mice. However, insulin-treated mice switched to the LFD exhibited a better HOMA-IR compared to those mice left on a HFD. Further, between the insulin-treated and sham control mice, in spite of similar HOMA-IR values, the insulin-treated mice switched to a LFD following insulin therapy did demonstrate significantly better HOMA-B% values than sham control and insulin-treated HFD mice.. Early insulin treatment in HFD-induced T2DM in C57BL6/J mice was only beneficial in animals that were switched to a LFD after insulin treatment which may explain why a similar legacy effect in humans is achieved clinically in only a portion of cases studied, emphasizing a vital role for diet adherence in diabetes control.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Mice

There is growing evidence that early development of obesity increases cardiovascular risk later in life, but less is known about whether there are effects of long-term excess body weight on the biological drivers associated with the atherosclerotic pathway, particularly adipokines, inflammatory and endothelial markers. This paper therefore investigates the influence of overweight across the life course on levels of these markers at retirement age.. Data from the Medical Research Council National Survey of Health and Development (n=1784) were used to examine the associations between overweight status at 2, 4, 6, 7, 11, 15, 20, 26, 36, 43, 53 and 60-64 years (body mass index (BMI)⩾25 kg m(-2) for adult ages and gender-specific cut-points for childhood ages equivalent to BMI⩾25 kg m(-2)) and measurements of adipokines (leptin and adiponectin), inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6)) and endothelial markers (E-selectin, tissue plasminogen activator (t-PA) and von Willebrand factor) at 60-64 years. In addition, the fit of different life course models (sensitive periods/accumulation) were compared using partial F-tests.. In age- and sex-adjusted models, overweight at 11 years and onwards was associated with higher leptin, CRP and IL-6 and lower adiponectin; overweight at 15 years and onwards was associated with higher E-selectin and t-PA. Associations between overweight at all ages earlier than 60-64 with leptin, adiponectin, CRP and IL-6 were reduced but remained apparent after adjustment for overweight at 60-64 years; whereas those with E-selectin and t-PA were entirely explained. An accumulation model best described the associations between overweight across the life course with adipokines and inflammatory markers, whereas for the endothelial markers, the sensitive period model for 60-64 years provided a slightly better fit than the accumulation model.. Overweight across the life course has a cumulative influence on adipokines, inflammatory and possibly endothelial markers. Avoidance of overweight from adolescence onwards is likely important for cardiovascular disease prevention.

Topics: Adiponectin; Adolescent; Adult; Age of Onset; Aging; Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Child; Child, Preschool; Diabetes Mellitus, Type 2; E-Selectin; Female; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Risk Factors; United Kingdom; von Willebrand Factor

Cytochrome P450 1b1 (Cyp1b1) expression is absent in mouse hepatocytes, but present in liver endothelia and activated stellate cells. Increased expression during adipogenesis suggests a role of Cyp1b1 metabolism in fatty acid homeostasis. Wild-type C57BL/6j (WT) and Cyp1b1-null (Cyp1b1-ko) mice were provided low or high fat diets (LFD and HFD, respectively). Cyp1b1-deletion suppressed HFD-induced obesity, improved glucose tolerance and prevented liver steatosis. Suppression of lipid droplets in sinusoidal hepatocytes, concomitant with enhanced glycogen granules, was a consistent feature of Cyp1b1-ko mice. Cyp1b1 deletion altered the in vivo expression of 560 liver genes, including suppression of PPARγ, stearoyl CoA desaturase 1 (Scd1) and many genes stimulated by PPARα, each consistent with this switch in energy storage mechanism. Ligand activation of PPARα in Cyp1b1-ko mice by WY-14643 was, nevertheless, effective. Seventeen gene changes in Cyp1b1-ko mice correspond to mouse transgenic expression that attenuated diet-induced diabetes. The absence of Cyp1b1 in mouse hepatocytes indicates participation in energy homeostasis through extra-hepatocyte signaling. Extensive sexual dimorphism in hepatic gene expression suggests a developmental impact of estrogen metabolism by Cyp1b1. Suppression of Scd1 and increased leptin turnover support enhanced leptin participation from the hypothalamus. Cyp1b1-mediated effects on vascular cells may underlie these changes.

Topics: Adiposity; Age Factors; Animals; Cytochrome P-450 CYP1B1; Diabetes Mellitus, Type 2; Dietary Fats; Energy Metabolism; Fatty Acids; Fatty Liver; Female; Gene Expression Profiling; Homeostasis; Leptin; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidative Stress; PPAR alpha; Stearoyl-CoA Desaturase

Obesity and type 2 diabetes (T2D) are associated with low-grade inflammation, activation of immune cells, and alterations of the gut microbiota. Mucosal-associated invariant T (MAIT) cells, which are innate-like T cells that recognize bacterial ligands, are present in blood and enriched in mucosal and inflamed tissues. Here, we analyzed MAIT cells in the blood and adipose tissues of patients with T2D and/or severe obesity. We determined that circulating MAIT cell frequency was dramatically decreased in both patient groups, and this population was even undetectable in some obese patients. Moreover, in both patient groups, circulating MAIT cells displayed an activated phenotype that was associated with elevated Th1 and Th17 cytokine production. In obese patients, MAIT cells were more abundant in adipose tissue than in the blood and exhibited a striking IL-17 profile. Bariatric surgery in obese patients not only improved their metabolic parameters but also increased circulating MAIT cell frequency at 3 months after surgery. Similarly, cytokine production by blood MAIT cells was strongly decreased after surgery. This study reveals profound MAIT cell abnormalities in patients harboring metabolic disorders, suggesting their potential role in these pathologies.

Topics: Adiponectin; Adipose Tissue; Adult; Bariatric Surgery; Blood Cells; Cytokines; Diabetes Mellitus, Type 2; Female; Humans; Inflammation; Interleukin-17; Leptin; Lymphocyte Count; Male; Middle Aged; Natural Killer T-Cells; Obesity; Omentum; Organ Specificity; Postoperative Period; Subcutaneous Tissue; T-Lymphocyte Subsets

Orexin A (OXA) is a neuropeptide implicated in the regulation of arousal status and energy metabolism. Orexin receptors are expressed not only in the central nervous system but also in the pancreas and adipose tissue. However, little is known about the physiological function of orexins. This study investigated the role of exogenous OXA in blood glucose control after glucose load in mice. In addition, the effect of OXA on insulin secretion was also identified in mouse pancreatic beta cells.. Insulin secretion and intracellular Ca(2+) levels were measured in perifused mouse islets. To investigate the effects of exogenous OXA on blood glucose levels in vivo, intraperitoneal glucose tolerance tests were performed after a subcutaneous injection of OXA in normal and high-fat diet-induced diabetic mice.. OXA significantly potentiated glucose-stimulated insulin secretion in vitro, which increased intracellular Ca(2+) levels, mainly through adenylate cyclase and ryanodine receptor activation. This Ca(2+)-dependent insulinotropic effect of OXA was blocked in Epac2 (Rapgef4)-deficient beta cells. After a glucose load in mice, exogenous OXA decreased blood glucose levels, compared with the control, by enhancing plasma insulin and decreasing plasma glucagon levels. Additionally, OXA caused a delayed increase in plasma leptin levels, resulting in lower plasma insulin levels when blood glucose levels fell to baseline.. These results suggest that OXA might be a critical regulator of insulin, glucagon and leptin secretion in response to glucose. Thus, exogenous OXA might have therapeutic potential in improving blood glucose control in patients with type 2 diabetes.

Topics: Animals; Blood Glucose; Calcium; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucagon; Glucose; Glucose Tolerance Test; Guanine Nucleotide Exchange Factors; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Orexin Receptors; Orexins

The IL-6 -174G/C (rs1800795), TNF-α -308G/A (rs1800629) and -238G/A (rs361525) and SDF-1 801G/A (rs1801157) are well characterized SNPs which have previously been linked to various diabetic complications. However, the involvement of these SNPs in DFU remains poorly studied. In the present study we looked at the association of these SNPs with DFU (disease phenotype) and correlated it with the serum levels of cytokines (intermediate phenotype) along with other clinical risk factors of DFU (adiponectin, leptin and hsCRP). Genotyping was carried out in Normal glucose tolerance ((NGT)/Control=106), T2DM without DFU (T2DM=139), T2DM with neuropathy (DFU-DN=191) and T2DM with PVD (DFU-PVD=79) subjects by PCR-RFLP and the serum cytokine levels were determined by ELISA. IL-6 -176 "C" allele conferred significant protection against T2DM but not against DFU. TNF-α -308 "A" allele (but not -238 SNP) conferred significant susceptibility towards both T2DM and DFU-DN. The SDF-1 "A" allele conferred significant protection against both DM and DFU-DN but not against DFU-PVD. Further, these alleles were shown to influence the serum cytokine/chemokine levels under diabetic conditions. Thus SNPs in cytokine/chemokine genes serve as valuable biomarkers for DFU.

Topics: Adiponectin; Adult; C-Reactive Protein; Chemokine CXCL12; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Genetic Association Studies; Humans; Interleukin-6; Leptin; Male; Middle Aged; Polymorphism, Single Nucleotide; Tumor Necrosis Factor-alpha

Insulin resistance is a major characteristic of obesity and type 2 diabetes, but the underlying mechanism is unclear. Recent studies have shown a metabolic role of capsaicin that may be mediated via the transient receptor potential vanilloid type-1 (TRPV1) channel. In this study, TRPV1 knockout (KO) and wild-type (WT) mice (as controls) were fed a high-fat diet (HFD), and metabolic studies were performed to measure insulin and leptin action. The TRPV1 KO mice became more obese than the WT mice after HFD, partly attributed to altered energy balance and leptin resistance in the KO mice. The hyperinsulinemic-euglycemic clamp experiment showed that the TRPV1 KO mice were more insulin resistant after HFD because of the ∼40% reduction in glucose metabolism in the white and brown adipose tissue, compared with that in the WT mice. Leptin treatment failed to suppress food intake, and leptin-mediated hypothalamic signal transducer and activator of transcription (STAT)-3 activity was blunted in the TRPV1 KO mice. We also found that the TRPV1 KO mice were more obese and insulin resistant than the WT mice at 9 mo of age. Taken together, these results indicate that lacking TRPV1 exacerbates the obesity and insulin resistance associated with an HFD and aging, and our findings further suggest that TRPV1 has a major role in regulating glucose metabolism and hypothalamic leptin's effects in obesity.

Topics: Adipose Tissue, Brown; Aging; Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Fats; Energy Metabolism; Glucose; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; TRPV Cation Channels

This study aimed to determine whether third-trimester adipokines during gestational diabetes (GDM) are associated with higher metabolic risk.. A total of 221 women with GDM (according to IADPSG criteria) were enrolled between 2011/11 and 2013/6 into a prospective observational study (IMAGE), and categorized as having elevated fasting blood glucose (FBG) or impaired fasting glucose (IFG, n = 36) if levels were ≥ 92 mg/dL during a 75-g oral glucose tolerance test (OGTT), impaired glucose tolerance (IGT, n = 116) if FBG was < 92 mg/dL but with elevated 1-h or 2-h OGTT values, or impaired fasting and stimulated blood glucose (IFSG, n = 69) if both FBG was ≥ 92 mg/dL and 1-h or 2-h OGTT values were elevated.. Pre-gestational body mass index (BMI) was higher in women with IFG or IFSG compared with IGT (P < 0.001), as were leptin levels in women with IFG vs IGT [34.7 (10.5-119.7) vs 26.6 (3.56-79.4) ng/L; P = 0.008]. HOMA2-IR scores were higher in women with IFG or IFSG vs IGT (1.87 ± 1.2 or 1.72 ± 0.9 vs 1.18 ± 0.8, respectively; P < 0.001). Also, those with IFSG vs those with IGT had significantly lower HOMA2-B scores (111.4 ± 41.3 vs 127.1 ± 61.6, respectively; P < 0.05) and adiponectin levels [5.00 (1.11-11.3) vs 6.19 (2.11-17.7) μg/mL; P < 0.001], and higher levels of IL-6 [1.14 (0.33-20.0) vs 0.90 (0.31-19.0); P = 0.012] and TNF-α [0.99 (0.50-10.5) vs 0.84 (0.45-11.5) pg/mL; P = 0.003]. After adjusting for age, parity, and pre-gestational and gestational BMI, the difference in adiponectin levels remained significant.. Diagnosing GDM by IADSPG criteria results in a wide range of heterogeneity. Our study has indicated that adipokine levels in addition to FBG may help to select women at high metabolic risk for appropriate monitoring and post-delivery interventions (ClinicalTrials.gov number NCP02133729).

Topics: Adiponectin; Biomarkers; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; France; Humans; Insulin Resistance; Leptin; Overweight; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third; Prenatal Diagnosis; Prospective Studies; Risk Factors; Severity of Illness Index

Metabolic syndrome and T2D produce significant health and economic issues. Many available animal models have monogenic leptin pathway mutations that are absent in the human population. Development of the ZDSD rat model was undertaken to produce a model that expresses polygenic obesity and diabetes with an intact leptin pathway. A lean ZDF rat with the propensity for beta-cell failure was crossed with a polygenetically obese Crl:CD (SD) rat. Offspring were selectively inbred for obesity and diabetes for >30 generations. In the current study, ZDSD rats were followed for 6 months; routine clinical metabolic endpoints were included throughout the study. In the prediabetic metabolic syndrome phase, ZDSD rats exhibited obesity with increased body fat, hyperglycemia, insulin resistance, dyslipidemia, glucose intolerance, and elevated HbA1c. As disease progressed to overt diabetes, ZDSD rats demonstrated elevated glucose levels, abnormal oral glucose tolerance, increases in HbA1c levels, reductions in body weight, increased insulin resistance with decreasing insulin levels, and dyslipidemia. The ZDSD rat develops prediabetic metabolic syndrome and T2D in a manner that mirrors the development of metabolic syndrome and T2D in humans. ZDSD rats will provide a novel, translational animal model for the study of human metabolic diseases and for the development of new therapies.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Rats; Signal Transduction

Plasma GlycA is a recently developed biomarker whose nuclear magnetic resonance signal originates from glycosylated acute-phase proteins. The aim of our study was to determine potential relationships between GlycA and adiposity, insulin resistance (HOMA(ir)), high sensitive C-reactive protein (hs-CRP), leptin, adiponectin, and the leptin/adiponectin ratio, and to test whether GlycA is elevated in subjects with impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM).. Plasma GlycA, hs-CRP, leptin, adiponectin, the leptin/adiponectin ratio, and insulin resistance (HOMA(ir)) were measured in 103 fasting subjects (30 with normal fasting glucose, 25 with IFG and 48 with T2DM).. In all subjects combined, plasma GlycA was correlated positively with body mass index (BMI), HOMA(ir), hs-CRP, leptin and the leptin/adiponectin ratio, and inversely with adiponectin (p < 0.05 to p < 0.001). GlycA did not significantly vary according to glucose tolerance category (p = 0.060). GlycA was related positively to the leptin/adiponectin ratio (p = 0.049), independent of BMI (p = 0.056) and HOMA(ir) (p = 0.50).. High plasma GlycA reflects a pro-inflammatory state. Adipose tissue-associated inflammatory processes could contribute to increased circulating levels of glycosylated acute-phase proteins.

Topics: Adiponectin; Biomarkers; Blood Glucose; C-Reactive Protein; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glycoproteins; Glycosylation; Humans; Inflammation; Leptin; Linear Models; Male; Middle Aged; Nuclear Magnetic Resonance, Biomolecular

The exact mechanism of ethanol's effects on glucose tolerance has not been well determined. The present study focuses for the first time on hypoxia and low-grade inflammation in adipose tissue (AT). In the in vivo experiments, twenty-four male Wistar rats were randomly allocated into control and ethanol feeding groups. Ethanol-treated rats received edible ethanol once a day at a total dosage of 5 g/kg per d, and the controls received distilled water. Ethanol volumes were adjusted every week. At the end of 8 weeks, we carried out an oral glucose tolerance test. Blood and AT were collected for measuring hypoxia-inducible factor-1α (HIF-1α), GLUT1, TNF-α, IL-6, leptin and vascular endothelial growth factor (VEGF). In the in vitro experiments, differentiated OP9 adipocytes were incubated with 100 mm of ethanol for 48 h; the media and cells were then collected for measuring HIF-1α, GLUT1, TNF-α and IL-6. The results showed that long-term ethanol consumption impaired glucose tolerance in rats. Ethanol consumption had little influence on body weight, but both epididymal and perirenal AT were markedly enlarged in the ethanol-treated rats as compared to the controls. Visceral adipose tissue (VAT) had accumulated, and the protein levels of HIF-1α and GLUT1, the indicators of hypoxia in rat epididymal AT and OP9 adipocytes, were elevated. Secondary to the AT hypoxia, the levels of inflammation-related adipokines, such as TNF-α, IL-6, leptin and VEGF, were increased. Based on these findings, we conclude that VAT hypoxia and low-grade inflammation might be a new mechanism in the treatment of ethanol-related diabetes.

Topics: Adipocytes; Adipose Tissue; Animals; Cell Hypoxia; Cell Line; Diabetes Mellitus, Type 2; Epididymis; Ethanol; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 1; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Male; Mice; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

New and clinically useful markers of cardiovascular risk are of essence in type 2 diabetes since ischemic heart disease is a major cause of death in these patients.. We analyzed baseline data from 476 men and 244 women who participated in "Cardiovascular Risk factors in Patients with Diabetes -a Prospective study in Primary care" study. All participants had type 2 diabetes and were 55-66 years old at recruitment during year 2005 to 2008. Except for established traditional risk markers for vascular disease, we also estimated vascular complications non-invasively by performance of carotid-femoral pulse-wave velocity (PWV, with applanation-tonometry) and intima-media thickness of carotid arteries (IMT, with B-mode ultrasound). Patients were followed for incidence of ischemic heart disease mortality and morbidity until end of the year 2012, using the national Swedish Cause of Death and Hospitalization Registries.. During the follow-up period of a median of 6 years 47 men and 10 women died or were hospitalized for ischemic heart disease including myocardial infarction. Leptin levels were positively related to the hazard ratio (HR) in men (HR for each log 10 unit 4.9, CI 1.99 to 11.8) and women (HR 11.5, CI 1.47 to 89.7). Leptin predicted ischemic heart disease independently of age, HbA1c, BMI, systolic blood pressure and LDL-cholesterol/HDL-cholesterol ratio (men: HR 12.9 CI 3.2-53, women: HR 19.9, CI 1.2-327) This finding of increased risk related to high leptin levels was also statistically significant when carotid-femoral PWV and IMT were both added to the equations in men (hazard ratio 9.2 CI 2.1-41).. Our data support the use of serum leptin in type 2 diabetes to add independent prognostic information in terms of ischemic heart disease when compared with traditional cardiovascular risk factors. In the men of the cohort this prognostic information was in addition also to data on IMT and PWV, two non-invasive measurements of the extent of vascular disease. The power to detect a similar relationship in women was less strong due to lower incidence of cardiovascular disease.. ClinicalTrials.gov: NCT01049737.

Topics: Carotid Arteries; Carotid Intima-Media Thickness; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Leptin; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Prognosis; Proportional Hazards Models; Prospective Studies; Pulse Wave Analysis

Reduced cardiac β-adrenoceptor (β-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac β-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac β-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats.. Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of β-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured.. At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced β-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6). At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function.. Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and β1- and β2-AR expression are inversely correlated with the progression of type-2 diabetes.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Echocardiography; Fatty Acids, Nonesterified; Gene Expression Regulation; Heart Diseases; Hyperglycemia; Insulin; Leptin; Male; Myocardium; Rats; Rats, Zucker; Receptors, Adrenergic, beta

The aims of this study were: (1) to assess the association of adiponectin, leptin and interleukin-6 (IL-6) with incidence of type 2 diabetes (T2DM) in Asian Indian men with impaired glucose tolerance (IGT) and (2) to evaluate the additional contribution of these with the well-established glycaemic marker HbA1c.. This is an ancillary analyses of a nested case-control study derived from a prospective, prevention trial in India. All the participants had IGT at baseline. For this subanalysis a total of 147 (T2DM: 71; nondiabetic: 76) participants were selected based on the final glycemic outcomes. Association of these selected adipokines with T2DM were assessed using logistic regression analyses. Clinical usefulness of adding adipokine markers with HbA1c on prediction of T2DM was assessed using the area under the curve (AUC) of the receiver operating characteristics.. Baseline levels of adiponectin were lower and the levels of IL-6 were higher in T2DM cases when compared with non-diabetic cases (P<0.05). Levels of leptin were similar in both groups. In fully adjusted models, adiponectin (odds ratio (OR): 0.55 [95%CI: 0.33-0.91]; P=0.019) and IL-6 (OR: 2.27 [95%CI: 1.40-3.691]; P=0.001) were associated with diabetes. Addition of adiponectin to HbA1c improved the AUC (ΔAUC: 0.0619; P=0.0251), whereas addition of IL-6 did not improve the predictive power of HbA1c alone.. Adiponectin and IL-6 are independently associated with incident diabetes. However, they are unlikely to serve as simple tools to predict future risk of diabetes but may have a role in understanding the pathogenesis.

Topics: Adiponectin; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Glucose Intolerance; Glycated Hemoglobin; Humans; Incidence; India; Interleukin-6; Leptin; Male; Middle Aged; Prospective Studies

Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetes-associated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations.. Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semi-quantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites.. Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, O-phosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state.. By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin.

Topics: 3-Hydroxybutyric Acid; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Fatty Acids; Gas Chromatography-Mass Spectrometry; Gene Expression Regulation; Glyoxylates; Insulin Resistance; Leptin; Liver; Lysine; Male; Metabolome; Metabolomics; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Obesity; Phosphotyrosine; Signal Transduction; Sorbitol

Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Energy Metabolism; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Transgenic; Obesity; Phenotype; Receptor, Insulin

Type 2 diabetes is associated with macro- and microvascular complications in man. Microvascular dysfunction affects both cardiac and renal function and is now recognized as a main driver of cardiovascular mortality and morbidity. However, progression of microvascular dysfunction in experimental models is often obscured by macrovascular pathology and consequently demanding to study. The obese type 2 diabetic leptin-deficient (ob/ob) mouse lacks macrovascular complications, i.e. occlusive atherosclerotic disease, and may therefore be a potential model for microvascular dysfunction. The present study aimed to test the hypothesis that these mice with an insulin resistant phenotype might display microvascular dysfunction in both coronary and renal vascular beds.. In this study we used non-invasive Doppler ultrasound imaging to characterize microvascular dysfunction during the progression of diabetes in ob/ob mice. Impaired coronary flow velocity reserve was observed in the ob/ob mice at 16 and 21 weeks of age compared to lean controls. In addition, renal resistivity index as well as pulsatility index was higher in the ob/ob mice at 21 weeks compared to lean controls. Moreover, plasma L-arginine was lower in ob/ob mice, while asymmetric dimethylarginine was unaltered. Furthermore, a decrease in renal vascular density was observed in the ob/ob mice.. In parallel to previously described metabolic disturbances, the leptin-deficient ob/ob mice also display cardiac and renal microvascular dysfunction. This model may therefore be suitable for translational, mechanistic and interventional studies to improve the understanding of microvascular complications in type 2 diabetes.

Topics: Animals; Coronary Circulation; Diabetes Mellitus, Type 2; Laser-Doppler Flowmetry; Leptin; Male; Mice; Renal Circulation; Ultrasonography

Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women.. We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates.. DM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p < 0.0001). Leptin was positively associated with birth weight (p = 0.0007) and SSF (p = 0.002) in Con-O and with maternal hemoglobin A1c in both groups (Con-O, p = 0.023; DM-O, p = 0.006). PEDF was positively associated with birth weight in all infants (p = 0.004). Leptin was positively associated with PEDF in both groups, with a stronger correlation in DM-O (p = 0.009). At 1-month, HMWA was positively associated with body weight (p = 0.004), SSF (p = 0.025) and % body fat (p = 0.004) across the cohort.. Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth.

Topics: Adiponectin; Adult; Birth Weight; Body Composition; Child Development; Child of Impaired Parents; Diabetes Mellitus, Type 2; Female; Fetal Blood; Hispanic or Latino; Humans; Indians, North American; Infant; Infant, Newborn; Leptin; Pregnancy; Prospective Studies; Young Adult

We have previously found that fasting plasma levels of totally assessed 10- and 12-(Z,E)-hydroxyoctadecadienoic acid (HODE) correlated well with levels of glycated hemoglobin (HbA1c) and glucose during oral glucose tolerance tests (OGTT); these levels were determined via liquid chromatography-mass spectrometry after reduction and saponification. However, 10- and 12-(Z,E)-HODE alone cannot perfectly detect early impaired glucose tolerance (IGT) and/or insulin resistance, which ultimately lead to diabetes. In this study, we randomly recruited healthy volunteers (n = 57) who had no known history of any diseases, and who were evaluated using the OGTT, the HODE biomarkers, and several additional proposed biomarkers, including retinol binding protein 4 (RBP4), adiponectin, leptin, insulin, glycoalbumin, and high sensitivity-C-reactive protein. The OGTT revealed that our volunteers included normal individuals (n = 44; Group N), "high-normal" individuals (fasting plasma glucose 100-109 mg/dL) with IGT (n = 11; Group HN+IGT), and diabetic individuals (n = 2; Group D). We then used these groups to evaluate the potential biomarkers for the early detection of type 2 diabetes. Plasma levels of RBP4 and glycoalbumin were higher in Group HN+IGT, compared to those in Group N, and fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids were significantly correlated with levels of RBP4 (p = 0.003, r = 0.380) and glycoalbumin (p = 0.006, r = 0.316). Furthermore, we developed a stepwise multiple linear regression models to predict the individuals' insulin resistance index (the Matsuda Index 3). Fasting plasma levels of 10- and 12-(Z,E)-HODE/linoleic acids, glucose, insulin, and leptin/adiponectin were selected as the explanatory variables for the models. The risks of type 2 diabetes, early IGT, and insulin resistance were perfectly predicted by comparing fasting glucose levels to the estimated Matsuda Index 3 (fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids, insulin, and leptin/adiponectin).

Topics: Adiponectin; Adult; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Leptin; Linoleic Acids; Male; Middle Aged; Retinol-Binding Proteins, Plasma

Adiposity is an inflammatory condition contributing to the morbidity and mortality of several disorders, including type 2 diabetes mellitus (T2D) and cardiovascular disease.. To compare cardiometabolic risk factors between obese and non-obese Thai patients with T2DM MATERIAL AND METHOD: The cross-sectional study was done in 20 obese (BM >25 kg/m2) and 20 non-obese (BMI 23 kg/m2) T2DM Researchers measured fasting plasma glucose and lipids, serum levels of insulin, leptin, adiponectin, and soluble tumor necrosis factor-alpha receptors type 1 and 2 (sTNF-R] andsTNF-R2). Insulin sensitivity check index (QUICIKI) and insulin resistance index (HOMA-IR) were calculated.. Thai obese adults with T2DMhad greater amounts ofsTNF-R2 and HOMA-IR, higher ratios of leptin/adiponectin, and more incidences of hypertension and hypertriglyceridemia in comparison to non-obese counterparts. Additionally, HOMA-IR values in non-obese T2DMwere greater than those reported among non-diabetic Thai adults. A reverse association between inflammatory markers (both sTNF-Rs) andHDLC was detected. Leptin/adiponectin ratios correlated directly with HOMA-IR, serum insulin, plasma triglycerides and BMI, whereas HOMA-IR did not relate to any studied plasma lipid.. The present study demonstrated an increased cardiometabolic risk in obese T2DM adults than non-obese T2DM adults among the Thai population. The leptin/adiponectin ratio may be more relevant to predict the risk of cardiovascular events in T2DMpatients than HOMA-IR.

Topics: Adiponectin; Adiposity; Adult; Aged; Asian People; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Risk Factors; Triglycerides

There is mounting evidence demonstrating causative links between hyperglycemia, oxidative stress, and insulin resistance, the core pathophysiological features of type 2 diabetes mellitus. Using a combinational approach, we synthesized a vanadium-antioxidant (i.e., l-ascorbic acid) complex and examined its effect on insulin resistance and oxidative stress. This study was designed to examine whether vanadyl(IV)-ascorbate complex (VOAsc) would reduce oxidative stress, hyperglycemia, and insulin resistance in high-fat high-sucrose diet (HFSD)-induced type 2 diabetes in mice. Male C57BL/6J mice were fed a HFSD for 12 weeks to induce insulin resistance, rendering them diabetic. Diabetic mice were treated with rosiglitazone, sodium l-ascorbate, or VOAsc. At the end of treatment, fasting blood glucose, fasting serum insulin, homeostasis model assessment-insulin resistance index, and serum adipocytokine levels were measured. Serum levels of nitric oxide (NO) parameters were also determined. The liver was isolated and used for determination of malondialdehyde, reduced glutathione, and catalase levels, and superoxide dismutase and glutathione peroxidase activities. VOAsc groups exhibited significant reductions in serum adipocytokine and NO levels, and oxidative stress parameters compared to the corresponding values in the untreated diabetic mice. The results indicated that VOAsc is non-toxic. In conclusion, we identified VOAsc as a potentially effective adjunct therapy for the management of type 2 diabetes.

Topics: Adiponectin; Adipose Tissue; Animals; Ascorbic Acid; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Feeding Behavior; Glucose Tolerance Test; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Liver; Male; Malondialdehyde; Mice, Inbred C57BL; Nitric Oxide; Organ Size; Oxidative Stress; Resistin; Sucrose; Tumor Necrosis Factor-alpha; Vanadates

It has been shown that visceral fat accumulation is associated with autonomic dysfunction, though the precise mechanism remains unclear. A recent basic study found that leptin can directly modulate autonomic function through the dorsomedial hypothalamus in relation to obesity. Here, we investigated the mutual relationships among plasma leptin, visceral fat accumulation, and cardiac autonomic dysfunction in patients with type 2 diabetes.. This cross-sectional study included 100 diabetic patients, and 100 age- and gender-matched non-diabetic patients with cardiovascular risk factors. Plasma leptin and soluble leptin receptor levels, visceral fat area (VFA), and heart rate variability (HRV) were determined in addition to classical cardiovascular risk factors.. In the type 2 diabetic patients, VFA was significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.238), while the plasma level of leptin, but not soluble leptin receptor, was also significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.231). Multiple regression analysis showed that plasma leptin was significantly associated with SDNN and SDANN5 independent of other factors, including age, gender, presence of hypertension and dyslipidemia, duration of diabetes, HbA1c, and eGFR. Furthermore, the relationship of leptin with SDNN and SDANN5 (β = -0.279 and -0.254, respectively) remained significant (p < 0.05) after adjustment for VFA. In patients without diabetes, no significant associations were observed between leptin and any of the HRV parameters.. Hyperleptinemia may be involved in cardiac autonomic dysfunction in patients with type 2 diabetes and visceral obesity.

Topics: Adiposity; Aged; Autonomic Nervous System; Biomarkers; Case-Control Studies; Chi-Square Distribution; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Heart; Heart Diseases; Heart Rate; Humans; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Multivariate Analysis; Obesity; Receptors, Leptin; Risk Factors; Up-Regulation

Obesity and diabetes mellitus type 2 (DM2) frequently coexist and increase the propensity of cardiovascular dysfunction by numerous mechanisms. Chief among them are oxidative stress and Ca(2+) dysregulation, and both are inducers of the mitochondrial permeability transition pore (MPTP). Nevertheless, it is unknown whether MPTP formation is triggered in DM2 animals, and thereby contributing to cardiac dysfunction. We assessed MPTP sensitivity and reactive oxygen species production in cardiac mitochondria, as well as cytosolic Ca(2+) handling in ventricular myocytes from rats with DM2.. Male Zucker Fa/fa rats (Fa/fa) 32weeks old presenting DM2, concentric hypertrophy, and diastolic dysfunction were used. MPTP formation was evaluated in isolated mitochondria and Ca(2+) handling in ventricular myocytes, by spectrophotometric and confocal microscope techniques, respectively.. We found that the systolic Ca(2+) transient relaxation was ~40% slower, while mitochondrial H2O2 production increased by ~6-fold. MPTP opening in isolated mitochondria from Fa/fa (mFa/fa) was more sensitive to Ca(2+) than in mitochondria from lean rats (mLean), and correlated with increased thiol group exposure. The mFa/fa showed decreased oxidative phosphorylation capacity. The ATP content decreased in myocytes, while the PCr/ATP ratio remained unchanged and caspase 9 activity largely increased in myocytes from Fa/fa animals.. Our results showed that oxidative stress and diastolic Ca(2+) dysregulation increased MPTP sensitivity leading to mitochondrial dysfunction and apoptosis. Mitochondrial dysfunction could compromise ATP synthesis, and lower ATP could be linked to decreased SERCA2 activity, which might underlie diastolic dysfunction. Prolonged Ca(2+) transients might further exacerbate mitochondrial dysfunction.

Topics: Animals; Atractyloside; Calcium Signaling; Diabetes Mellitus, Type 2; Heart Diseases; Leptin; Lipids; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Mitochondrial ADP, ATP Translocases; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocytes, Cardiac; Oxidative Stress; Oxygen Consumption; Permeability; Rats; Rats, Zucker; Ultrasonography

The present study was motivated by the lack of data on the role ofvariations in the levels of leptin and its soluble receptors and their interaction with proinflammatory factors in the development of acute coronary syndrome. The study included patients suffering myocardial infarction with and without type 2 diabetes mellitus. Hyperleptinemia and its relationship with myocardial necrosis markers (creatine phosphokinase, creatine phosphokinase-MB, troponin) give reason to suggest the important role of leptin in the development of inflammatory process associated with myocardial infarction in patients with and without diabetes mellitus. The results of the study provide a basis for the elaboration of a new therapeutic strategy for the correction of metabolic disorders in patients with acute coronary syndrome.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Myocardial Infarction; Receptors, Leptin

Diabetic trauma patients exhibit delayed postsurgical wound, bony healing, and dysregulated bone development. However, the impact of diabetes on the pathologic development of ectopic bone or heterotopic ossification (HO) following trauma is unknown. In this study, we use leptin-deficient mice as a model for type 2 diabetes to understand how post-traumatic HO development may be affected by this disease process. Male leptin-deficient (ob/ob) or wild-type (C57BL/6 background) mice aged 6-8 weeks underwent 30% total body surface area burn injury with left hind limb Achilles tenotomy. Micro-CT (μCT) imaging showed significantly lower HO volumes in diabetic mice compared with wild-type controls (0.70 vs. 7.02 mm(3), P < 0.01) 9 weeks after trauma. Ob/ob mice showed evidence of HO resorption between weeks 5 and 9. Quantitative real time PCR (qRT-PCR) demonstrated high Vegfa levels in ob/ob mice, which was followed by disorganized vessel growth at 7 weeks. We noted diminished chondrogenic gene expression (SOX9) and diminished cartilage formation at 5 days and 3 weeks, respectively. Tartrate-resistant acid phosphatase stain showed increased osteoclast presence in normal native bone and pathologic ectopic bone in ob/ob mice. Our findings suggest that early diminished HO in ob/ob mice is related to diminished chondrogenic differentiation, while later bone resorption is related to osteoclast presence.

Topics: Animals; Cartilage; Cells, Cultured; Chondrogenesis; Diabetes Mellitus, Type 2; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Ossification, Heterotopic; Osteoblasts; Osteogenesis; SOX9 Transcription Factor

Scavenger receptor, class B type I (SR-BI) is a physiologically relevant regulator of high density lipoprotein (HDL) metabolism. Low HDL is a common feature of patients with non-alcoholic fatty liver disease (NAFLD). Here, hepatic SR-BI expression was analyzed in human and murine NAFLD. In primary human hepatocytes NAFLD relevant factors like inflammatory cytokines, lipopolysaccharide and TGF-β did not affect SR-BI protein. Similarly, oleate and palmitate had no effect. The adipokines chemerin, adiponectin, leptin and omentin did not regulate SR-BI expression. Accordingly, hepatic SR-BI was not changed in human and murine fatty liver and non-alcoholic steatohepatits. SR-BI was higher in type 2 diabetes patients but not in those with hypercholesterolemia. The current study indicates a minor if any role of SR-BI in human and murine NAFLD.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Animals; Chemokines; Cytokines; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; GPI-Linked Proteins; Hepatocytes; Humans; Intercellular Signaling Peptides and Proteins; Lectins; Leptin; Lipopolysaccharides; Lipoproteins, HDL; Liver; Male; Mice; Middle Aged; Non-alcoholic Fatty Liver Disease; Oleic Acid; Palmitic Acid; Primary Cell Culture; Scavenger Receptors, Class B; Signal Transduction; Transforming Growth Factor beta

Diabetic cardiomyopathy (DCM) is one of the most severe complications of diabetes without a clear pathogenesis. Th is study investigated the adiponectin (APN) and leptin levels in type II DCM, as well as their correlation with advanced glycation end-products (AGEs). From 2011-2013, 78 type II diabetes mellitus (T2DM) cases (40-65 years old) in the Taian region were randomly selected. Based on the results of colour Doppler ultrasonography and coronary angiography, the cases were divided into a simple T2DM group (40 cases) and a DCM group (38 cases). Forty healthy subjects were used as normal control (NC). An enzyme-linked immunosorbent assay was performed to determine the levels of fa tty inflammatory factors such as APN, leptin and AGEs, and a correlation analysis was conducted. In the T2DM group, the APN levels were decreased but the leptin and AGE levels were significantly increased compared to the NC group. In the DCM group, the APN levels were decreased but the leptin and AGE levels were significantly increased (P<0.01) compared to the T2DM group. Th e AGE levels were positively correlated with disease progression and with fasting plasma glucose levels, glycated haemoglobin, insulin resistance and leptin, but were negatively correlated with APN levels. Additionally, the APN and leptin levels were independently related to the AGE levels. Fatty inflammatory factors play a significant role in the progression of both simple T2DM and DCM. Th e results of this study revealed the pathogenesis of DCM and indicated the potential significance of AGEs in DCM prevention and treatment.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Progression; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Inflammation Mediators; Insulin Resistance; Leptin; Male; Middle Aged

Approximately 5-10% of subjects with pre-diabetes eventually progress to diabetes every year. While inflammation is thought to be involved in the development of obesity-related type 2 diabetes mellitus (T2DM), the relation between inflammation and pre-diabetes remains largely unexplored. In this study we examined a comprehensive panel of 10 serum biomarkers involved in overweight and obese subjects with pre-diabetes. A total of 98 subjects (23 males, 75 females) were advised to reduce total intake of fat, increase fiber intake and physical activity. Serum cytokines, MCP and other hormones were assessed by multiplex cytokine profiling. Results show that CRP, IL-6, leptin, IL-10, MCP, resistin, serpin, and TNF-α were significantly lower after 12-months than baseline. Serum concentrations of other adipocytokines, including adipsin and leptin were modestly lower in the 12-month follow-up than baseline, but failed to reach statistical significance. Changes in HbA1c was found to be positively correlated with adipsin, CRP, IL-6, IL-10, resistin, serpin, and TNF-α. The results suggest that promotion of lifestyle changes for one year among overweight and obese subjects modestly changes several circulating inflammatory biomarkers which maybe favorable in reducing risk for T2DM progression.

Topics: Adipokines; Adult; Biomarkers; Chemokines; Cytokines; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Inflammation; Leptin; Male; Middle Aged; Obesity; Overweight; Prospective Studies; Saudi Arabia

Previous investigations provide evidence of an association of hypogonadism with type 2 diabetes in men, and low testosterone levels have been regarded a risk factor for the disease. Since a strong genetic predisposition to type 2 diabetes has been demonstrated, here we investigate a possible tendency towards hypogonadism in young male offspring of diabetic parents.. The study compares 32 male offspring of diabetic parents with 31 male offspring of nondiabetic parents matched by age. The subjects comprised boys (9-17 years) and young adults (19-25 years). Anthropomorphic measurements were made in all subjects. Fasting blood samples were analyzed for glucose and serum concentrations of testosterone (T), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), insulin and leptin were measured by ELISA. Free testosterone (FT) was calculated using T and SHBG levels.. Serum T, FT and bioavailable T (BAT) levels in offspring of diabetic parents were significantly lower than those of offspring of nondiabetic parents across all age groups. Mean serum LH levels were also lower in offspring of diabetic parents compared to the controls. Although LH levels in young adults with diabetic parents, tended to be lower than those of age-matched controls but the difference was not statistically significant. Serum insulin and leptin, and insulin resistance measured by HOMA-IR were significantly raised in older offspring of diabetic parents but were within the normal range.. Whereas hypogonadism was the only indicator of a possible predisposition to metabolic dysfunction in peripubertal children of diabetic parents, a significant change in other metabolic markers becomes apparent at a more advanced age.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Body Weight; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Eunuchism; Family; Fasting; Humans; Insulin; Insulin Resistance; Leptin; Luteinizing Hormone; Male; Prospective Studies; Risk Factors; Sex Hormone-Binding Globulin; Testosterone; Young Adult

Clinical practice shows that thiazolidinediones (TZDs) induce weight gain in patients with type-II diabetes mellitus during treatment, which restrains its application and generalization clinically. It has been demonstrated that acupuncture therapy is useful in easing obesity in clinical trials. In the present paper, we summarize the underlying mechanism of weight gain induced by TZDs through food intake-related targets in the central nervous system and analyze the possible effects of acupuncture therapy. Acupuncture therapy is expected to reduce weight gain side effect of TZDs through 1) lowering permeability of blood brain barrier to reduce TZDs concentration in the brain, 2) upregulating the expression of hypothalamic leptin and inhibiting hypothalamic neuropiptide Y expression, and 3) down-regulating activities of peroxisome proliferator-activated receptor to reduce energy intake and fat syntheses.

Topics: Acupuncture Therapy; Animals; Central Nervous System; Diabetes Mellitus, Type 2; Eating; Humans; Hypoglycemic Agents; Leptin; Peroxisome Proliferator-Activated Receptors; Thiazolidinediones; Weight Gain

The aim of this study was to investigate the association between glycemic control in Type 2 diabetes mellitus patients and common genetic variants of ADIPQO gene. A total of 427 Type 2 diabetes patients were recruited in the study and divided into two groups: 172 patients with good glycemic control and 249 with poor glycemic control. Genotyping of C11377G, G276T and T45G ADIPQO SNPs were carried out using restriction fragment length polymorphisms-polymerase chain reaction. The results showed that C11377G ADIPQO SNP is strongly associated with glycemic control in Type 2 diabetes patients. Patients with the GG genotype at adiponectin C11377G had better glycemic control than those with CC or CG genotypes. However, other examined SNPs were not correlated with glycemic control in Type 2 diabetes patients. Other parameters that impacted glycemic control include duration of the disease (p < 0.01), use of insulin therapy (p < 0.01) and presence of neuropathy complications (p < 0.01). However, no contribution was observed for gender, statin use, lipid profile and other oral medications to glycemic control (p > 0.05). Glycemic control among Type 2 diabetes patients might be affected by variants in ADIPQO gene.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Treatment Outcome

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

Topics: Diabetes Mellitus, Type 2; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genome, Human; Guanine Nucleotide Dissociation Inhibitors; Haplotypes; Humans; Leptin; MicroRNAs; Monocarboxylic Acid Transporters; Polymorphism, Single Nucleotide

Leptin's in vivo effect on the rodent skeleton depends on the model used and the mode of administration. Superactive mouse leptin antagonist (SMLA) was produced and then pegylated (PEG) to prolong and enhance its in vivo activity. We blocked leptin signaling by injecting this antagonist peripherally into normal mice at various time points and studied their metabolic and skeletal phenotypes. Subcutaneous PEG-SMLA injections into 4-wk-old female C57BL/6J mice increased weight gain and food consumption significantly after only 1 mo, and the effect lasted for the 3 mo of the experiment, proving its central inhibiting activity. Mice showed a significant increase in serum glucose, cholesterol, triglycerides, insulin, and HOMA-IR throughout the experiment. Quantification of gene expression in "metabolic" tissues also indicated the development of insulin resistance. Bone analyses revealed a significant increase in trabecular and cortical parameters measured in both the lumbar vertebrae and tibiae in PEG-SMLA-treated mice in the 1st and 3rd months as well as a significant increase in tibia biomechanical parameters. Interestingly, 30 days of treatment with the antagonist in older mice (aged 3 and 6 mo) affected body weight and eating behavior, just as they had in the 1-mo-old mice, but had no effect on bone parameters, suggesting that leptin's effect on bones, either directly or through its obesogenic effect, is dependent upon stage of skeletal development. This potent and reversible antagonist enabled us to study leptin's in vivo role in whole body and bone metabolism and holds potential for future therapeutic use in diseases involving leptin signaling.

Topics: Animals; Biomechanical Phenomena; Blood Glucose; Body Weight; Bone and Bones; Cholesterol; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Female; Gene Expression; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Metabolism; Mice; Mice, Inbred C57BL; Triglycerides

The link between diabetic retinopathy (DR) and adipokines is controversial. Some studies suggest that visceral fat and adipokines could be additional risk factors for DR. The aim of this study was to determine the relationship between abdominal fat or adipokine secretion and DR in patients with type 2 diabetes mellitus (DM).. A total of 179 patients with type 2 DM were included. Each patient underwent measurement of plasma adiponectin and leptin and an evaluation of body fat distribution (visceral and subcutaneous) with MRI. The severity of DR was evaluated according to the classification of the American Academy of Ophthalmology. Patients were classified in 3 groups: absence of DR, mild and moderate DR, and advanced DR (severe, proliferative and laser-treated DR).. There were no significant differences between the 3 groups for adiponectin, leptin and visceral or subcutaneous fat accumulation. Patients with DR had a mean duration of diabetes, serum creatinine concentration and percentage of macroalbuminuria significantly higher than patients without DR (p < 0.001, p = 0.003 and p < 0.001, respectively). Serum adiponectin increased with the diabetic nephropathy stage (p = 0.007).. Our study suggests that body fat distribution and adipokine secretion are not associated with DR in patients with type 2 DM.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Albuminuria; Body Fat Distribution; Creatinine; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Humans; Leptin; Magnetic Resonance Imaging; Male; Middle Aged

Research on the characteristics and mechanisms of diabetes in Tibetans is scant. Especially, there is no study on the relationship between osteocalcin and glucose metabolism. The objective of this study was to investigate the associations of serum total osteocalcin (tOC) and undercarboxylated osteocalcin (ucOC) with glucose and lipid metabolism in Chinese indigenous Tibetans with different degrees of glucose tolerance.. In this study, 160 middle-aged Tibetan men were involved, including 46 subjects with normal glucose tolerance (NGT), 52 subjects with impaired glucose regulation (IGR) and 62 subjects with type 2 diabetes. The homeostasis model assessment (HOMA) parameters, including HOMA-IR and HOMA-B, were used to estimate insulin resistance and β-cell function, respectively. Adiponectin, leptin, testosterone, 1,25-dihydroxyvitamin D, tOC and ucOC were measured using ELISA kits.. After adjustment for age and body mass index, plasma tOC level was correlated negatively with fasting and 30-min post-OGTT glucose, HOMA-IR, leptin and testosterone; plasma ucOC level was correlated negatively with 30-min post-OGTT glucose, total cholesterol and 1,25-dihydroxyvitamin D; ucOC : tOC was correlated positively with leptin. The negative association between HOMA-IR and tOC remained significant after correcting for adiponectin; however, the association disappeared after correcting for leptin. HOMA-IR was correlated negatively with age, adiponectin and tOC, and positively with total cholesterol, triglyceride and leptin. Stepwise linear regression analysis revealed that total cholesterol, leptin and adiponectin were independent predictors for HOMA-IR in all subjects.. Our data support a link between osteocalcin and glucose metabolism in middle-aged Tibetan men. The improved glucose tolerance exerted by tOC may be related to improved insulin sensitivity rather than improved β-cell function.

Topics: Adiponectin; Adult; Blood Glucose; Calcitriol; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Down-Regulation; Glucose Intolerance; Hospitals, University; Humans; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Osteocalcin; Protein Processing, Post-Translational; Testosterone; Tibet

The adipocyte-derived hormone leptin plays a key role in the regulation of appetite and body weight. Recent studies have suggested that leptin is also involved in the pathogenesis of obesity-related atherosclerosis and cardiovascular disease. In this study, we investigated the association of plasma leptin levels with vascular endothelial function in lean and overweight patients with type 2 diabetes.. One hundred seventy-one type 2 diabetic patients, of which 85 were overweight (body mass index (BMI) ≥ 25 kg/m2), were enrolled in this cross-sectional study. Plasma leptin concentrations were measured by enzyme-linked immunosorbent assay. Flow-mediated dilatation (FMD) of the brachial artery was measured to evaluate vascular endothelial function using ultrasound.. No significant difference in FMD was found between the lean and overweight groups (7.0 ± 3.8% and 6.5 ± 3.6%, respectively; p = 0.354). FMD was negatively correlated with age (r = -0.371, p < 0.001) and serum creatinine levels (r = -0.236, p = 0.030), but positively correlated with BMI (r = 0.330, p = 0.002) and plasma leptin levels (r = 0.290, p = 0.007) in the overweight group. FMD was not associated with any parameters in the lean group. Multiple regression analysis including possible atherosclerotic risk factors revealed that the plasma leptin level (β = 0.427, p = 0.013) was independently associated with FMD in the overweight group (R2 = 0.310, p = 0.025), but not the lean group.. Plasma leptin levels are associated with vascular endothelial function in overweight patients with type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Flow Velocity; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Leptin; Male; Middle Aged; Overweight

Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.

Topics: AMP-Activated Protein Kinases; Animals; Blood Glucose; Blotting, Western; Body Weight; Cell Respiration; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Fatty Acids; HSP72 Heat-Shock Proteins; Insulin Resistance; Leptin; Male; Mice; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Peroxisome Proliferator-Activated Receptors; Rats; Real-Time Polymerase Chain Reaction; Sirtuin 1

Type 2 diabetes (T2D) is a major risk factor for late-onset Alzheimer's disease (AD). A variety of metabolic changes related to T2D (e.g. hyperinsulinemia, hyperglycemia, and elevated branched-chain amino acids) have been proposed as mechanistic links, but the basis for this association remains unknown. Retromer-dependent trafficking is implicated in the pathogenesis of AD, and two key retromer proteins, VPS35 and VPS26, are deficient in the hippocampal formation of AD patients. We characterized VPS35 levels in five different mouse models of T2D/obesity to identify specific metabolic factors that could affect retromer levels in the brain. Mouse models in which hyperleucinemia was present displayed hippocampus-selective retromer deficiency. Wild-type lean mice fed a high leucine diet also developed hippocampal-selective retromer deficiency, and neuronal-like cells grown in high ambient leucine had reduced retromer complex proteins. Our results suggest that hyperleucinemia may account, in part, for the association of insulin resistance/T2D with AD.

Topics: Alzheimer Disease; Analysis of Variance; Animals; Cell Line, Tumor; Diabetes Mellitus, Type 2; Disease Progression; Enzyme-Linked Immunosorbent Assay; Glucose Tolerance Test; Hippocampus; Humans; Leptin; Leucine; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; Vesicular Transport Proteins

The pathogenesis of diabetic retinopathy (DR) in metabolic syndrome (MetS) and type 2 diabetes (T2D) is not well studied, partly because an appropriate model has not been developed. Recently, we introduced a novel model of spontaneous T2D and MetS that replicates the relevant features of the human disease. In the current study, we investigated the retinal vascular changes in these animals. Experimental DR in streptozotocin (STZ)-injected rodents is described as an inflammatory disease, in which intercellular adhesion molecule 1 (ICAM-1) plays a key role. In comparison, advanced diabetes (HbA1c>10%) in the Nile grass rat (NGR) was associated with lower ICAM-1 protein expression when compared with that in normal or moderately diabetic animals. Vascular cell adhesion molecule 1 (VCAM-1) expression, however, was unaffected by the disease state. As opposed to the STZ-induced model of DR, in diabetic NGRs, most leukocytes accumulated in the retinal arteries. Consistent with the ICAM-1 reduction, leukocyte accumulation was significantly reduced in advanced disease. Similarly, leukocyte adhesions were significantly lower, with elevated plasma triglycerides (>200 mg/dl), and cholesterol (>240 mg/dl). However, these adhesions were significantly higher in animals with higher plasma insulin (>5 μIU/ml) and leptin (>20 ng/ml), suggesting a role for these hormones in diabetic retinal leukostasis. Diabetic NGRs showed substantial retinal endothelial injury, primarily in the microvessels, including vascular tortuosity, obliterated acellular capillaries, and pericyte ghosts. The NGR provides a convenient and realistic model for investigation of retinal changes in MetS/T2D with convincing advantages over the commonly used STZ-induced T1D.

Topics: Adiponectin; Animals; Blood-Retinal Barrier; Cell Adhesion; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Female; Glycated Hemoglobin; Inflammation; Insulin; Intercellular Adhesion Molecule-1; Leptin; Leukocytes; Lipids; Male; Metabolic Syndrome; Rats; Retina; Retinal Vessels; Streptozocin; Triglycerides; Vascular Cell Adhesion Molecule-1

Resistin was originally identified as an adipocyte-derived factor upregulated during obesity and as a contributor to obesity-associated insulin resistance. Clinically, resistin has also been implicated in cardiovascular disease in a number of different patient populations. Our aim was to simultaneously address these phenomena.. We generated mice with modest adipocyte-specific resistin overexpression. These mice were crossed with mice deficient in the LDL receptor (Ldlr (-/-)) to probe the physiological role of resistin. Both metabolic and atherosclerotic assessments were performed.. Resistin overexpression led to increased atherosclerotic progression in Ldlr (-/-) mice. This was in part related to elevated serum triacylglycerol levels and a reduced ability to clear triacylglycerol upon a challenge. Additional phenotypic changes, such as increased body weight and reduced glucose clearance, independent of the Ldlr (-/-) background, confirmed increased adiposity associated with a more pronounced insulin resistance. A hallmark of elevated resistin was the disproportionate increase in circulating leptin levels. These mice thus recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. A unifying mechanism for this complex phenotype was a resistin-mediated central leptin resistance, which we demonstrate directly both in vivo and in organotypic brain slices. In line with reduced sympathetic nervous system outflow, we found decreased brown adipose tissue (BAT) activity. The resulting elevated triacylglycerol levels provide a likely explanation for accelerated atherosclerosis.. Resistin overexpression leads to a complex metabolic phenotype driven by resistin-mediated central leptin resistance and reduced BAT activity. Hypothalamic leptin resistance thus provides a unifying mechanism for both resistin-mediated insulin resistance and enhanced atherosclerosis.

Topics: Adipose Tissue; Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Female; Insulin Resistance; Leptin; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Obesity; Receptors, LDL; Resistin; Triglycerides

This study aimed to analyse the impact of obesity in type 2 diabetes (T2D) on adipocytokines (adiponectin, leptin and resistin) and inflammatory markers (TNF-α, IL-6 and hsCRP) as cardiovascular risk factors. A cross-sectional study comparing the basal levels of adipocytokines and inflammatory markers was done in 18 obese (BMI ≥ 30 kg/m²) (group A), 21 overweight (25 kg/m² ≤ BMI < 30 kg/m²) (group B), 25 non-obese T2D patients (group C) and 15 non-obese controls (group D). The lowest levels of adiponectin and the highest levels of leptin, resistin, TNF-α, IL-6 and hsCRP were found in group A. Adiponectin levels were significantly lower, and resistin, TNF-α, and hsCRP levels were elevated in group C vs. D. However, leptin and IL-6 levels differed significantly between groups A and B, but not between groups C and D. Moreover, we found a significant negative correlation between adiponectin and TNF-α, but not with other markers, which was independent of the presence of obesity. In contrast, leptin and resistin correlated with the inflammatory markers, and this correlation was obesity-dependent. Our results suggest that obesity influences cardiovascular risk primarily through changes in leptin and resistin and less efficiently at the level of adiponectin.

Topics: Adiponectin; Adult; Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Resistin; Risk Factors; Tumor Necrosis Factor-alpha

To explore the mechanism of Panax notoginseng saponins (PNS) on diabetes treatment and mass loss in KK-Ay mice with genetic type 2 diabetes mellitus (DM), and to identify the main hypoglycemic ingredients.. C57 and KK-Ay DM mice were divided into eight groups each comprising six mice: healthy normal, DM model, and DM model treated with PNS (200 mg/kg body mass), ginsenoside Re (Re, 14 mg/kg body mass), ginsenoside Rd (Rd, 15 mg/kg body mass), ginsenoside Rgl (Rg1, 40 mg/kg body mass), ginsenoside Rb1 (Rb1, 60 mg/kg body mass) and notoginsenoside R1 (R1, 6 mg/kg body mass). The PNS were intraperitoneal injection administered for 30 d, while the Re, RB1, Rg1, Rd and Re were intraperitoneal injection administered for 12 d. The fasting blood sugar (FBG), glucose tolerance (GT), serum insulin, leptin, body weight, food consumption, and levels of adipose tissue and blood lipid were determined.. On 12 d, lower FBG levels were found in the PNS and Rb1 treated mice compared with the model mice (P < 0.05). No statistical differences in FBG levels were found between the rest of the treatment groups and the model group (P > 0.05). After 30 d continuous administration of PNS, the FBG level of the mice further declined (P < 0.01). Meanwhile, the serum insulin (P < 0.05) and insulin resistance index (P < 0.01) of the PNS treated mice also declined significantly. Compared with model group, the PNS group had lower levels of body weight growth, food consumption, adipose tissue, and leptin (P < 0.05). Lower FBG level was also found in Rb1 treated mice (12 d of administration), P < 0.05.. PNS has anti-hyperglycemic and anti-obesity activities by improving insulin and leptin sensitivities in KK-Ay mice. Rb1 may be the hypoglycemic ingredient in the PNS extract.

Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Ginsenosides; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Mice; Mice, Inbred C57BL; Obesity; Panax notoginseng; Saponins

The role of leptin has been more clear in the endocrinology area after the discovery of its secretion from the adipose tissue. The aim of the study is to investigate the leptin levels in obese women in whom type 2 diabetes mellitus were present or absent.. Fifty obese women with type 2 diabetes mellitus (group 1) and another 50 obese women without type 2 diabetes mellitus (group 2) were enrolled in the study. In both groups the body mass index (BMI), waist circumference, and waist-to-hip ratio were measured. Leptin, HbA1c, creatinine and the lipid profile were assessed.. Leptin was found to be statistically significantly lower in group 1 than in group 2 (38.79 ± 18.75 ng/ml versus 52.45 ± 16.89 ng/ml, respectively; P=0.017). In group 1, correlation of leptin was moderate with creatinine and high-density lipoprotein-cholesterol (r=0.46, p = 0.039 versus r=0.47, p=0.028, respectively), whereas triglyceride had a negative correlation (r= -0.35, p=0.047). In group 2, the only significant correlation with leptin was BMI (r=0.41, p=0.02). Leptin was also significantly lower in 24 patients with poorly controlled diabetes mellitus patients than in 26 well-controlled diabetics (35.45 ± 14.92 ng/ml versus 45.72 ± 16.69 ng/ml, respectively; p=0.029).. Since leptin is lower in obese women with diabetes than without diabetes and additionally it is even lower in the poorly controlled diabetes subgroup, we think that further studies are required to make clear the issue for lower leptin levels, whether it is a reason or an outcome.

Topics: Adult; Body Mass Index; Creatinine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Leptin; Lipids; Middle Aged; Obesity; Sampling Studies; Waist Circumference; Waist-Hip Ratio

The present study deals with the synthesis, characterization of zinc-morin complex and evaluation of its antidiabetic efficacy in High Fat Diet (HFD)-fedStreptozotocin (STZ) induced diabetic rats. Oral administration of zinc-morin complex to diabetic rats (5mg/kg body weight/day) for a period of 30 days resulted in the decreased levels of blood glucose and HbA1c. Oral administrations of the zinc-morin complex for 30 days significantly improved hyperglycemia, glucose intolerance, and insulin resistance. The elevated levels of lipid peroxides declined and the antioxidant competence was found to be improved in diabetic rats treated with the complex. The status of the lipid and lipoprotein profile in the serum was normalized upon treatment. Levels of TNFα decreased upon treatment with the complex. The altered levels of adipokines such as adiponectin and leptin were normalized upon treatment with the complex. In conclusion, the present study indicates that the zinc-morin complex possesses antidiabetic, antidyslipidemic and antioxidant potentials in HFD-fedSTZ induced diabetic rats.

Topics: Adiponectin; Animals; Blood Glucose; Coordination Complexes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Flavonoids; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Leptin; Magnetic Resonance Spectroscopy; Male; Random Allocation; Rats, Wistar; Spectroscopy, Fourier Transform Infrared; Tumor Necrosis Factor-alpha; Zinc

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling, which suggests that it is an attractive therapeutic target in type II diabetes and obesity. The aim of this research is to explore residues which interact with phosphotyrosine substrate can be affected by D181 point mutations and lead to increased substrate binding. To achieve this goal, molecular dynamics simulations were performed on wild type (WT) and two mutated PTP1B/substrate complexes. The cross-correlation and principal component analyses show that point mutations can affect the motions of some residues in the active site of PTP1B. Moreover, the hydrogen bond and energy decomposition analyses indicate that apart from residue 181, point mutations have influence on the interactions of substrate with several residues in the active site of PTP1B.

Topics: Binding Sites; Catalytic Domain; Diabetes Mellitus, Type 2; Humans; Hydrogen Bonding; Insulin; Leptin; Molecular Dynamics Simulation; Phosphotyrosine; Point Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Substrate Specificity

Lactation may influence future progression to type 2 diabetes after gestational diabetes mellitus (GDM). However, biomarkers associated with progression to glucose intolerance have not been examined in relation to lactation intensity among postpartum women with previous GDM. This study investigates whether higher lactation intensity is related to more favorable blood lipids, lipoproteins and adipokines after GDM pregnancy independent of obesity, socio-demographics and insulin resistance.. The Study of Women, Infant Feeding, and Type 2 Diabetes (SWIFT) is a prospective cohort study that recruited 1035 women diagnosed with GDM by the 3-h 100g oral glucose tolerance tests (OGTTs) after delivery of a live birth in 2008-2011. Research staff conducted 2-h 75 g OGTTs, and assessed lactation intensity, anthropometry, lifestyle behaviors and socio-demographics at 6-9 weeks postpartum (baseline). We assayed fasting plasma lipids, lipoproteins, non-esterified free fatty acids, leptin and adiponectin from stored samples obtained at 6-9 weeks postpartum in 1007 of the SWIFT participants who were free of diabetes at baseline. Mean biomarker concentrations were compared among lactation intensity groups using multivariable linear regression models.. Increasing lactation intensity showed graded monotonic associations with fully adjusted mean biomarkers: 5%-8% higher high-density lipoprotein cholesterol (HDL-cholesterol), 20%-28% lower fasting triglycerides, 15%-21% lower leptin (all trend P-values < 0.01), and with 6% lower adiponectin, but only after adjustment for insulin resistance (trend P-value = 0.04).. Higher lactation intensity was associated with more favorable biomarkers for type 2 diabetes, except for lower plasma adiponectin, after GDM delivery. Long-term follow-up studies are needed to assess whether these effects of lactation persist to predict progression to glucose intolerance.

Topics: Adiponectin; Adult; Biomarkers; Cohort Studies; Diabetes Mellitus, Type 2; Diabetes, Gestational; Disease Progression; Fatty Acids, Nonesterified; Female; Humans; Insulin Resistance; Lactation; Leptin; Lipids; Lipoproteins; Middle Aged; Postpartum Period; Prediabetic State; Pregnancy; Young Adult

This study investigated the effect of leptin (LEP) 2548A/G and leptin receptor (LEPR) Q223R polymorphisms on the levels of HDL, LDL, TG, and total cholesterol (t-chol). In addition, the interactions between examined polymorphisms, statin therapy and environmental factors on lipid profile were examined.. Adult diabetic patients (n-418) were recruited from diabetes/endocrine clinics in north of Jordan. Lipid profile was measured using standard protocols. Genotyping of LEP 2548A/G and LEPR Q223R polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphisms.. No significant association between LEP 2548A/G and LEPR genotypes and levels of HDL (P = 0.83), LDL (P = 0.40), TG (P = 0.23) and t-chol (P = 0.91). However, in patient on atorvastatin, those with GG or GA genotypes of LEP 2548 experienced significantly higher levels of LDL compared with AA genotype of LEP 2548 (P < 0.002). Patients with dyslipidemia had higher TG in comparison with those without (P < 0.03). Smokers had lower HDL and higher TG levels compared with none smokers or previous smokers (P < 0.002 and P < 0.02, respectively). Female patients tend to have a higher HDL in comparison with male patients (P < 0.05). Patients with HbA1c value greater than or equal to 7 had higher LDL and t-chol compared with patients who had an HbA1c levels of <7 (P < 0.02 and < 0.005, respectively). Patients with disease duration of 5 or more years had a lower HDL compared with those patients with duration of <5 years (P < 0.03).. In conclusion, and although lipid profile regulation is a multifactorial process, -2548G/A LEP polymorphism seems to affect statins treatment response among diabetic patients. More studies are required to specifically define factors that influence lipid profiles interaction with statin treatment response especially among patients with diabetes.

Topics: Atorvastatin; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Gene-Environment Interaction; Genotype; Glycated Hemoglobin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Male; Middle Aged; Polymorphism, Genetic; Pyrroles; Receptors, Leptin; Sex Factors; Triglycerides

Leptin, an adipocytokine produced by adipose tissue, along with the traditional cardiometabolic risk factors, contributes to the development of cardiovascular complications. At the same time, ethnic features of adipocytokines have been insufficiently investigated, especially among Asians, who have an increased risk of cardiovascular complications compared with Europeans. Aim of study was to investigate the relationship between leptin levels and age, gender, anthropometric parameters, lipid parameters, arterial hypertension (AH), and obesity in the adult population of ethnic Kyrgyz people living in Central Asia.. In total, 322 ethnic Kyrgyz (145 men, 177 women) aged ≥ 30 years were studied. Waist and hip circumference, body mass index, blood glucose, lipids, leptin, and homeostatic model assessment were measured. Patients in the upper quartile of leptin levels had high values of BMI, WC, systolic and diastolic blood pressure, glucose, and HOMA index compared with patients with lower leptin levels. The prevalence of metabolic syndrome and AH increased with higher levels of leptin. Leptin positively correlated with BMI, WC, triglycerides, and glucose concentrations in patients of both sexes. According to the multivariate logistic regression analysis, elevated leptin levels increased by 30 times the risk of obesity in men, regardless of the presence of type 2 diabetes, and 17.7 times in women.. Leptin is associated with general and abdominal obesity, dyslipidemia, and insulin resistance in Kyrgyz patients.

Topics: Adipose Tissue; Adult; Blood Glucose; Blood Pressure; Body Composition; Body Mass Index; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Humans; Hypertension; Insulin; Insulin Resistance; Kyrgyzstan; Leptin; Logistic Models; Male; Middle Aged; Obesity; Risk Factors; Triglycerides; Waist Circumference

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin signaling as well as insulin signaling. JTT-551 is a new PTP1B inhibitor, which is reported to improve glucose metabolism by enhancement of insulin signaling. We have evaluated an antiobesity effect of JTT-551 using diet-induced obesity (DIO) mice. A single administration of JTT-551 was provided to DIO mice with or without leptin, and DIO mice were given food containing JTT-551 for six weeks. A single administration of JTT-551 with leptin treatment enhanced the food inhibition and the signal transducer and activator of transcription 3 (STAT3) phosphorylation in hypothalamus. Moreover, chronic administration of JTT-551 showed an antiobesity effect and an improvement of glucose and lipid metabolism in DIO mice. JTT-551 shows an antiobesity effect possibly by enhancement of leptin signaling and could be useful in the treatment of type 2 diabetes and obesity.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Glycine; Hypothalamus; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Signal Transduction; STAT3 Transcription Factor; Thiazoles

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Leptin; Lovastatin; Male

Type 2 Diabetes mellitus (T2DM) is characterized by peripheral insulin resistance, impaired insulin secretion, and reduced β-cell mass. Mechanisms that underlie β-cell failure include glucotoxicity, lipotoxicity, endoplasmic reticulum (ER) stress, and oxidative stress. This study was designed to assess the protective effect of trigonelline and diosgenin against changes in ER stress-associated apoptotic proteins CHOP, Caspase12, and Caspase3 and antioxidant levels in pancreas as well as adipose tissue PPARγ mRNA in T2DM rats. Markers of diabetes and obesity such as serum glucose, insulin, free fatty acid (FFA), TNF-α, IL-6, and leptin were also assessed. T2DM rats showed significantly elevated levels of pancreatic ER stress proteins and lipid peroxidation, while the antioxidants were significantly reduced. Histological examination also confirmed T2DM-associated damage in pancreas. In addition, a significant increase in serum FFA, TNF-α, IL-6, and decrease in leptin levels along with significantly decreased adipose mass and reduced PPARγ expression were observed in T2DM rats. On the other hand, trigonelline and diosgenin treatment independently brought about significant improvement in serum parameters, decrease in apoptotic ER stress proteins, and reinforced antioxidant status in pancreas. Histological examination of pancreas showed normal morphology. Treated groups also showed increased adipose tissue mass and enhanced PPARγ expression. Data from docking studies indicated good interaction of both compounds with PPARγ, and diosgenin showed better binding efficiency. These findings suggest that the insulin-sensitizing effects of trigonelline and diosgenin are mediated through moderation of ER stress and oxidative stress in pancreas as well as by PPARγ activation in adipose tissue.

Topics: Adipose Tissue; Alkaloids; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Diosgenin; Endoplasmic Reticulum Stress; Insulin; Interleukin-6; Leptin; Male; Molecular Docking Simulation; Oxidative Stress; Pancreas; PPAR gamma; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair β-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired β-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 μg·kg⁻¹·day⁻¹) and/or exenatide (20 μg·kg⁻¹·day⁻¹) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity.

Topics: Adiposity; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Drug Implants; Drug Synergism; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Leptin; Male; Mice, Inbred C57BL; Overweight; Pancreas; Peptides; Recombinant Proteins; Streptozocin; Triglycerides; Venoms

Recent studies focused on the adipose tissue hormones role, especially leptin as one of the basic and generalized nonspecific inflammation markers among them. Some of the major markers are IL-2, IL -6 and TNF-alpha in the pathogenesis of diabetes (DM) and its complications. It is established that patients with type 2 diabetes lasting from 5 to 10 years represent the highest leptin and cytokines levels, and during this period cardiovascular complications of type 2 diabetes are formed. Also it is found that the leptin level was significantly lower in patients with normal body weight, while the levels of IL-6 and TNF-a are the highest in these patients. Obviously, the increased level of these cytokines helps to maintain a normal body weight in these patients. Despite the fact that type 2 diabetes is considered a non-autoimmune disease, it is known that for a long glucose toxicity and lipotoxicity metabolic immunosuppression occurs, which causes changes in T-cell immunity, and consequently to autoimmunity.

Topics: Adipose Tissue; Body Weight; Cytokines; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-2; Interleukin-6; Leptin; Male; Obesity; Time Factors; Tumor Necrosis Factor-alpha

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; History, 20th Century; Humans; Leptin; Obesity

The aim of the study was to assess the links between leptin, resistin and tumor necrosis factor-alpha (TNF-α) and indexes of the functional liver condition in patients with non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (DM 2) and with its combination.. It were examined 110 patients: 20 of them were with NAFLD, 20 patients with DM 2 and 70 patients with combined disorders (NAFLD+ DM 2), which were divided into 2 subgroups -20 patients with normal body weight and 50 patients with obesity (body mass index ≥ 30 kg/m2). The control group included 20 healthy individuals. It was a complex clinical, laboratory (with definition of indexes of protein, pigment, enzyme and carbohydrate metabolism, levels of adipokines) and instrumental (ultrasound of the liver and liver biopsy (for 8 patients)) investigation.. It was shown a significant increase of plasma levels of leptin, resistin, TNF-α in patients with this combined pathology. It was established the significant correlations between leptin, resistin, TNF-α and indexes of functional liver condition in these patients.. In patients with NAFLD, DM 2 and with its combination, particularly with concomitant obesity, there is an imbalance of the products of adipose tissue, which sign is increasing of leptin, resistin and TNF-α. Relationships between leptin, resistin, TNF-α and indexes of the functional liver condition mainly in subgroup 3-b would give a reason to believe that obesity is activated and compounded te hormone-metabolic disorders that affect liver function.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Leptin; Liver Function Tests; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Resistin; Tumor Necrosis Factor-alpha

Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β-cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors 2 and 4 could mediate danger signals in β-cells. We examined whether RAGE contributes to β-cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet-induced obesity (DIO), RAGE-null (RAGE(-/-) ), and RAGE(+/+) wild-type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin-positive β-cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE(-/-) mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE(+/+) db/db mice, RAGE(-/-) db/db mice showed higher β-cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.

Topics: Adiponectin; Animals; Apoptosis; Blood Glucose; Cell Line; Cell Proliferation; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Acids, Nonesterified; Gene Expression; Glucose Intolerance; Glycation End Products, Advanced; Insulin; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Receptors, Leptin

The intercellular adhesion molecule-1 (ICAM-1) and leptin are important inflammatory biomarkers. We investigated whether plasma-soluble ICAM-1 levels were related to the diabetic nephropathy and systemic inflammation. One hundred forty-seven type 2 diabetic patients and 46 healthy control subjects were studied. Plasma sICAM-1 concentrations were significantly higher in the diabetic groups than controls and increased significantly as diabetic nephropathy advanced. Plasma sICAM-1 levels were positively correlated with body mass index, fasting and postprandial blood glucose, urinary albumin excretion, and negatively correlated with creatinine clearance. Multiple regression analysis showed that plasma leptin levels were associated with a significant increase in plasma sICAM-1 levels. In cultured HUVECs, leptin increased ICAM-1 production in a dose-dependent manner, and this stimulating effect of leptin on ICAM-1 expression was reversed by MEK inhibitor, PD98059. Overall, these findings suggest that activation of leptin synthesis in a diabetic environment promotes ICAM-1 activation via mitogen-activated protein kinase pathway in type 2 diabetic patients.

Topics: Albuminuria; Blood Glucose; Body Mass Index; Cells, Cultured; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enzyme Activation; Fasting; Female; Flavonoids; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leptin; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors

Staple-line disruption (SLD) following Roux-en-Y gastric bypass (RYGB) results in weight regain. This study evaluated glucose homeostasis and gut hormonal changes following surgical repair of gastrogastric fistula.. Three patients with SLD underwent an oral 75 g glucose tolerance test (OGTT) before (baseline) and one week after gastric pouch restoration. Plasma glucose, insulin and glucagon glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) were measured in the OGTT samples. Fasting plasma levels of ghrelin and leptin were assessed.. Restoration of gastric pouch provided moderate amelioration of glucose metabolism and gut hormones, yet without complete normalisation of glucose homeostasis at one week after surgery. Duodenal passage exclusion resulted in early improvement of control fasting plasma glucose with decrease of glucagon from 18.5 to 15 (ng/mL, by 19%), relatively stable insulin and decline of incretin hormones (GIP and GLP-1). Post-challenge measurements confirmed amelioration of glycaemic control with decrease of plasma glucose from 182 to 158 mg/dL at 60 minutes. Surgical re-intervention resulted in exacerbation of GIP response with brisk rise in plasma level, accompanied by considerable increase of peak insulin concentration. The overall post-challenge glucagon and GLP-1 responses were decreased. Marked decrease in fasting plasma ghrelin and leptin were observed.. Our report gives further insight into the hormonal mechanisms underlying the effects of surgically altered anatomy of different parts of the small intestine on glucose homeostasis that is highly important, since it may facilitate novel conservative therapies of diabetes without the need for surgery.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Leptin; Male; Middle Aged; Obesity, Morbid; Secondary Prevention; Surgical Stapling; Surgical Wound Dehiscence

Plasma fractalkine (FRACT) is involved in the development of numerous inflammatory conditions including atherosclerosis. It is associated with type 2 diabetes mellitus and adipose inflammation. However, whether FRACT is associated with major risk factors for cardiovascular disease, in particular obesity, metabolic syndrome and blood lipids, is virtually unknown.. The study included a large community-based sample of 3306 middle-aged women drawn from the general UK population. Blood samples were analyzed for circulating levels of FRACT, leptin, insulin, glucose, LDL-C, HDL-C, Apo-A, ApoB and IL-6. Obesity was assessed by fat body mass (FBM) using dual-energy x-ray absorptiometry and by body mass index (BMI).. We found no association between FRACT and body composition, in particular adiposity. Obese and non obese subjects with metabolic syndrome tended to have higher levels of FRACT compared with non-obese subjects without metabolic syndrome but this did not reach statistical significance. Most importantly we report significant correlations between FRACT and circulating IL-6, Apo-B, LDL-C and insulin. The associations with IL-6 and Apo-B were particularly significant (P-value<0.001), and survived correction for multiple testing and adjustment for age and other covariates.. Higher FRACT levels correlated with elevated levels of IL-6, Apo-B, LDL-C and insulin, all known risk factors for several clinical related diseases suggesting a potential role of FRACT in inflammation and tissue injury. Variations of FRACT levels are not influenced by body composition and are not correlated with leptin indicating that fat mass alone is not responsible for elevation of FRACT seen in obese individuals.

Topics: Apolipoproteins B; Atherosclerosis; Blood Glucose; Body Composition; Body Mass Index; Chemokine CX3CL1; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Interleukin-6; Leptin; Metabolic Syndrome; Middle Aged; Regression Analysis; Risk Factors; United Kingdom

In addition to the well known regulating effects of leptin on energy balance and glucose homeostasis through the central nervous system, circulating leptin has a direct effect on pancreatic islet and insulin secretion through its receptor (OBRb). The LIM-homeodomain transcription factor Isl-1 is expressed in all classes of pancreatic endocrine cells and is involved in regulating both islet development and insulin secretion. Both OBRb and Isl-1 mutations result in obesity-related diabetes. However, the interactions and physiological significance of leptin and Isl-1 in pancreatic islets remain to be established. Here, we show that most of leptin target cells in pancreatic islets and NIT beta cells express Isl-1. Both in vivo and in vitro results demonstrate that leptin suppresses Isl-1 expression and insulin secretion in islet in physiological and pathophysiological conditions, e.g. high fat diet. This effect of leptin on insulin secretion is lost in leptin receptor-defective db/db and Isl-1-inducible knock-out mice. We conclude that the action of leptin on insulin secretion is at least partly mediated by Isl-1. Another new finding of this study is that Isl-1 acts as a direct downstream target of leptin signaling molecule STAT3 to influence the effect of leptin on insulin secretion, whereas inversely, insulin has feedback regulating effects on Isl-1 expression through JAK-STAT3 pathway. These findings are crucial for understanding the mechanisms regulating insulin secretion and metabolism in related diseases, such as obesity and type 2 diabetes.

Topics: Animals; Cell Line; Diabetes Mellitus, Type 2; Gene Expression Regulation; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; LIM-Homeodomain Proteins; Mice; Mice, Knockout; Mice, Obese; Mutation; Obesity; Receptors, Leptin; STAT3 Transcription Factor; Transcription Factors

Soluble CD163 (sCD163) is a new macrophage-specific serum marker elevated in inflammatory conditions. sCD163 is elevated in obesity and found to be a strong predictor of the development of type 2 diabetes. We investigated whether dietary intervention and moderate exercise was related to changes in sCD163 and how sCD163 is associated to insulin resistance in obesity.. Ninety-six obese subjects were enrolled: 62 followed a very low energy diet (VLED) program for 8 weeks followed by 3-4 weeks of weight stabilization, 20 followed a moderate exercise program for 12 weeks, and 14 were included without any intervention. Fasting blood samples and anthropometric measures were taken at baseline and after intervention. Thirty-six lean subjects were included in a control group.. sCD163 was significantly higher in obese subjects (2.3 ± 1.0 mg/l) compared with lean (1.6 ± 0.4 mg/l, P < 0.001). Weight loss (11%) induced by VLED resulted in a reduction and partial normalization of sCD163 to 2.0 ± 0.9 mg/l (P < 0.001). Exercise for 12 weeks had no effect on sCD163. At baseline, sCD163 was significantly correlated with BMI (r = 0.46), waist circumference (r = 0.40), insulin resistance measured by the homeostasis model assessment (HOMA-IR; r = 0.41; all P < 0.001), and the leptin-to-adiponectin ratio (r = 0.28, P < 0.05). In a multivariate linear regression analysis with various inflammatory markers, sCD163 (β = 0.25), adiponectin (β = -0.24), and high sensitivity C-reactive protein (hs-CRP; β = 0.20) remained independently and significantly associated to HOMA-IR (all P < 0.05). After further adjustment for waist circumference, only sCD163 was associated with HOMA-IR (P < 0.05).. The macrophage-specific serum marker sCD163 is increased in obesity and partially normalized by dietary-induced weight loss but not by moderate exercise. Furthermore, we confirm that sCD163 is a good marker for obesity-related insulin resistance.

Topics: Adiponectin; Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; C-Reactive Protein; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Linear Models; Macrophages; Male; Middle Aged; Multivariate Analysis; Obesity; Randomized Controlled Trials as Topic; Receptors, Cell Surface; Waist Circumference; Weight Loss

Most Swedish studies show stable diabetes prevalence despite increasing obesity, but glucose levels may shift upwards below the diagnostic threshold for diabetes. Our aim was to explore trends in glucose distribution in northern Sweden; whether these trends were uniformly distributed throughout the spectrum of glucose concentrations; and to relate trends to traditional risk factors and the obesity-related adipokine leptin.. The project consisted of four cross-sectional surveys between 1990 and 2009, with 7069 participants aged 25-64 years. The overall participation rate was 74.4%. Trend analyses of glucose concentrations along the entire distribution and linear regression in relation to survey years and risk markers were used.. Fasting and post-load glucose increased in women (both P < 0.001) and post-load glucose in men (P = 0.004). The increase was seen in most deciles of glucose concentrations. The prevalence of impaired glucose tolerance doubled in women to 14.5% and tripled in men to 10.1% (both P = 0.004). The prevalence of impaired fasting glucose rose in women from 4.5 to 7.7% (P < 0.001). The prevalence of diabetes was unchanged-6.4% in 2009. In men, leptin, together with traditional risk factors, explained 7.8 and 10.8% of the variance in fasting (P = 0.008) and post-load (P < 0.001) glucose, respectively.. Increasing fasting and post-load glucose concentrations were seen in most deciles of the glucose distribution, indicating a shift in the entire population. Leptin was significantly associated with fasting and post-load glucose in men.

Topics: Adult; Biomarkers; Blood Glucose; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Health Surveys; Health Transition; Humans; Leptin; Male; Middle Aged; Models, Biological; Prediabetic State; Prevalence; Risk Factors; Sex Factors; Sweden

Competitive endogenous RNAs (ceRNAs) regulate mRNA transcripts containing common microRNA (miRNA) recognition elements (MREs) through sequestration of shared miRNAs. Interactions of ceRNA have been demonstrated in cancerous cells. However, a paucity of information is available relative to the interactions of ceRNAs interaction in diabetes mellitus and the myocardium. The purpose of this study is to assess the potential role of DKK1 and PTEN in ceRNA regulation utilizing their common miRNAs in diabetic cardiomyocytes. The interactions' regulation between PTEN and DKK1 were determined in two diabetic models in vivo (streptozotocin-induced type-1 DM mice and db/db mice) and in vitro (human cardiomyocytes cells exposed to hyperglycemia). The levels of DKK1 and PTEN (mRNA and protein) were upregulated in parallel in all three diabetic models. DKK1 modulates PTEN protein levels in a miRNA and 3'UTR-dependent manner. RNAi-mediated DKK1 gene silencing resulted in a decreased PTEN expression and vice versa. The effect was blocked when Dicer was inhibited. Silencing either PTEN or DKK1 resulted in an increase of the availabilities of shared miRNAs. The silencing of either PTEN or DKKI resulted in a suppression end of the luciferase-PTEN 3'UTR activity. However, the over expression of DKK1 3'UTR or PTEN 3'UTR resulted in an increase in the activity. The attenuation of DKK1 increased AKT phosphorylation, improved glucose uptake and decreased apoptosis in HCMs exposed to hyperglycemia. The effects were blocked by PI3K inhibition. DKK1 and PTEN transcripts are co-upregulated in DM and hyperglycemia. DKK1 and PTEN serve as ceRNA, affecting the expression of each other via competition for miRNAs binding.

Topics: 3' Untranslated Regions; Animals; Apoptosis; Binding Sites; Binding, Competitive; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Genes, Reporter; Heart Diseases; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; RNA Interference; RNA, Messenger; Signal Transduction; Transfection

Zinc (Zn) deficiency and obesity are global public health problems. Zn deficiency is associated with obesity and comorbid conditions that include insulin resistance and type 2 diabetes. However, the function of Zn in obesity remains unclear. Using a mouse model of combined high-fat and low-Zn intake (0.5-1.5 mg/kg), we investigated whether Zn deficiency exacerbates the extent of adiposity as well as perturbations in metabolic and immune function. C57BL/6 mice were randomly assigned to receive either a high-fat diet (HFD) or a control (C) diet for 6 wk, followed by further subdivision into 2 additional groups fed Zn-deficient diets (C-Zn, HFD-Zn), along with a C diet and an HFD, for 3 wk (n = 8-9 mice/group). The extent of visceral fat, insulin resistance, or systemic inflammation was unaffected by Zn deficiency. Strikingly, Zn deficiency significantly augmented circulating leptin concentrations (HFD-Zn vs. HFD: 3.15 ± 0.16 vs. 2.59 ± 0.12 μg/L, respectively) and leptin signaling in the liver of obese mice. Furthermore, gene expression of macrophage-specific markers ADAM8 (A disintegrin and metalloproteinase domain-containing protein 8) and CD68 (cluster of differentiation 68) was significantly greater in adipose tissue in the HFD-Zn group than in the HFD group, as confirmed by CD68 protein analysis, indicative of increased macrophage infiltration. Inspection of Zn content and mRNA profiles of all Zn transporters in the adipose tissue revealed alterations of Zn metabolism to obesity and Zn deficiency. Our results demonstrate that Zn deficiency increases leptin production and exacerbates macrophage infiltration into adipose tissue in obese mice, indicating the importance of Zn in metabolic and immune dysregulation in obesity.

Topics: Adipokines; Adiposity; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Blotting, Western; Cytokines; Diabetes Mellitus, Type 2; Diet, High-Fat; Immunohistochemistry; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Leptin; Liver; Macrophages; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Obese; NF-kappa B; NIH 3T3 Cells; Obesity; PPAR gamma; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Transfection; Zinc

The increasing prevalence of diabetes mellitus (DM) worldwide has underscored the urgency of developing an efficient therapeutic agent. Recently, Zn complexes have been attracting attention due to their antidiabetic activity. In this study, we designed and synthesized a new Zn complex, Zn-3,4-heptanedione-bis(N (4)-methylthiosemicarbazonato) (Zn-HTSM), characterized its physicochemical properties, and examined its antidiabetic activity in KK-A(y) type 2 DM model mice. It was demonstrated that Zn-HTSM has adequate lipophilicity for the cellular permeability, shows potent hypoglycemic activity, and improves glucose intolerance in KK-A(y) mice. We also analyzed the levels of serum adipokines after continuous oral administration of Zn-HTSM. The level of serum leptin of KK-A(y) mice is significantly reduced by the treatment of Zn-HTSM. Nevertheless, the levels of serum insulin and adiponectin were not improved. These data suggested that the Zn-HTSM acts on the leptin metabolism. Our present studies indicate that Zn-HTSM is a candidate oral antidiabetic agent for the treatment of type 2 DM.

Topics: Administration, Oral; Animals; Blood Glucose; Coordination Complexes; Diabetes Mellitus, Type 2; Leptin; Lipid Metabolism; Male; Mice; Molecular Structure; Thiosemicarbazones; Zinc

Obesity is a critical risk factor for the development of metabolic syndrome, and many obese animal models are used to investigate the mechanisms responsible for the appearance of symptoms. To establish a new obese mouse model, we screened ∼13,000 ICR mice and discovered a mouse demonstrating spontaneous obesity. We named this mouse "Daruma" after a traditional Japanese ornament. Following the fixation of the genotype, these animals exhibited obese phenotypes according to Mendel's law of inheritance. In the Daruma mouse, the leptin receptor gene sequence carried two base mutations that are good candidates for the variation(s) responsible for the obese phenotype. The Daruma mice developed characteristic visceral fat accumulation at 4 wk of age, and the white adipose and liver tissues exhibited increases in cell size and lipid droplets, respectively. No histological abnormalities were observed in other tissues of the Daruma mice, even after the mice reached 25 wk of age. Moreover, the onset of impaired leptin signaling was early and manifested as hyperleptinemia and hyperinsulinemia. Pair feeding completely inhibited obesity, although these mice rapidly developed hyperphagia and obesity followed by hyperleptinemia when pair feeding ceased and free-access feeding was permitted. Therefore, the Daruma mice exhibited unique characteristics and may be a good model for studying human metabolic syndrome.

Topics: Adipose Tissue; Animals; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Ghrelin; Glucose Tolerance Test; Hemodynamics; Hyperphagia; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mutation; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Tomography, X-Ray Computed; Triglycerides

Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored.. For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations.. For prevention, oral sCT reduced body weight by ∼16% to 19% (P < 0.001), reduced plasma insulin and leptin by ∼50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation.. Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes.

Topics: Animals; Blood Glucose; Body Weight; Calcitonin; Diabetes Mellitus, Type 2; Diet, High-Fat; Fasting; Female; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Obesity; Ovariectomy; Rats; Rats, Sprague-Dawley

The shortage of data concerning the character of changes of leptin concentration and its role information of insulin resistance under development of acute coronary events determined the appropriateness of the present study. The cardiac infarction patients with and without diabetes type II were examined. The identified hyperleptinemia, its relationship with basal and post-prandial hyperglycemia and with increase of C-peptide concentration and free fatty acids made possible to consider leptin both as one of the important components in the series of carbohydrate and lipid metabolism disorders and the additional marker of development of insulin resistance under cardiac infarction. These study results can be applied to patients with diabetes anamnesis and to patients without this concomitant pathology. The study results can be used as a foundation for new diagnostic and therapy tactics of metabolic disorders correction in patients with acute coronary vascular pathology.

Topics: Aged; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Myocardial Infarction

Bariatric surgery has been established as the best option of treatment for morbid obesity. Recently, laparoscopic sleeve gastrectomy (SG) has become very popular because of good postoperative weight loss and low morbidity. The aim of this study was to report our single-center experience with SG regarding feasibility, morbidity, and outcome.. From January 2006 to December 2011, 93 patients (68 female) with a median age of 46 years underwent laparoscopic SG at our department. Thirteen patients had a history of gastric banding with insufficient weight loss or band-related complications. Clinical outcome and laboratory findings were analyzed.. The mean preoperative and postoperative body mass index (BMI) was 44.1 ± 6.9 and 33.4 ± 6.8 kg/m(2), respectively (p < 0.001). The mean excessive body weight loss after a median follow-up of 11.9 months was 55.7 % ± 24.9 %. Three bleedings, two staple line leakages, and a deep wound infection required conversion to laparotomy (n = 1), reoperation (n = 4), or endoscopic stent implantation (n = 2). Resolution of diabetes and dyslipidemia was seen in 85 and 50 % of patients, respectively. Blood test results of HbA1c, cholesterols, triglycerides, and leptin showed significant postoperative improvement.. Laparoscopic SG represents a feasible bariatric procedure with good short-term weight loss, low morbidity rate, and efficient resolution of diabetes and dyslipidemia, especially in patients with lower BMI. The significant decrease of leptin necessitates further studies to understand the ambiguous role of leptin in bariatric surgery.

Topics: Adult; Aged; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 2; Dyslipidemias; Feasibility Studies; Female; Follow-Up Studies; Gastric Bypass; Gastroplasty; Glycated Hemoglobin; Humans; Laparoscopy; Leptin; Male; Middle Aged; Obesity, Morbid; Reoperation; Retrospective Studies; Treatment Outcome; Triglycerides; Weight Loss

First Nations and other Aboriginal children are disproportionately affected by cardiometabolic diseases, including type 2 diabetes (T2D). In T2D, the disruption of insulin signalling can be driven by pro-inflammatory immunity. Pro-inflammatory responses can be fueled by toll-like receptors (TLR) on immune cells such as peripheral blood mononuclear cells (PBMC, a white blood cell population). TLR4 can bind to lipids from bacteria and food sources activating PBMC to produce cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1β. These cytokines can interfere with insulin signalling. Here, we seek to understand how TLR4 activation may be involved in early onset T2D. We hypothesized that immune cells from youth with T2D (n = 8) would be more reactive upon TLR4 stimulation relative to cells from age and body mass index (BMI)-matched controls without T2D (n = 8).. Serum samples were assayed for adipokines (adiponectin and leptin), as well as cytokines. Freshly isolated PBMC were examined for immune reactivity upon culture with TLR4 ligands bacterial lipopolysaccharide (LPS, 2 and 0.2 ng/ml) and the fatty acid palmitate (200 µM). Culture supernatants were evaluated for the amount of TNF-α and IL-1β produced by PBMC.. Youth with T2D displayed lower median serum adiponectin levels compared to controls (395 vs. 904 ng/ml, p < 0.05). PBMC isolated from youth with and without T2D produced similar levels of TNF-α and IL-1β after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1β synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1β synthesis in PBMCs isolated from youth with T2D versus controls (p < 0.05). These differences in cytokine production corresponded to greater monocyte activation in the T2D cohort.. These preliminary results suggest that cellular immune responses are exaggerated in T2D, particularly with respect to IL-1β activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people.

Topics: Adiponectin; Adolescent; Age Factors; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Immunity, Cellular; Indians, North American; Interleukin-1beta; Leptin; Male; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

NK cells rapidly kill tumor cells, virus infected cells and even self cells. This is mediated via killer receptors, among which NKp46 (NCR1 in mice) is prominent. We have recently demonstrated that in type 1 diabetes (T1D) NK cells accumulate in the diseased pancreas and that they manifest a hyporesponsive phenotype. In addition, we found that NKp46 recognizes an unknown ligand expressed by beta cells derived from humans and mice and that blocking of NKp46 activity prevented diabetes development. Here we investigated the properties of the unknown NKp46 ligand. We show that the NKp46 ligand is mainly located in insulin granules and that it is constitutively secreted. Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases. We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin. Finally, we studied the expression of the NKp46 ligand in type 2 diabetes (T2D) using 3 different in vivo models and 2 species; mice and gerbils. We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

Topics: Animals; Antigens, Ly; Autoimmunity; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gene Expression; Gene Expression Regulation; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Ligands; Male; Mice; Natural Cytotoxicity Triggering Receptor 1; Protein Binding

Stress and hypercaloric food are recognized risk factors for obesity, Metabolic Syndrome (MetS) and Type 2 Diabetes (T2D). Given the complexity of these metabolic processes and the unavailability of animal models, there is poor understanding of their underlying mechanisms. We established a model of chronic psychosocial stress in which subordinate mice are vulnerable to weight gain while dominant mice are resilient. Subordinate mice fed a standard diet showed marked hyperphagia, high leptin, low adiponectin, and dyslipidemia. Despite these molecular signatures of MetS and T2D, subordinate mice fed a standard diet were still euglycemic. We hypothesized that stress predisposes subordinate mice to develop T2D when synergizing with other risk factors. High fat diet aggravated dyslipidemia and the MetS thus causing a pre-diabetes-like state in subordinate mice. Contrary to subordinates, dominant mice were fully protected from stress-induced metabolic disorders when fed both a standard- and a high fat-diet. Dominant mice showed a hyperphagic response that was similar to subordinate but, unlike subordinates, showed a significant increase in VO2, VCO2, and respiratory exchange ratio when compared to control mice. Overall, we demonstrated a robust stress- and social status-dependent effect on the development of MetS and T2D and provided insights on the physiological mechanisms. Our results are reminiscent of the effect of the individual socioeconomic status on human health and provide an animal model to study the underlying molecular mechanisms.

Topics: Adiponectin; Animals; Calorimetry, Indirect; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; Energy Intake; Energy Metabolism; Glucose Tolerance Test; Hyperphagia; Immunohistochemistry; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Mice; Risk Factors; Social Dominance; Social Environment; Stress, Psychological

Type 2 diabetes is characterized by insulin resistance and mitochondrial dysfunction in classical target tissues such as muscle, fat, and liver. Using a murine model of type 2 diabetes, we show that there is hypothalamic insulin resistance and mitochondrial dysfunction due to downregulation of the mitochondrial chaperone HSP60. HSP60 reduction in obese, diabetic mice was due to a lack of proper leptin signaling and was restored by leptin treatment. Knockdown of Hsp60 in a mouse hypothalamic cell line mimicked the mitochondrial dysfunction observed in diabetic mice and resulted in increased ROS production and insulin resistance, a phenotype that was reversed with antioxidant treatment. Mice with a heterozygous deletion of Hsp60 exhibited mitochondrial dysfunction and hypothalamic insulin resistance. Targeted acute downregulation of Hsp60 in the hypothalamus also induced insulin resistance, indicating that mitochondrial dysfunction can cause insulin resistance in the hypothalamus. Importantly, type 2 diabetic patients exhibited decreased expression of HSP60 in the brain, indicating that this mechanism is relevant to human disease. These data indicate that leptin plays an important role in mitochondrial function and insulin sensitivity in the hypothalamus by regulating HSP60. Moreover, leptin/insulin crosstalk in the hypothalamus impacts energy homeostasis in obesity and insulin-resistant states.

Topics: Animals; Cell Line; Chaperonin 60; Diabetes Mellitus, Type 2; Female; Gene Knockdown Techniques; Humans; Hypothalamus; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mitochondria; Mitochondrial Proteins; Obesity; Oxidative Stress; Signal Transduction

TZQ has been used in traditional Chineses medicine for treating diabetes. Based on the recipe of traditional anti-diabetic formula TZQ, we have developed TZQ-F which has been in phase 2 clinical trails. To study the mechanisms by which TZQ-F ameliorates diabetes, we examined whether treatment with TZQ-F improves hyperinsulinemia, hyperglycemia and obesity in type 2 diabetic KKA(y) mice and whether this is associated with an improvement of adipocyte differentiation and insulin action.. TZQ-F, fenofibrate, rosiglitazone or distilled water was administered to 7-week-old diabetic KKA(y) and nondiabetic C57BL/6J mice for 8 weeks. Insulin resistance index, body weight and levels of serum blood glucose, leptin, insulin and adiponectin were evaluated. The expression of peroxisome proliferator-activated receptor γ (PPARγ) in skeletal muscle and liver tissues were determined with real-time PCR and western boltting. The mRNA expressions of insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), glucose transporter-1 (Glut-1) and Phosphoenolpyruvate 3-kinases (PI3K) in skeletal muscle and liver tissues were determined with real-time PCR. Histopathology of liver has been observed.. Treatment of TZQ-F for 8 weeks ameliorated hyperglycemia, hyperinsulinemia, hyperleptinemia and hypoadiponectinemia in KKA(y) mice. TZQ-F also up-regulated expression of PPARγ in liver tissue. However, it had no effect on regulation of expression of PPARγ in muscle tissue. In addition, TZQ-F upregulates InsR, IRS-1, IRS-2, Glut-1, and PI3K mRNA expression. Consistent with the in vivo results, histology study demonstrated that TZQ-F alleviated pathologic changes of the liver induced by high-fat diet.. These results first indicate that TZQ-F can be beneficial for reducing hyperinsulinemia, hyperglycemia and obesity through its potency of regulating adipocyte differentiation and insulin action.

Topics: Adipocytes; Adiponectin; Animals; Anti-Obesity Agents; Blood Glucose; Cell Differentiation; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Female; Hypoglycemic Agents; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; PPAR gamma; RNA, Messenger

Insulin resistance, dyslipidemia and hypertension are independent mediators of endothelial dysfunction. It is incompletely defined whether dyslipidemia and hypertension in addition to diabetes mellitus type II (DMII), as seen in the metabolic syndrome (MS), worsen diabetes-induced endothelial dysfunction. Furthermore, it is unclear whether treatment influences endothelial dysfunction similarly in MS and DMII. Therefore, we studied vascular reactivity and the effect of in vivo treatment with angiotensin-converting enzyme inhibition (ACE-I) or hypocaloric diet in LDL receptor- and leptin-deficient (ob/ob), double knockout mice (DKO), featuring MS and in ob/ob mice with DMII.. Vascular reactivity was studied in isolated aortic ring segments. Maximum vasorelaxant response to acetylcholine (Ach) was more depressed in DKO than in ob/ob mice, whereas response to bradykinin (BK) was equally attenuated in both genotypes (52 ± 3 and 23 ± 9% reversal of preconstriction induced by 10(-7) M phenylephrine in DKO vs. 76 ± 3 and 23 ± 8% reversal of preconstriction in ob/ob mice, respectively). ACE-I and hypocaloric diet improved ACh-induced vasorelaxation significantly (89 ± 2 and 59 ± 2% reversal of preconstriction in DKO vs. 80 ± 3 and 84 ± 4% in ob/ob mice, respectively), but not the response to BK.. These results indicate a differential impact of DMII and MS on endothelial function. ACE-I and hypocaloric diet improved ACh-, but not BK-induced vasorelaxation in these mouse models of DMII and MS.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Blood Glucose; Caloric Restriction; Captopril; Combined Modality Therapy; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Endothelium, Vascular; Female; Hypertension; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Nitric Oxide; Receptors, LDL; Time Factors; Vasodilation; Vasodilator Agents; Weight Loss

Sedentary behaviour has been identified as a distinct risk factor for several health outcomes. Nevertheless, little research has been conducted into the underlying mechanisms driving these observations. This study aimed to investigate the association of objectively measured sedentary time and breaks in sedentary time with markers of chronic low-grade inflammation and adiposity in a population at a high risk of type 2 diabetes mellitus.. This study reports data from an ongoing diabetes prevention programme conducted in Leicestershire, UK. High risk individuals were recruited from 10 primary care practices. Sedentary time (<25 counts per 15 s) was measured using Actigraph GT3X accelerometers (15 s epochs). A break was considered as any interruption in sedentary time (≥25 counts per 15 s). Biochemical outcomes included interleukin-6 (IL-6), C-reactive protein (CRP), leptin, adiponectin and leptin:adiponectin ratio (LAR). A sensitivity analysis investigated whether results were affected by removing participants with a CRP level >10 mg/L, as this can be indicative of acute inflammation.. 558 participants (age = 63.6±7.7 years; male = 64.7%) had complete adipokine and accelerometer data. Following adjustment for various confounders, sedentary time was detrimentally associated with CRP (β = 0.176±0.057, p = 0.002), IL-6 (β = 0.242±0.056, p = <0.001), leptin (β = 0.146±0.043, p = <0.001) and LAR (β = 0.208±0.052, p = <0.001). Associations were attenuated after further adjustment for moderate-to-vigorous physical activity (MVPA) with only IL-6 (β = 0.231±0.073, p = 0.002) remaining significant; this result was unaffected after further adjustment for body mass index and glycosylated haemoglobin (HbA1c). Similarly, breaks in sedentary time were significantly inversely associated with IL-6 (β = -0.094±0.047, p = 0.045) and leptin (β = -0.075±0.037, p = 0.039); however, these associations were attenuated after adjustment for accelerometer derived variables. Excluding individuals with a CRP level >10 mg/L consistently attenuated the significant associations across all markers of inflammation.. These novel findings from a high risk population recruited through primary care suggest that sedentary behaviour may influence markers associated with inflammation, independent of MVPA, glycaemia and adiposity.

Topics: Adiponectin; Adiposity; Biomarkers; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Motor Activity; Risk Factors; Sedentary Behavior

Leptin, an adipocyte-derived hormone, has a pivotal role in the regulation of body weight through acting on its specific leptin receptor (LEPR). The 223A/G polymorphism of the LEPR gene is one of the most common polymorphism in all populations.  In this study, we aimed to investigate the impact of the 223A/G polymorphism of the LEPR gene on serum levels of leptin in type 2 diabetes mellitus (T2DM) in a sample of Iranian population.. One hundred and forty-four T2DM patients were screened and compared to 147 healthy controls.  The 223A/G LEPR polymorphism was genotyped using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). The serum levels of leptin were measured.. The mean serum levels of leptin in T2DM patients were significantly higher than that of healthy control subjects; 22.90 ng/ml (95 % confidence interval [CI] = 20.79 - 25.23) vs.  8.70 ng/ml (95 % CI = 7.87 - 9.63). The genotypes (AA, AG, and GG) distributions of the 223A/G polymorphism were 55.5 %, 41 %, and 3.5 % in T2DM and 54.4 %, 42.2 %, and 3.4 % in healthy controls. The results showed no significant differences in the 223A/G LEPR genotype and allele frequencies between T2DM and control subjects (χ2 = 0.043, P = 0.979 and χ2 = 0.003, P = 0.957), respectively. In addition, the serum leptin levels were markedly higher in subjects with GG genotype than those with AG or GG genotype only in T2DM CONCLUSION: The 223A/G LEPR gene polymorphism is associated with markedly increased serum leptin levels in T2DM. However, no differences were determined in genotype and allele frequencies between T2DM patients and control subjects.

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Humans; Iran; Leptin; Male; Middle Aged; Polymorphism, Restriction Fragment Length; Receptors, Leptin

Pulmonary tuberculosis (TB) patients often suffer from anorexia and poor nutrition, causing weight loss. The peptide hormones leptin and its counterpart ghrelin, acting in the regulation of food intake and fat utilization, play an important role in nutritional balance. This study aimed to investigate the association of blood concentrations of leptin, ghrelin and inflammatory cytokines with body mass index (BMI) in TB patients with and without type 2 diabetes mellitus (T2DM).. BMI, biochemical parameters and plasma levels of leptin, ghrelin and inflammatory cytokines were measured before the start of treatment in 27 incident TB patients with T2DM, 21 TB patients and 23 healthy subjects enrolled in this study.. The levels of leptin were significantly higher in TB patients (35.2 ± 19.1 ng/ml) than TB+T2DM (12.6 ± 6.1 ng/ml) and control (16.1 ± 11.1 ng/ml) groups. The level of ghrelin was significantly lower in TB (119.9 ± 46.1 pg/ml) and non-significantly lower in TB+T2DM (127.7 ± 38.6 pg/ml) groups than control (191.6 ± 86.5 pg/ml) group. The levels of TNF-α were higher, while IFN-γ and IL-6 levels were lower in patients than in the control group. Leptin showed a negative correlation with BMI in TB (r=-0.622, p<0.05) and TB+T2DM (r= -0.654, p<0.05) groups, but a positive correlation with BMI in the control group (r=0.521, p<0.05). Contrary ghrelin showed a positive correlation with BMI in TB (r=0.695, p<0.05) and TB+T2DM (r= 0.199, p>0.05) groups, but negative correlation with BMI in the control (r=-0.693, p<0.05) group. Inflammatory cytokines were poorly correlated with BMI in this study. Only IFN-γ showed a significant negative correlation with BMI in the control group (r=-0.545, p<0.05).. This study may suggest that possible abnormalities in ghrelin and leptin regulation (high levels of leptin and low levels of ghrelin) may be associated with low BMI and may account for the poor nutrition associated with TB and TB+T2DM.

Topics: Body Mass Index; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Inflammation; Interferon-gamma; Interleukin-6; Leptin; Male; Middle Aged; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

To investigate the effects of acute and chronic exercise on glucose and lipid metabolism in liver of rats with type 2 diabetes caused by a high fat diet and low dose streptozotocin (STZ).. Animals were classified into control (CON), diabetes (DC), diabetic chronic exercise (DCE), and diabetic acute exercise (DAE) groups.. Compared to CON, the leptin levels in serum and liver and ACC phosphorylation were significantly higher in DC, but the levels of liver leptin receptor, AMPK α 1/2, AMPK α 1, and ACC proteins expression and phosphorylation were significantly lower in DC. In addition, the levels of liver glycogen reduced significantly, and the levels of TG and FFA increased significantly in DC compared to CON. Compared to DC, the levels of liver AMPK α 1/2, AMPK α 2, AMPK α 1, and ACC phosphorylation significantly increased in DCE and DAE. However, significant increase of the level of liver leptin receptor and glycogen as well as significant decrease of the level of TG and FFA were observed only in DEC.. Our study demonstrated that both acute and chronic exercise indirectly activated the leptin-AMPK-ACC signaling pathway and increased insulin sensitivity in the liver of type 2 diabetic rats. However, only chronic and long-term exercise improved glucose and lipid metabolism of the liver.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Leptin; Liver; Male; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors

Adipokines are known to play a fundamental role in the etiology of obesity, that is, in the impaired balance between increased feeding and decreased energy expenditure. While the adipokine-induced changes of insulin resistance in obese diabetic and nondiabetic subjects are well known, the possible role of fat source in modulating insulin sensitivity (IS) remains controversial. The aim of our study was to explore in overweight type 2 diabetic patients (T2DM) with metabolic syndrome IS in different energy storage conditions (basal and dynamic) for relating it to leptin and adiponectin. Sixteen T2DM (5/11 F/M; 59 ± 2 years; 29.5 ± 1.1 kg/m(2)) and 16 control (CNT 5/11; 54 ± 2; 29.1 ± 1.0) underwent an oral glucose tolerance test. Fasting IS was measured by QUICKI, while the dynamic one with OGIS. The insulinogenic index (IGI) described beta cell function. Also, the lipid accumulation product parameter (LAP) was assessed. LAP accounts for visceral abdominal fat and triglycerides, and it is known to be related to IS. Possible interrelationships between LAP and adipokines were explored. In T2DM and CNT, adiponectin (7.4 ± 0.5 vs. 7.8 ± 0.9 μg/mL), leptin (13.3 ± 3.0 vs. 12.4 ± 2.6 ng/mL), and QUICKI (0.33 ± 0.01 vs. 0.33 ± 0.01) were not different (P > 0.40), at variance with OGIS (317 ± 11 vs. 406 ± 13 mL/min/m(2); P = 0.006) and IGI (0.029 ± 0.005 vs. 0.185 ± 0.029 × 10(3) pmolI/mmolG; P = 0.00001). LAP was 85 ± 15 cm × mg/dL in T2DM and 74 ± 10 in CNT (P > 0.1), correlated with OGIS in all subjects (R = -0.42, P = 0.02) and QUICKI (R = -0.56, P = 0.025) in T2DM. Leptin correlated with QUICKI (R = -0.45, P = 0.009), and adiponectin correlated with OGIS (R = 0.43, P = 0.015). In overweight T2DM, insulin sensitivity in basal condition appears to be multifaceted with respect to the dynamic one, because it should be more fat-related. Insulin sensitivity appears to be incompletely described by functions of fasting glucose and insulin values alone and the use of other indices, such as LAP could be suggested.

Topics: Adiponectin; Blood Glucose; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Insulin-Secreting Cells; Intra-Abdominal Fat; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight

Diabetic patients often exhibit severe, asymptomatic coronary artery disease (CAD). The relationship between osteoprotegerin (OPG), inflammatory markers and silent myocardial ischemia remains to be elucidated.. We recruited 45 type 2 diabetic patients and 33 healthy controls and assessed them for silent myocardial ischemia (SMI) by myocardial perfusion imaging. Patient blood was tested for OPG, IL-6 and leptin concentrations.. OPG, leptin and IL-6 levels were found significantly elevated in diabetic patients (p < 0.001, p < 0.01, p < 0.05). Based on our classification of presence/absence of SMI in our diabetic group, we found that there was a significant association between SMI and the biomarkers IL-6 (p < 0.001), leptin (p < 0.001) and OPG (p < 0.05). In multivariate regression analyses, OPG was found to be significantly related to diabetes mellitus and to SMI. Age, sex and smoking increased the association between OPG and SMI.. High OPG, leptin and IL-6 levels are associated with the presence and severity of SMI in type 2 diabetic patients.

Topics: Adult; Biomarkers; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exercise Test; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Myocardial Perfusion Imaging; Osteoprotegerin; Regression Analysis

To investigate the relationship of body mass index and serum adipokines with incidence of diabetes in men.. Ten-year cohort study of a random population sample of 1011 men aged 35-69 years from the MONICA-Catalonia survey (1986-1988). WHO-MONICA protocol and the US Hispanic NHANES diabetes questionnaire were applied. Fasting serum glucose and lipids were measured by enzymatic methods, adipokines and insulin by Luminex xMAP technology,and hs-CRP by nephelometry in stored baseline samples (-80°C). Type2 diabetes was defined as fasting glucose ≥ 7.0 mmol/L or diagnosed diabetes. Incident diabetes was defined as absence of these criteria at baseline but presence at re-examination. Cox regression analysis was used.. Incidence of diabetes (n = 85) was 10.3/1000 person-years, increasing significantly with BMI but decreasing by quartiles of adiponectin. Incidence increased above median BMI and glucose (45.3/1000 person-years, OR = 19.97). Log-adiponectin associated with reduced risk of diabetes after multivariate adjustment (HR = 0.24, 95% CI 0.08-0.72), with significant modification of this effect by baseline glycaemia. C-reactive protein was not a significant factor. Leptin lost strength when adjusted for BMI.. In a population with relatively high diabetes incidence, BMI and glucose were strong risk factors, while adiponectin protected against diabetes, especially in men with high glycaemic level.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; C-Reactive Protein; Cholesterol, HDL; Diabetes Mellitus, Type 2; Humans; Incidence; Leptin; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Spain; Surveys and Questionnaires; Triglycerides

In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes.. The effects repeated dose treatment for 14 days with exendin-4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity.. Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content.. Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gastrins; Glucagon; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Omeprazole; Peptides; Venoms

Epidemiological data in humans and experiments in laboratory animals have demonstrated that the developmental programming of hypertension may occur as a consequence of dietary manipulations during pregnancy. Surprisingly, there is a scarcity of data regarding the development of hypertension as a consequence of a maternal low-protein diet (MLPD), particularly in the mouse. Furthermore, the role of sex in developmental programming is not well understood. We used FVB/NJ mice, because of their value in genetic/mechanistic analysis, to test the hypothesis that a MLPD during gestation leads to the sexually dimorphic developmental programming of hypertension and related disorders, such as intra-uterine growth restriction (IUGR), type 2 diabetes mellitus and obesity. We administered iso-caloric, normal (control), moderate protein (moderate MLPD) and severe protein (severe MLPD) diets to the mice, beginning 1 week before mating and continuing until the delivery of the pups. From 4 weeks onward, using a non-invasive tail-cuff method, we measured blood pressure and other parameters in the offspring. Our results demonstrate the following: (1) MLPD caused IUGR (low birthweight) in a dose-dependent manner; (2) Female offspring developed severe hypertension, whereas males were affected only moderately; (3) The blood glucose level was elevated only in females from the moderate MLPD group, although their insulin levels remained normal; (4) Rapid catch-up growth was observed in both sexes, with moderate MLPD females and severe MLPD males becoming overweight. Notably, blood leptin levels in the control group were significantly higher in females than in male offspring and were reduced in females from the severe MLPD group. We conclude that an antenatal MLPD during gestation leads to sexually dimorphic programming in mice.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diet, Protein-Restricted; Dietary Proteins; Female; Fetal Growth Retardation; Heart Rate; Hypertension; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Sex Characteristics

The objective of this study was to determine potential added value of novel risk factors in predicting the development of type 2 diabetes beyond that provided by standard clinical risk factors.. The Atherosclerosis Risk in Communities (ARIC) Study is a population-based prospective cohort study in four U.S. communities. Novel risk factors were either measured in the full cohort or in a case-control sample nested within the cohort. We started with a basic prediction model, previously validated in ARIC, and evaluated 35 novel risk factors by adding them independently to the basic model. The area under the curve (AUC), net reclassification index (NRI), and integrated discrimination index (IDI) were calculated to determine if each of the novel risk factors improved risk prediction.. There were 1,457 incident cases of diabetes with a mean of >7.6 years of follow-up among 12,277 participants at risk. None of the novel risk factors significantly improved the AUC. Forced expiratory volume in 1 s was the only novel risk factor that resulted in a significant NRI (0.54%; 95% CI: 0.33-0.86%). Adiponectin, leptin, γ-glutamyl transferase, ferritin, intercellular adhesion molecule 1, complement C3, white blood cell count, albumin, activated partial thromboplastin time, factor VIII, magnesium, hip circumference, heart rate, and a genetic risk score each significantly improved the IDI, but net changes were small.. Evaluation of a large panel of novel risk factors for type 2 diabetes indicated only small improvements in risk prediction, which are unlikely to meaningfully alter clinical risk reclassification or discrimination strategies.

Topics: Adiponectin; Atherosclerosis; Case-Control Studies; Complement C3; Diabetes Mellitus, Type 2; Factor VIII; Female; Forced Expiratory Volume; Genotype; Humans; Intercellular Adhesion Molecule-1; Leptin; Male; Middle Aged; Prospective Studies; Risk Factors

The adipocyte-derived hormone leptin plays a key role in the regulation of food intake and energy expenditure. Recent studies have suggested that leptin is also involved in the pathogenesis of obesity-associated atherosclerosis and cardiovascular disease. In this study, we investigated the associations of leptin and the soluble leptin receptor (sOb-R) with atherosclerosis in patients with type 2 diabetes.. Three hundred seventeen type 2 diabetic subjects were enrolled in this cross-sectional study. Fasting plasma leptin and sOb-R concentrations were measured by enzyme-linked immunosorbent assays. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasound.. The IMT was significantly associated with sOb-R concentrations, age, diabetes duration, serum creatinine (sCre) levels, and systolic blood pressure (SBP), but not with leptin concentrations or the leptin/sOb-R ratio. The concentrations of leptin (r=0.478, p<0.001) and the sOb-R (r= -0.404, p<0.001) and the leptin/sOb-R ratio (r=0.501, p<0.001) were strongly correlated with IMT in subjects treated with insulin for glycemic control, but not in those treated with diet alone or oral hypoglycemic agents. Multiple regression analysis, including age, sex, diabetes duration, body mass index, SBP, HbA1c, triglycerides, LDL-cholesterol, sCre, smoking, and insulin therapy, revealed that plasma leptin and the leptin/sOb-R ratio were independently associated with IMT in subjects treated with insulin.. Plasma leptin and the leptin/sOb-R ratio are associated with atherosclerosis in patients with type 2 diabetes on insulin therapy, and these associations were independent of obesity and other cardiovascular risk factors.

Topics: Adipocytes; Adult; Aged; Aged, 80 and over; Atherosclerosis; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity; Receptors, Leptin

The aim of this study was to investigate the syste-matic changes in ghrelin and leptin expression, as well as their correlation with insulin resistance (IR) during the development of type 2 diabetes mellitus (T2DM) in a rat model. T2DM was induced in rats fed a high-fat (HF)-diet followed by the intraperitoneal injection of low-dose streptozotocin (STZ, 35 mg/kg). Sixty male Sprague-Dawley rats were divided into 4 groups: the control, HF-4W (HF diet for 4 weeks), HF-8W (HF diet for 8 weeks) and the T2DM group. During the development of T2DM, the production of ghrelin in the stomach and leptin in adipose tissue, the blood levels of ghrelin and leptin, and the expression of leptin and ghrelin receptors (OB-Rb and GHS-R1a) in the hypothalamus were measured by enzyme-linked immunosorbent assay (ELISA), radioimmunology assay (RIA), immunohistochemistry (IHC) and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). IR was assessed using the hyperinsulinemic-euglycemic clamp technique. The production of ghrelin in the stomach, the plasma ghrelin levels and the expression of GHS-R1a in the hypothalamus were significantly reduced in the HF-4W and HF-8W rats compared with the control rats; however, no significant difference was found between the HF-8W and T2DM group rats. Comparing the control to the T2DM group, the production of leptin in the adipose tissue and the serum leptin levels increased, whereas the expression of OB-Rb in the hypothalamus decreased. At the same time, the glucose infusion rate (GIR), indicating the insulin sensitivity, decreased significantly; GIR positively correlated with plasma ghrelin and negatively correlated with serum leptin levels. In conclusion, increased leptin levels are associated with obesity and T2DM, while decreased ghrelin levels are associated with obesity/IR rather than T2DM.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Ghrelin; Insulin; Leptin; Lipids; Male; Rats

To compare maternal and fetal leptin among women without diabetes, women with type 1 diabetes, and women with type 2 diabetes.. In a prospective study at the National Maternity Hospital, Dublin, 40 women with type 1 diabetes, 10 with type 2 diabetes, and 30 without diabetes were enrolled between July 2006 and July 2008. Maternal (36-week) and cord blood leptin was measured by enzyme-linked immunoassay.. No difference was found in maternal leptin among the groups: without diabetes (mean, range): 325 pg/mL, 36-1492 pg/mL; type 1 diabetes: 343.2 pg/mL, 55.5-1108.2 pg/mL; type 2 diabetes: 202.2 pg/mL, 35.1-1553.3 pg/mL (P>0.05). Leptin levels were higher among fetuses of women with type 1 (223 pg/mL, 25.7-810 pg/mL) and type 2 (447.2 pg/mL, 136.3-679 pg/mL) diabetes than among women without diabetes (80.3 pg/mL, 27.3-623.1 pg/mL; P<0.05). The single significant predictor of fetal leptin for the whole cohort was maternal body mass index (BMI; r=0.39, P=0.01). Only third-trimester glycosylated hemoglobin (HbA1c) was significantly related to fetal leptin after controlling for maternal BMI among women with diabetes (r=0.28, P=0.04).. Fetuses of women with diabetes might have some degree of leptin resistance. This might be important in appetite regulation in extrauterine life.

Topics: Adult; Birth Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Fetal Blood; Humans; Infant, Newborn; Insulin Resistance; Leptin; Pregnancy; Pregnancy in Diabetics; Prospective Studies; Young Adult

Marked anthropometric changes are seen in Prader-Willi syndrome (PWS). Emaciation is observed during infancy, whereas severe obesity is found in older children and adults. Growth hormone (GH) treatment modifies the anthropometric changes in PWS patients. In this study, we examined changes in the body composition of 51 PWS patients (age range, 6-54 years; median, 16.5 years), with a focus on the amount of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), VAT/SAT ratio, and serum levels of adipocytokines (adiponectin, leptin, and resistin). The relationships between VAT, SAT, and adipocytokines, and lipid abnormalities and type 2 diabetes in 24 patients with obese PWS were also evaluated. With increasing age, SAT and VAT both increased markedly, but in 18 patients receiving GH treatment, VAT remained low at ≤30 cm(2) . In the GH-completed patients (n = 19), VAT and SAT increased with age to levels similar to those in non-GH-treated patients (n = 14). In the obese group, adiponectin decreased as VAT increased (r = -0.35, P = 0.11). Leptin (r = 0.67, P < 0.001) and resistin (r = 0.45, P = 0.04) showed positive correlations with SAT. Total cholesterol, low-density lipoprotein, and triglyceride levels correlated negatively with adiponectin (r = -0.59, r = -0.56, r = -0.56, respectively, P < 0.05) and hemoglobin A1c (r = -0.42, P = 0.08). To maintain lower VAT and prevent cardiovascular disease risk factors, GH treatment may be advisable even in adult patients with PWS.

Topics: Adiponectin; Adolescent; Adult; Anthropometry; Blood Glucose; Body Fat Distribution; Child; Cholesterol; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Human Growth Hormone; Humans; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Male; Metabolic Diseases; Middle Aged; Obesity; Prader-Willi Syndrome; Resistin; Retrospective Studies; Subcutaneous Fat; Triglycerides; Young Adult

To determine the association between serum levels of high-sensitivity C-reactive protein (hs-CRP) and the incidence of type 2 diabetes in a prospective cohort from southern Spain (Pizarra study).. The study formed part of the Pizarra cohort study, a prospective study started in 1995 with a follow-up of 11 years. Anthropometric and metabolic variables were measured at baseline and at 6 years and 11 years of follow-up. All subjects underwent an oral glucose tolerance test. Serum levels of TNFα and its receptors, hs-CRP, IL-6, leptin, adiponectin and FABP4 were measured at 6 years of follow-up.. After adjusting for age, sex and obesity, subjects with levels of hs-CRP> 2.9 mg/L in the second study (2003-4) had a higher risk of developing type 2 diabetes by the third study (2008-9) (OR = 7.97; 95% CI = 1.72-36.89; P = 0.008), and subjects with adiponectin levels > 13.2 mg/L had a lower risk of developing type 2 diabetes (OR = 0.23, P = 0.02). High values of hs-CRP and high values of adiponectin were associated positively (OR = 8.26; 95% CI = 1.84-37.19; P = 0.006) and negatively (OR = 0.17; 95% CI = 0.04-0.69; P = 0.01), respectively, with the risk of having HbA1c ≥ 6.5% at 11 years of follow-up.. Subjects with high serum hs-CRP levels and low serum adiponectin levels have a higher risk of developing type 2 diabetes within five years.

Topics: Adiponectin; Adult; C-Reactive Protein; Cohort Studies; Cytokines; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Incidence; Leptin; Male; Middle Aged; Prospective Studies; Spain; Statistics as Topic; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Diagnostic Self Evaluation; Female; Humans; Hypoglycemic Agents; Leptin; Male; Metformin; Middle Aged; Randomized Controlled Trials as Topic

Chronic low-grade inflammation and/or obesity are suggested to induce chronic kidney disease (CKD) in patients with type 2 diabetes. This cross-sectional study was performed to investigate the relationship between inflammatory biomarkers and CKD in non-obese patients with type 2 diabetes.. 106 non-obese Japanese patients with type 2 diabetes were recruited for the measurement of GFR, TNF, HMW adiponectin, leptin, hsCRP and some variables including urinary albumin. BMI, serum creatinine, and urinary albumin levels were 22.2 ± 0.2 kg/m(2) (17.1-24.9 kg/m(2)), 0.76 ± 0.02 mg/dl (0.39-1.38 mg/dl), 40.4 ± 4.3mg/gCr (1.6-195.0mg/gCr), respectively. They were stratified into two groups based on the value of eGFR: low eGFR (eGFR<60 ml/min/1.73 m(2)) and normal eGFR (eGFR>60 ml/min/1.73 m(2)). Logistic regression analysis was used for statistical analysis.. Whereas univariate logistic regression analysis showed that gender, diabetes duration, triglyceride, HDL cholesterol, uric acid, urinary albumin, and soluble TNF receptors (sTNF-R1, sTNF-R2) are associated with the development of stage 3 CKD, multivariate logistic regression analysis revealed that sTNF-R2 (Odds ratio 1.003, 95% confidence interval 1.000 to 1.005, P=0.030) showed significant associations with the development of stage 3 CKD.. Circulating TNF receptor 2 is an independent risk factor for CKD in non-obese Japanese patients with type 2 diabetes.

Topics: Adiponectin; Aged; Asian People; Creatinine; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Leptin; Male; Middle Aged; Obesity; Receptors, Tumor Necrosis Factor; Renal Insufficiency, Chronic

The recognition of prediabetic patients with the genetic risk of type 2 diabetes is very important as prediabetes is the last stage when manifestation of diabetes could be prevented by life style modification or drug intervention. This suggests the need for diagnostic processes to trace the risk of patients in time.. The authors looked for metabolic differences between age and BMI in adjusted healthy men with or without first degree type 2 diabetic relatives.. The study included 73 healthy men (21 with and 52 without) first-degree relatives with type 2 diabetes.. Total body and muscle tissue glucose utilization, glucose tolerance did not differ between the two groups, but free fatty acid levels were not suppressed by glucose load in subjects with diabetic relatives. In addition the body fat content, leptin and IL-6 levels were higher, while adiponectin and the free fatty acid/adiponectin ratio were significantly lover in healthy men with diabetic relatives. In this group HDL cholesterol, and the large buoyant LDL fraction were lower whereas the high density LDL - small molecular lipid fraction was higher than those measured in subjects without diabetic relatives.. These data suggest that deteriorations of insulin sensitivity and glucose tolerance is preceded by disturbances of fatty acid metabolism. The observed alteration in free fatty acid/adiponectin ratio, and/or the absence of free fatty acid suppression during glucose tolerance tests could be a screening tool for diabetes risk among men.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Biomarkers; Blood Glucose; Cholesterol, LDL; Diabetes Mellitus, Type 2; Family; Fatty Acids, Nonesterified; Glucose Tolerance Test; Humans; Insulin Resistance; Interleukin-6; Leptin; Male; Mass Screening; Middle Aged

Leptin resistance may be intensified by insulin resistance. This vicious cycle between insulin resistance and leptin resistance may increase feelings of hunger and reduce energy expenditure and ultimately increase obesity. In this study, postprandial changes in leptin, insulin and glucose were compared between healthy subjects and patients with Type 2 diabetes mellitus (DM).. Six men with Type 2 DM and seven healthy men (matched for age and body mass index), after 12 hours of fasting, ate the same Iranian meal (chelo kebab kobibeh) consisting of 46% carbohydrate, 21% protein, 33% fat and 743 kcal energy. Blood samples were obtained before and 1, 2 and 4 hours after the meal, and serum leptin, insulin and glucose levels were measured. The area under incremental curve (AUIC) computed using the Trapezoidal method with fasting values was deducted from each time point, yielding net postprandial changes.. Leptin levels at the first hour were significantly reduced in both groups and then increased at the second and fourth hours after the meal, although not reaching fasting values in the diabetic group at the 4th hour. AUIC for leptin was significantly lower in the diabetic group (p = 0.023). Despite high levels before the meal, the early increase in insulin in the diabetic group was lower and declined more slowly than in the healthy group. The incremental area under the insulin curve was significantly lower in the control group than in the diabetic group (p = 0.006).. It appears that an increased leptin level two hours after the meal is due to increased serum insulin and glucose levels. Leptin AUIC after meals in people with Type 2 DM is lower than in healthy people and may be due to decreased responsiveness to insulin in adipocytes because of insulin resistance.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Fasting; Food; Humans; Insulin; Iran; Leptin; Male; Middle Aged; Postprandial Period

Some studies have pointed to a role of uncoupling protein 3 (UCP3) in the regulation of fat distribution. The aim of our study was to investigate the influence of -55CT polymorphism of UCP3 gene on fat mass and adipocytokines in naïve patients with Type 2 diabetes mellitus.. A population of 57 patients with Type 2 diabetes mellitus and obesity was analyzed in a cross-sectional study. Genotype of UCP3 gene -55CT was studied.. Forty-six patients (80.7%) had the 55CC genotype and 11 patients (19.3%) the 55CT genotype. Fat mass (39.1±15.4 vs 53.3±16.8 kg; p<0.05), weight (92.6±17.7 vs 106.3±17.3 kg; p<0.05), body mass index (36.2±6.5 vs 42.8±5.2 kg/m²; p<0.05), waist circumference (112.8±13.6 vs 127.9±12.3 cm; p<0.05), waist-to-hip ratio (0.96±0.1 vs 1.1±0.2; p<0.05), C reactive protein (6.1±5.1 vs 12.4±6.1 mg/dl; p<0.05) and leptin (92.8±86 vs 114±89 ng/ml; p<0.05) were higher in patients with mutant genotype than in those with wild genotype.. C reactive protein and fat mass were higher in the mutant group of -55 CT UCP3 gene diabetic patients than in wild type patients.

Topics: Adiposity; Aged; Body Fat Distribution; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Genetic Association Studies; Humans; Ion Channels; Leptin; Male; Middle Aged; Mitochondrial Proteins; Mutation; Obesity; Polymorphism, Genetic; Promoter Regions, Genetic; Risk Factors; Spain; Uncoupling Protein 3

To determine whether leptin receptor (LEPR) 223A>G polymorphism has an effect on the plasma leptin levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM). The genotypes and allelic frequencies of the LEPR 223A>G were examined with polymerase chain reaction and restriction fragment length polymorphism in 301 patients with T2DM and 172 unrelated healthy subjects. The plasma concentrations of leptin were determined in all subjects. The mean plasma leptin levels in the T2DM group were significantly higher than that of controls and the plasma levels of leptin were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P < 0.05). The genotype (GG, AG and AA) distribution of 223A>G polymorphism was 58.3, 32.5, and 9.2% in diabetic patients with macroangiopathy, 75.3, 22.1, and 2.6% in patients without macroangiopathy, and 70.3, 27.5, 2.2% in controls respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P < 0.05). The frequency of the allele A was higher in patients with macroangiopathy than in patients without macroangiopathy (25.6 vs. 16.3%; P < 0.05). Moreover, the plasma leptin levels were markedly higher in patients with AA genotype than those with AG or GG genotype in patients with macroangiopathy (P < 0.05). The LEPR 223A>G gene polymorphism associated with a predisposition to increased plasma leptin levels could constitute a useful predictive marker for diabetic macroangiopathy.

Topics: Alleles; Anthropometry; Demography; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Leptin; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Factors

The goal of the study was to determine the association between diabetes and inflammation in clinically diagnosed diabetes patients. We hypothesized that low-grade inflammation in diabetes is associated with the level of glucose control. Using a cross-sectional design we compared pro- and anti-inflammatory cytokines in a community-recruited cohort of 367 Mexican Americans with type 2-diabetes having a wide range of blood glucose levels. Cytokines (IL-6, TNF-α, IL-1β, IL-8) and adipokines (adiponectin, resistin and leptin) were measured using multiplex ELISA. Our data indicated that diabetes as whole was strongly associated with elevated levels of IL-6, leptin, CRP and TNF-α, whereas worsening of glucose control was positively and linearly associated with high levels of IL-6, and leptin. The associations remained statistically significant even after controlling for BMI and age (p=0.01). The association between TNF-α, however, was attenuated when comparisons were performed based on glucose control. Strong interaction effects between age and diabetes and BMI and diabetes were observed for IL-8, resistin and CRP. The cytokine/adipokine profiles of Mexican Americans with diabetes suggest an association between low-grade inflammation and quality of glucose control. Unique to in our population is that the chronic inflammation is accompanied by lower levels of leptin.

Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Body Mass Index; Cross-Sectional Studies; Demography; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Inflammation Mediators; Interleukin-6; Leptin; Male; Mexican Americans; Models, Biological; Odds Ratio; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

BMI is a widely used method to evaluate adiposity. However, it has several limitations, particularly an inability to differentiate lean from fat mass. A new method, body adiposity index (BAI), has been recently proposed as a new measurement capable to determine fat excess better than BMI. The aim of this study was to investigate BAI as a mean to evaluate adiposity in a group of women with familial partial lipodystrophy (FPLD) and compare it with BMI. Thirteen women with FLPD Dunnigan type (FPLD2) and 13 healthy volunteers matched by age and BMI were studied. Body fat content and distribution were analyzed by dual X-ray absorptiometry (DXA). Plasma leptin was also measured. BAI was significantly lower in FPLD2 in comparison to control group (24.6 ± 1.5 vs. 30.4 ± 4.3; P < 0.001) and presented a more significant correlation with total fat (%) (r = 0.71; P < 0.001) and fat Mass (g) (r = 0.80; P < 0.001) than BMI (r = 0.27; P = 0.17 for total fat and r = 0.52; P = 0.006 for fat mass). There was a correlation between leptin and BAI (r = 0.57; P = 0.01), [corrected] but not between leptin and BMI. In conclusion, BAI was able to catch differences in adiposity in a sample of FPLD2 patients. It also correlated better with leptin levels than BMI. Therefore, we provide further evidence that BAI may become a more reliable indicator of fat mass content than the currently available measurements.

Topics: Absorptiometry, Photon; Adipose Tissue; Adiposity; Adult; Body Composition; Body Mass Index; Brazil; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Lipodystrophy, Familial Partial; Reproducibility of Results

Diabetics die from cardiovascular disease at a much greater rate than nondiabetics. Cardiac autonomic imbalance predicts increased cardiovascular risk and mortality. We studied the relationship between cardiac autonomic imbalance and adipose tissue-derived inflammation in newly diagnosed and established type 2 diabetes.. Non-diabetics, newly diagnosed diabetics, and established diabetics were included. Anthropomorphic and biochemical measurements were obtained, and insulin resistance was approximated. Cardiac autonomic function was assessed using conventional measures and with power spectral analysis of heart rate.. Heart rate variability was reduced in all diabetics. Interleukin-6 was higher in diabetics, as was the high molecular weight adiponectin-to-leptin ratio. Interleukin-6 correlated negatively with measures of autonomic balance. Ratios of adiponectin to leptin correlated positively with measures of autonomic balance. Cardiac autonomic imbalance and inflammation occur early in diabetes and are interrelated.. Cardiac autonomic imbalance correlates with the adipose tissue-derived inflammation seen early in type 2 diabetes.

Topics: Adiponectin; Adipose Tissue; Autonomic Nervous System Diseases; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart; Heart Rate; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin

Serotonin and insulin are key regulators of homeostatic mechanisms in the hypothalamus. However, in type 2 diabetes, the hypothalamic responsiveness to serotonin is not clearly established. We used a diabetic model, the Goto Kakizaki (GK) rats, to explore insulin receptor expression, insulin and serotonin efficiency in the hypothalamus and liver by means of Akt phosphorylation. Insulin or dexfenfluramine (stimulator of serotonin) treatment induced Akt phosphorylation in Wistar rats but not in GK rats that exhibit down-regulated insulin receptor. Studies in a neuroblastoma cell line showed that serotonin-induced Akt phosphorylation is PI3-kinase dependent. Finally, in response to food intake, hypothalamic serotonin release was reduced in GK rats, indicating impaired responsiveness of this neurotransmitter. In conclusion, hypothalamic serotonin as insulin efficiency is impaired in diabetic GK rats. The insulin-serotonin cross-talk and impairment observed is one potential key modification in the brain during the onset of diabetes.

Topics: Animals; Blood Glucose; Cell Line, Tumor; Dexfenfluramine; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Humans; Hypothalamus; Insulin; Leptin; Liver; Male; Phosphatidylinositol 3-Kinases; Phosphorylation; Postprandial Period; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptor Cross-Talk; Receptor, Insulin; Serotonin; Serotonin Receptor Agonists

Depression in Type 2 diabetes is associated with obesity, cardiovascular disease, and mortality. Leptin is a plausible mediating factor because it has been related to obesity, depression, and cardiovascular disease in nondiabetic populations. We sought to assess whether leptin is related to depressive symptoms in people with Type 2 diabetes.. One thousand fifty-seven subjects (48.5% women, mean [standard deviation] age = 67.9 [4.2] years) with Type 2 diabetes were assessed for depressive symptoms using the Hospital Anxiety and Depression Scale and other clinical variables by interview and physical examination. Plasma leptin was determined by radioimmunoassay. Multiple linear regression was performed to assess the relationship between depressive symptoms and ln leptin while adjusting for other covariates. A mediation analysis was performed to test whether depressive symptoms mediated the relationship between obesity and leptin.. In univariate analyses, symptoms of depression were related to leptin in men (r = 0.214, p < .001) and women (r = 0.146, p = .007). When adjusting for other covariates including body mass index, ischemic heart disease, glycated hemoglobin, duration of diabetes, and treatment with antidepressants, insulin, or glucocorticoids, using a hierarchical multiple linear regression, depressive symptoms (ln Hospital Anxiety and Depression Scale-depression score) were significant only in men (B = 0.083, standard error = 0.037, p = .03). In the mediation analysis, depressive symptoms partially mediated the effect of obesity (body mass index) on leptin in men but not in women.. There is a sex difference in the relationship between depressive symptoms and leptin in people with Type 2 diabetes, with a positive association in men but not in women. Adipocyte-derived factors are associated with depressive symptoms in Type 2 diabetes.

Topics: Adipose Tissue; Aged; Body Mass Index; Comorbidity; Depression; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Myocardial Ischemia; Obesity; Prospective Studies; Psychiatric Status Rating Scales; Radioimmunoassay; Regression Analysis; Scotland; Sex Characteristics; Sex Factors

For some years now, reduced testosterone levels have been related to obesity, insulin resistance, type 2 diabetes, heart disease, benign prostatic hypertrophy and even prostate cancer--often considered guilty more by association, than actual cause--with little attention paid to the important role of increased intracellular oestrogen, in the pathogenesis of these chronic diseases. In the final stage of the steroidogenic cascade, testosterone is metabolised to oestradiol by P450 aromatase, in the cytoplasm of adipocytes, breast cells, endothelial cells and prostate cells, to increase intracellular oestradiol concentration at the expense of testosterone. It follows therefore, that any compound that up-regulates aromatase, or any molecule that mimics oestrogen, will not only increase the activation of the mainly proliferative, classic ER-α, oestrogen receptors to induce adipogenesis and growth disorders in oestrogen-sensitive tissues, but also activate the recently identified transmembrane G protein-coupled oestrogen receptors (GPER), and deleteriously alter important intracellular signalling sequences, that promote mitogenic growth and endothelial damage. This paper simplifies how stress, xeno-oestrogens, poor dietary choices and reactive toxins up-regulate aromatase to increase intracellular oestradiol production; how oestradiol in combination with leptin and insulin cause insulin resistance and leptin resistance through aberrant serine phosphorylation; how the increased oestradiol, insulin and leptin stimulate rapid, non-genomic G protein-coupled phosphorylation cascades, to increase fat deposition and create the vasoconstrictive, dyslipidemic features of metabolic syndrome; how aberrant GPER signalling induces benign prostatic hypertrophy; and how increased intracellular oestradiol stimulates mitogenic change and tumour-cell activators, to cause prostate cancer. In essence, the up-regulation of aromatase produces increased intracellular oestradiol, increases ER-α activation and increases GPER activation, in combination with insulin, to cause aberrant downstream transduction signaling, and thus induce metabolic syndrome and mitogenic prostate growth. To understand this fact, that raised intracellular oestradiol levels in men, induce and promote obesity, gynecomastia, metabolic syndrome, type two diabetes, benign prostatic hypertrophy and prostate cancer, rather than low testosterone, represents a shift in medical thinking, a new awareness, that will reduce

Topics: Adiposity; Aromatase; Body Fat Distribution; Diabetes Mellitus, Type 2; Estrogen Receptor alpha; Estrogens; Gynecomastia; Humans; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Syndrome; Obesity; Phosphorylation; Prostatic Diseases; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction; Testosterone; Up-Regulation

Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic β-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 μg·kg⁻¹·day⁻¹), amylin (A; 100 μg·kg⁻¹·day⁻¹), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPKα2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes.

Topics: Animals; Anti-Obesity Agents; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Resistance; Drug Therapy, Combination; Energy Intake; Energy Metabolism; Hypoglycemic Agents; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Triglycerides; Weight Loss

Adiponectin and leptin and their ratio have been associated with incident type 2 diabetes (T2DM), although the data presented are conflicting and the populations studied have been small. In this large, prospective, nested, case referent study, we hypothesized that these associations are sex specific and may be modified by insulin resistance.. Men and women aged 30-60 years with incident T2DM (n=640) and a prior health survey within the Västerbotten Intervention Programme (VIP) and matched referents (n=1564) were identified. Using conditional logistic regression analyses, we tested whether baseline plasma adiponectin and leptin levels and their ratio independently predicted incident T2DM, stratified for gender and insulin resistance.. Adjusted for traditional risk factors, fourth-quartile levels of adiponectin were associated with a reduced risk of T2DM in men [odds ratio (OR) 0.55 (0.36-0.86)] and women [OR 0.47 (0.27-0.83)]. Quartile four of the leptin/adiponectin ratio predicted T2DM in both men [OR 3.08 (1.68-5.67)] and women [OR 3.31 (1.56-7.03)], whereas quartile-four levels of leptin predicted T2DM only in men [OR 2.30 (1.32-4.02)]. When stratified for insulin sensitivity and adjusted for body mass index (BMI), log(e)-transformed leptin predicted T2DM in insulin-sensitive men [OR 1.56 (1.13-2.17)] but not in insulin-resistant men [OR 1.03 (0.76-1.39)]. The effect of adiponectin and the leptin/adiponectin ratio was not influenced by the insulin sensitivity status.. Leptin in men and adiponectin in both sexes were independent predictors of T2DM. The association was modified by the degree of insulin sensitivity. The leptin/adiponectin ratio may add predictive information beyond the separate hormones.

Topics: Adiponectin; Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Insulin Resistance; Leptin; Male; Middle Aged; Registries; Risk Factors; Sex Factors; Sweden

We aimed to evaluate whether leptin and ghrelin responses to cardiopulmonary bypass (CPB) are dependent on type 2 diabetes and whether these responses are associated with interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), cortisol and insulin.. We examined stress-response patterns in plasma leptin, ghrelin, hsCRP, IL-6, cortisol and insulin levels before and up to 5 days after cardiopulmonary bypass in 20 patients with type 2 diabetes and 20 patients without diabetes.. Plasma leptin levels increased significantly in both groups (p<0.05) and rose significantly higher in diabetics when compared with nondiabetic patients (p=0.004). Plasma ghrelin levels increased significantly only in diabetics (p=0.033). Patients with and without diabetes showed significantly elevated serum concentrations of IL-6, hsCRP, cortisol and insulin (p<0.005 for IL-6, hsCRP; p<0.05 for cortisol, insulin) but the difference between the two groups was nonsignificant. Leptin was independently predicted by hsCRP (p<0.05, F=2.9), gender (women p<0.001, F=4.7), body mass index (BMI p<0.0001, F=6.1) whereas ghrelin levels were not associated with any variables in the total patient population. (critical F=2.26, p≤0.05).. Acute phase response in diabetics differs by higher leptin levels independent of BMI, gender and IL-6, hsCRP, insulin and cortisol levels.

Topics: Blood Glucose; Body Mass Index; C-Reactive Protein; Cardiopulmonary Bypass; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Ghrelin; Humans; Hydrocortisone; Insulin; Interleukin-6; Leptin; Male; Middle Aged

The aim of our work was to investigate the hormones that control glycemic status and in vitro β-cell function in diabetes mellitus after a duodenal-jejunal exclusion in Goto-Kakizaki rats (Taconic, Denmark).. Twenty-three rats (age, 12-14 wk) were randomized as follows: group 1 (n = 14), no intervention (control); or group 2 (n = 9), duodenal-jejunal exclusion.. In group 2, levels of glucagon and leptin were lower than in group 1 at 1 week and at 8 weeks. Glucagon-like peptide 1 levels had a significant increase at 8 weeks from basal value in group 2 and this value was higher than in group 1. The insulin secretion at 60 minutes in group 2 was higher than in group 1 (group 1, 12.9 ± 12.0 μg/L vs group 2, 41.9 ± 36.3 μg/L; P < .05). Messenger RNA (mRNA) expression of insulin at 2 months was higher in the rat pancreas of the experimental group than in the control group (group 1, .99 ± .48 mRNA amount vs group 2, 1.66 ± .33 mRNA amount; P < .05).. Gastrojejunal bypass in this model improves glucose ratios, with a significant increase of glucagon-like peptide 1 and decrease of homeostasis model assessment, glucagon, and leptin levels after surgery. This type of surgery improves mRNA insulin expression in pancreatic islets and insulin secretion as well.

Topics: Animals; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Insulin; Insulin-Secreting Cells; Leptin; Male; Models, Animal; Pancreas; Random Allocation; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Animal models of type 2 diabetes exhibit reduced peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) messenger RNA (mRNA) levels, which are associated with decreased oxidative capacity, in skeletal muscles. In contrast, animal models with metabolic syndrome show normal PGC-1α mRNA levels. We hypothesized that a high-fat diet decreases PGC-1α mRNA levels in skeletal muscles of rats with metabolic syndrome, reducing muscle oxidative capacity and accelerating metabolic syndrome or inducing type 2 diabetes. We examined mRNA levels and fiber profiles in the soleus muscles of rats with metabolic syndrome (SHR/NDmcr-cp [cp/cp]; CP) fed a high-fat diet. Five-week-old CP rats were assigned to a sedentary group (CP-N) that was fed a standard diet (15.1 kJ/g, 23.6% protein, 5.3% fat, and 54.4% carbohydrates) or a sedentary group (CP-H) that was fed a high-fat diet (21.6 kJ/g, 23.6% protein, 34.9% fat, and 25.9% carbohydrates) and were housed for 10 weeks. Body weight, energy intake, and systolic blood pressure were higher in the CP-H group than in the CP-N group. Nonfasting glucose, triglyceride, total cholesterol, and leptin levels were higher in the CP-H group than in the CP-N group. There was no difference in insulin levels between the CP-N and CP-H groups. Muscle PGC-1α mRNA levels and succinate dehydrogenase activity were lower in the CP-H group than in the CP-N group. We concluded that a high-fat diet reduces PGC-1α mRNA levels and oxidative capacity in skeletal muscles and accelerates metabolic syndrome.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Fats; Energy Intake; Insulin; Leptin; Male; Metabolic Syndrome; Muscle, Skeletal; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Rats; Rats, Inbred Strains; RNA-Binding Proteins; RNA, Messenger; Sedentary Behavior; Succinate Dehydrogenase; Transcription Factors; Triglycerides

Cardiac autonomic neuropathy (CAN) is a common complication of diabetes associated with poor prognosis. In addition, the autonomic imbalance is associated with cardiovascular disease (CVD) in diabetes. It is thought that adipocytokines contribute to the increased risk of vascular complications in patients with type 2 diabetes mellitus (T2DM). However, literature data on the association between CAN with adipocytokines such as leptin, tumor necrosis factor-alpha (TNF-alpha), adiponectin in subjects with T2DM is limited.Therefore, in the present study, we examined the relationship between fasting serum leptin, TNF- alpha and adiponectin and CAN in Korean T2DM patients.. A total of 142 T2DM patients (94 males, 48 females) were recruited. CAN was assessed by the five tests according to the Ewing's protocol and the time and frequency domain of the heart rate variability (HRV) was evaluated. Serum TNF-alpha and adiponectin levels were measured using enzyme-linked immunosorbent assay and serum leptin levels were measured using radioimmunoassay.. Although, the mean levels of leptin, TNF-alpha and adiponectin were not significantly different between the groups with and without CAN, the levels of leptin and adiponectin had a tendency to increase as the score of CAN increased (p = 0.05, p = 0.036). Serum leptin levels demonstrated a negative correlation with low frequency (LF) in the upright position (p = 0.037). Regarding TNF-alpha, a significant negative correlation was observed with SDNN and RMSSD in the upright position (p = 0.023, p = 0.019). Adiponectin levels were not related to any HRV parameters. Multivariate logistic regression analysis demonstrated that the odds of CAN increased with a longer duration of diabetes (1.25, [1.07-1.47]) and higher homeostatic model of assessment-insulin resistance (HOMA-IR) (5.47, [1.8-16.5]). The relative risks for the presence of CAN were 14.1 and 51.6 for the adiponectin 2nd, 3rd tertiles when compared with first tertile (p-value for trend = 0.022).. In the present study, the higher serum adiponectin levels and HOMA-IR were associated with an increased risk for the presence of CAN. Also, the CAN score correlated with the serum adiponectin. Serum adipocytokines such as leptin and TNF-alpha were significantly correlated with parameters of HRV, representative markers of CAN. Future prospective studies with larger number of patients are required to establish a direct relationship between plasma adipocytokine concentrations and the development or severity of CAN.

Topics: Adipokines; Adiponectin; Adult; Aged; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Heart Diseases; Heart Rate; Humans; Korea; Leptin; Logistic Models; Male; Middle Aged; Severity of Illness Index; Tumor Necrosis Factor-alpha

Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg⁻¹ d⁻¹ metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db+mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Conditioning, Psychological; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Resistance; Fear; Hippocampus; Hypoglycemic Agents; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Maze Learning; Memory; Metformin; Mice; Mice, Obese; Neurofibrillary Tangles; Phosphorylation; Plaque, Amyloid; Protein Phosphatase 2; Synaptophysin; tau Proteins; Vesicular Transport Proteins

Obesity and diabetes have become the most common human health problems worldwide. Obesity's contribution to type 2 diabetes might be due to dysregulation of adipokines and glucose uptake.. In this study, we performed in-vivo and in-vitro studies to evaluate the effects of Platycodon grandiflorum extract (PGE) on adipokines and glucose uptake. Before study, platycodin D concentrations were analysed by HPLC in PGE prepared in water, in 50% ethanol and in 80% ethanol, and we selected the 80% ethanol extract as the PGE for this study based on the HPLC results.. We found that inclusion of PGE in the high-fat diet (HFD) markedly attenuated food intake, body weight, epididymal fat weight, adipocyte size and blood glucose levels by the oral glucose tolerance test in mice, and maintained serum levels of adiponectin, resistin, leptin, fructosamine and triglycerides. Gene expression analysis revealed that PGE up-regulated adiponectin, and down-regulated TNF-α and leptin in fat tissue. In L6 muscle cells in vitro, PGE increased insulin-stimulated glucose uptake..   We conclude that PGE may improve obesity in mice fed an HFD and glucose uptake in L6 muscle cells by modifying adipokines, and could offer clinical benefits as a supplement to treat obesity and diabetes.

Topics: Adipocytes; Adipokines; Adiponectin; Animals; Blood Glucose; Body Weight; Cell Line; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Intake; Fructosamine; Gene Expression; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Leptin; Male; Mice; Mice, Inbred ICR; Muscle Cells; Obesity; Phytotherapy; Plant Extracts; Platycodon; Resistin; Saponins; Triglycerides; Triterpenes; Tumor Necrosis Factor-alpha

Dysregulation of hepatic triglyceride (TG)-rich very low-density lipoproteins (VLDL-TG) in obesity and type 2 diabetes contributes to the dyslipidemia that leads to cardiovascular morbidity. The central nervous system (CNS), particularly the hypothalamus, regulates hepatic lipid metabolism. Although the underlying neurocircuitry remains elusive, glycine has been documented to enhance CNS N-methyl-d-aspartate (NMDA) receptor-mediated transmission.. We tested the hypothesis that glycine regulates hepatic VLDL-TG secretion by potentiating NMDA receptor-mediated transmission in the CNS.. Using 10-hour fasted male Sprague-Dawley rats implanted with stereotaxic cannulae into an extrahypothalamic region termed the dorsal vagal complex (DVC) and vascular catheters to enable direct DVC infusion and blood sampling, respectively, the rate of hepatic VLDL-TG secretion was measured following tyloxapol (an inhibitor of lipoprotein lipase) injection. Direct DVC infusion of glycine lowered VLDL-TG secretion, whereas NMDA receptor blocker MK-801 fully negated glycine's effect. NR1 subunit of NMDA receptor antagonist 7-chlorokynurenic acid, adenoviral injection of NR1 short hairpin RNA (shRNA), and hepatic vagotomy also nullified glycine's effect. Finally, DVC glycine normalized the hypersecretion of VLDL-TG induced by high-fat feeding.. Molecular and pharmacological inhibition of the NR1-containing NMDA receptors in the DVC negated the ability of glycine to inhibit hepatic secretion of VLDL-TG in vivo. Importantly, the hypersecretion of VLDL-TG from the liver induced by a model of high-fat feeding was restored by the hepatic lipid control of CNS glycine sensing. These findings collectively suggest that glycine or glycine analogues may have therapeutic benefits in lowering plasma lipid levels in diabetes and obesity by triggering the CNS.

Topics: Adiponectin; Animals; Cholesterol, VLDL; Diabetes Mellitus, Type 2; Dietary Fats; Dyslipidemias; Fatty Acids, Nonesterified; Glycine; Hypothalamus; Insulin; Leptin; Lipid Metabolism; Liver; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stearoyl-CoA Desaturase; Triglycerides; Vagotomy

People with obesity and type 2 diabetes are at increased risk of cognitive impairment. We aimed to investigate the association of leptin with cognitive abilities in an elderly population with type 2 diabetes. We performed a cross-sectional study of 1057 men and women aged 60-75 years with type 2 diabetes living in Lothian (Scotland). A cognitive battery was administered. Prior intelligence was estimated from vocabulary testing and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning leptin levels and cognitive ability and estimated cognitive change were tested. Higher leptin levels were associated with significantly poorer estimated overall cognitive decline, and poorer performance in 2 cognitive domains assessing mental flexibility and executive function, only amongst men (p < 0.05). High morning leptin levels in elderly men with type 2 diabetes are associated with estimated age-related cognitive change.

Topics: Aged; Cognition Disorders; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Linear Models; Male; Middle Aged; Neuropsychological Tests; Radioimmunoassay; Retrospective Studies; Verbal Learning

In normal platelets, insulin inhibits agonist-induced Ca(2+) mobilization by raising cyclic AMP. Platelet from patients with type 2 diabetes are resistant to insulin and show increased Ca(2+) mobilization, aggregation and procoagulant activity. We searched for the cause of this insulin resistance.. Platelets, the megakaryocytic cell line CHRF-288-11 and primary megakaryocytes were incubated with adipokines and with plasma from individuals with a disturbed adipokine profile. Thrombin-induced Ca(2+) mobilization and signaling through the insulin receptor and insulin receptor substrate 1 were measured. Abnormalities induced by adipokines were compared with abnormalities found in platelets from patients with type 2 diabetes.. Resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 left platelets unchanged but induced insulin resistance in CHRF-288-11 cells. Interleukin-6, tumor necrosis factor-α and visfatin had no effect. These results were confirmed in primary megakaryocytes. Contact with adipokines for 2 hours disturbed insulin receptor substrate 1 Ser(307)-phosphorylation, while contact for 72 hours caused insulin receptor substrate 1 degradation. Plasma with a disturbed adipokine profile also made CHRF-288-11 cells insulin-resistant. Platelets from patients with type 2 diabetes showed decreased insulin receptor substrate 1 expression.. Adipokines resistin, leptin, plasminogen activator-1 and retinol binding protein 4 disturb insulin receptor substrate 1 activity and expression in megakaryocytes. This might be a cause of the insulin resistance observed in platelets from patients with type 2 diabetes.

Topics: Adipokines; Blood Platelets; Calcium; Cell Line; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Male; Megakaryocytes; Metabolic Syndrome; Plasminogen Activator Inhibitor 1; Resistin; Retinol-Binding Proteins, Plasma

n-3 Polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and taurine are functional compounds abundantly present in seafoods. In this study, we examined the combined effects of EPA- and DHA-rich fish oil and taurine on white adipose tissue (WAT) weight and blood glucose levels in diabetic/obese KK-A(y) mice. After a 4-wk administration of experimental diets (soybean oil or fish oil, supplemented with 0%, 2%, or 4% taurine), the increase in WAT weight of the mice fed the "fish oil + 4% taurine" diet was significantly suppressed compared to the "soybean oil + 4% taurine" and "fish oil only" diets. Serum triglycerides, free fatty acids, and total cholesterol levels decreased by fish oil administration. In addition, fish oil and taurine increased the activity of acyl-CoA oxidase, which is the rate-limiting enzyme of peroxisomal β-oxidation, increased in the liver of KK-A(y) mice. The activity of fatty acid synthase decreased by fish oil diets. Furthermore, blood glucose and insulin levels were significantly lower in the mice fed fish oil than in the soybean oil-fed mice. In fish oil + 4% taurine group, hyperglycemia and hyperinsulinemia were effectively improved in KK-A(y) mice compared to the fish oil only groups. In particular, the combination of fish oil and taurine enhanced the glucose transporter 4 (GLUT4) distribution in the plasma membrane of muscle tissue. These results suggest that EPA- and DHA-rich fish oil, especially in combination with taurine, exhibits preventive effects on WAT weight gain and hyperglycemia in diabetic/obese KK-A(y) mice.

Topics: Acyl-CoA Oxidase; Adipose Tissue, White; Adiposity; Animals; Diabetes Mellitus, Type 2; Fatty Acid Synthases; Fatty Acids, Omega-3; Fish Oils; Functional Food; Glucose Transporter Type 4; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Leptin; Liver; Male; Mice; Mice, Obese; Muscle, Skeletal; Obesity; Seafood; Taurine

Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45-65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p<0.01) and lean controls (p<0.05). Two T2DM subjects failed to produce any detectable melatonin, although did exhibit plasma cortisol rhythms comparable to others in the group. Consistent with the literature, there was a significant (p<0.001) effect of subject group on absolute plasma leptin concentration and, when expressed relative to an individual's 24-hour mean, plasma leptin showed significant (p<0.001) diurnal variation. However, there was no difference in amplitude or timing of leptin rhythms between experimental groups. There was also no significant effect of time on leptin mRNA expression. Despite an overall effect (p<0.05) of experimental group, post-hoc analysis revealed no significant pair-wise effects of group on leptin mRNA expression. Altered plasma melatonin rhythms in weight-matched T2DM and non-diabetic individuals supports a possible role of melatonin in T2DM aetiology. However, neither obesity nor T2DM changed 24-hour rhythms of plasma leptin relative to cycle mean, or expression of subcutaneous adipose leptin gene expression, compared with lean subjects.

Topics: Analysis of Variance; Circadian Rhythm; Diabetes Mellitus, Type 2; DNA Primers; Gene Expression Profiling; Humans; Leptin; Male; Melatonin; Middle Aged; Obesity; Radioimmunoassay; RNA, Messenger; Thinness

The objective of the present study was to determine the suitability of a swine breed with leptin resistance and predisposition to obesity (the Iberian pig) as model for studies on metabolic syndrome and type 2 diabetes. Thus, six Iberian sows had ad libitum access to food enriched with saturated fat (SFAD group; food consumption was estimated to be 4.5 kg/animal/day) whilst four females acted as controls and were fed with 2 kg/animal/day of a commercial maintenance diet. After three months of differential feeding, SFAD animals developed central obesity, dyslipidemia, insulin resistance and impaired glucose tolerance, and elevated blood pressure; the five parameters associated with the metabolic syndrome. Thus, the current study characterizes the Iberian pig as a robust, amenable, and reliable translational model for studies on nutrition-associated diseases.

Topics: Animals; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Female; Humans; Leptin; Metabolic Syndrome; Obesity; Species Specificity; Swine

The finding of adipocyte-derived hormone leptin as an overstimulator of sympathetic activity brought a new perspective to the pathophysiological mechanisms of obesity-hypertension.. As aldosterone also increases sympathetic activity, we aimed to assess the relationship between sympathetic overactivity and plasma leptin and aldosterone levels in resistant hypertension (RHTN), comparing the groups with and without T2D.. Twenty-five RHTN patients underwent ambulatory electrocardiography to analyze heart rate variability (HRV) in time and frequency domains, which were stratified into two periods: 24 hours and daytime (DT), comprising the records between 2:00 p.m to 6:00 p.m (time domain) and one hour at 3:00 p.m (frequency domain).. T2D group (n=10) had higher serum aldosterone and plasma leptin levels than the non-T2D (n=15) (26.0 ± 11.5 vs. 16.9 ± 7.0 ng/dL - p=0.021; 81.368.7 ± 47.086.1 vs 41.228.1 ± 24.523.1 pg/mL - p=0.048, respectively). Both groups had aldosterone correlated with HRV in frequency domain. Non-T2D had aldosterone correlated with DT low frequency in normalized units (LF nu) (r=0.6 [0.12-0.85] p=0.018) and DT high frequency in normalized units (HF nu) (r=-0.6 [-0.85- -0.12] p=0.018). Type-2-diabetes group had aldosterone correlated with DT LF nu (r=0.72 [0.16-0.93] p=0.019) and DT HF nu (r=-0.72 [-0.93- -0.16] p=0.019). However, despite of the importance of leptin in sympathetic overactivity in hypertension, leptin did not correlate with HRV.. Aldosterone seems to overdrive sympathetic activity in RHTN with and without T2D. This information combined with the clinical efficacy of mineralocorticoid receptor blocker in RHTN may reinforce that aldosterone is a major player to be a therapeutic target in RHTN.

Topics: Adult; Aldosterone; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Drug Resistance; Female; Heart Rate; Humans; Hypertension; Leptin; Male; Middle Aged; Statistics, Nonparametric; Sympathetic Nervous System

In the face of the current obesity epidemic, the nature of the relationship between overnutrition and type 2 diabetes is of great importance. Obesity can be considered a state of excessive insulin action that elicits a series of cellular homeostatic responses, producing systemic insulin resistance. These responses occur in four steps: homologous desensitization to insulin action, leptin secretion, inflammation, and, finally, a counter-inflammatory phase that serves to conserve energy storage. The molecular mechanisms underlying these steps are discussed in the context of potential new therapeutic approaches.

Topics: Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Obesity

Rhodiola species are traditionally used as tonics and stimulants to treat asthenia, suggesting their possible regulatory effect on energy metabolism. Clinical trials have demonstrated their glucose-lowering effect in type 2 diabetes.. To examine the effects of Rhodiola on glucose and lipid metabolism in the metabolic syndrome and type 2 diabetes.. Zucker diabetic fatty (ZDF) rats were treated with Rhodiola crenulata root (RCR) powder (100 and 500 mg/kg, by gavage, once daily for 4 weeks). In addition, the effects of RCR on sucrose-induced acute hyperglycemia in mice and olive oil-induced hypertriglyceridemia in rats were also examined. Biochemical variables were determined enzymatically or by ELISA.. In ZDF rats, RCR treatment decreased the increased plasma insulin and triglyceride concentrations at baseline, the index of the homeostasis model assessment of insulin resistance (HOMA-IR) and excessive hepatic triglyceride accumulation. This treatment also inhibited abnormal increases in plasma glucose and insulin concentrations during oral glucose tolerance test. Furthermore, RCR reversed the increased adipose insulin resistance index, and accelerated the decline of plasma concentrations of non-esterified fatty acids after exogenous glucose stimulation. However, RCR minimally affected sucrose-induced acute hyperglycemia in mice and olive oil-induced acute hypertriglyceridemia in rats.. The present results demonstrate that RCR treatment improves metabolic derangements in animal model of the metabolic syndrome and type 2 diabetes. Our findings may provide new pharmacological basis of therapeutics for the adaptogenic plants to treat metabolic derangements-associated disorders, such as asthenia.

Topics: Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hyperglycemia; Hypertriglyceridemia; Hypoglycemic Agents; Leptin; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Zucker; Rhodiola; Triglycerides

Sleep deficits associated with sleep apnea and insomnia increase the risk of vascular inflammation and insulin resistance. This study examined the hypothesis that inflammation markers are higher in those diabetic patients who experience sleep deficits compared with those without any history of a sleep disorder.. Fasting blood was obtained after written informed consent, and sleep disorder histories were obtained from type 2 diabetic patients (n=81) attending clinics of the Louisiana State University Health Sciences Center.. There was a significant correlation between body weight and leptin, and leptin in turn was significantly correlated with 10-kDa interferon-γ-induced protein (IP-10) levels and insulin resistance in type 2 diabetic patients. Fasting blood levels of leptin, IP-10, and insulin resistance were significantly elevated in patients with sleep deficits compared with diabetics with normal sleep patterns. There were no differences in glycosylated hemoglobin (HbA1c) or fasting glucose in patients with sleep deficits compared with those with normal sleep patterns. Sleep deficits increase circulating levels of leptin, IP-10, and insulin resistance compared to levels seen in patients with diabetes who reported no difficulty with sleep. Patients with sleep apnea had significantly lower hydrogen sulfide (H(2)S) levels compared with patients with normal sleep patterns or patients with insomnia. Low levels of circulating H(2)S could contribute to higher vascular inflammation in patients with sleep apnea.. These results suggest that sleep apnea is associated with a decrease in circulating H(2)S and sleep disorders increase the risk of inflammation and insulin resistance, which can contribute to the increased risk of vascular disease in subjects with type 2 diabetes.

Topics: Adult; Body Weight; Case-Control Studies; Chemokine CXCL10; Diabetes Mellitus, Type 2; Female; Humans; Hydrogen Sulfide; Insulin Resistance; Leptin; Male; Middle Aged; Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders

The number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome.. C57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student's t-test or factorial ANOVA followed by a Fisher's LSD post hoc test.. Infarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR.. ACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Caloric Restriction; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Receptors, LDL; Time Factors; Ventricular Function, Left; Ventricular Pressure

The kallikrein-kinin system (KKS) has been previously linked to glucose homeostasis. In isolated muscle or fat cells, acute bradykinin (BK) stimulation was shown to improve insulin action and increase glucose uptake by promoting glucose transporter 4 translocation to plasma membrane. However, the role for BK in the pathophysiology of obesity and type 2 diabetes remains largely unknown. To address this, we generated genetically obese mice (ob/ob) lacking the BK B2 receptor (obB2KO). Despite similar body weight or fat accumulation, obB2KO mice showed increased fasting glycemia (162.3 ± 28.2 mg/dl vs 85.3 ± 13.3 mg/dl), hyperinsulinemia (7.71 ± 1.75 ng/ml vs 4.09 ± 0.51 ng/ml) and impaired glucose tolerance when compared with ob/ob control mice (obWT), indicating insulin resistance and impaired glucose homeostasis. This was corroborated by increased glucose production in response to a pyruvate challenge. Increased gluconeogenesis was accompanied by increased hepatic mRNA expression of forkhead box protein O1 (FoxO1, four-fold), peroxisome proliferator-activated receptor gamma co-activator 1-alpha (seven-fold), phosphoenolpyruvate carboxykinase (PEPCK, three-fold) and glucose-6-phosphatase (eight-fold). FoxO1 nuclear exclusion was also impaired, as the obB2KO mice showed increased levels of this transcription factor in the nucleus fraction of liver homogenates during random feeding. Intraportal injection of BK in lean mice was able to decrease the hepatic mRNA expression of FoxO1 and PEPCK. In conclusion, BK modulates glucose homeostasis by affecting hepatic glucose production in obWT. These results point to a protective role of the KKS in the pathophysiology of type 2 diabetes mellitus.

Topics: Analysis of Variance; Animals; Bradykinin; Cell Line, Tumor; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Humans; Insulin; Insulin Resistance; Kallikrein-Kinin System; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); PPAR gamma; Rats; Receptors, Bradykinin

To assess the association between leptin gene promoter methylation and serum leptin concentrations in patients with impaired glucose regulation (IGR) and type 2 diabetes mellitus (T2DM).. Methylation status of leptin gene promoter was determined with methylation-specific polymerase chain reaction. Serum leptin concentrations were determined using enzyme-linked immunosorbent assay.. Among three groups of individuals with different levels of glucose, the methylation rates of leptin gene in IGR and T2DM groups were 43.6 % and 31.5 %, respectively, which were significantly lower than that of healthy subjects (59.2%; Chi-square=22.499 and 5.109, respectively, P<0.05). A lower methylation rate was also observed in T2DM group compared with IGR group (Chi-square=3.962, P<0.05). Leptin levels in both T2DM and IGR groups were elevated compared with normoglycemic subjects, but only T2DM group was significantly higher (q=6.81, P<0.01). Linear regression analysis indicated that serum leptin concentrations has increased along with declining of DNA methylation rate (r=-0.95, P<0.01).. Lower levels of leptin gene promoter DNA methylation and serum leptin concentrations are associated with the development of diabetes. Measurement of the methylation status of leptin gene promoter and expression can facilitate early intervention of the disease.

Topics: Diabetes Mellitus, Type 2; DNA Methylation; Female; Genetic Predisposition to Disease; Glucose; Humans; Leptin; Male; Middle Aged; Promoter Regions, Genetic

The TALLYHO/Jng (TH) mouse is an inbred polygenic model for type 2 diabetes (T2D) with moderate obesity. Both male and female TH mice are characterized by increased body and fat pad weights, hyperleptinemia, hyperinsulinemia, and hyperlipidemia. Glucose intolerance and hyperglycemia are exhibited only in males. Reduced 2-deoxy-glucose uptake occurs in adipose tissue and skeletal muscle of male TH mice. While both sexes of TH mice exhibit enlarged pancreatic islets, only males have degranulation and abnormal architecture in islets. Endothelial dysfunction and considerably decreased bone density are also observed in male TH mice. The blood pressure of male TH mice is normal. Genetic outcross experiments with non-diabetic strains revealed multiple susceptibility loci (quantitative trait loci) for obesity, hypertriglyceridemia, hypercholesterolemia, and hyperglycemia. In conclusion, TH mice encompass many aspects of polygenic human diabetes and are a very useful model for T2D.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Humans; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Insulin Resistance; Leptin; Male; Mice; Obesity; Phenotype; Quantitative Trait Loci

The effects of type 2 diabetes on bone mass and microstructure are not clear. The aim of this study was to evaluate bone microstructural properties and volumetric bone mineral density (vBMD) in type 2 diabetic Goto-Kakizaki non-obese rats after gastrojejunal bypass and their relationship with hormonal parameters.. We designed an experimental study in Goto-Kakizaki rats with and without gastrojejunal bypass, performing densitometric and microstructural studies of the distal femur using X-ray computed microtomography (micro-CT). Levels of insulin, glucagon, leptin, and glucagon-like peptide-1 (GLP-1) were also determined.. We observed reduced cortical (1,488.92 ± 98.2 vs. 1,727.92 ± 133.45 mg/cm(3), p = 0.028) and trabecular (180.8 ± 9 vs. 261.23 ± 45.54 mg/cm(3), p = 0.036) vBMD in operated rats. Bone volume fraction (BV/TV) and trabecular connectivity were reduced in operated rats, while there was a reduction in cortical thickness and an increase in rod-like trabeculae at the expense of plate-like trabeculae. Leptin was reduced (1,042 ± 549 vs. 2,447 ± 1,035 pg/ml, p = 0.05) and GLP-1 increased (1.62 ± 0.32 vs. 0.96 ± 0.1 ng/ml, p = 0.008) but only leptin showed a significant association with vBMD CONCLUSIONS: In type 2 diabetic Goto-Kakizaki rats, gastrojejunal bypass produces a reduction in cortical and trabecular bone mineral density and a deterioration in bone quality that could be explained, in part, by the reduction in leptin levels.

Topics: Animals; Bariatric Surgery; Biomarkers; Biomechanical Phenomena; Bone Density; Diabetes Mellitus, Type 2; Femur; Leptin; Male; Rats; Reproducibility of Results; X-Ray Microtomography

The study herein determined the role of nuclear factor erythoid 2-related factor 2 (Nrf2) in the pathogenesis of hepatic steatosis, insulin resistance, obesity, and type 2 diabetes. Lep(ob/ob)-Keap1-knockdown (KD) mice, which have increased Nrf2 activity, were generated. Markers of obesity and type 2 diabetes were measured in C57Bl/6J, Keap1-KD, Lep(ob/ob), and Lep(ob/ob)-Keap1-KD mice. Lep(ob/ob)-Keap1-KD mice exhibited less lipid accumulation, smaller adipocytes, decreased food intake, and reduced lipogenic gene expression. Enhanced Nrf2 activity impaired insulin signaling, prolonged hyperglycemia in response to glucose challenge, and induced insulin resistance in Lep(ob/ob) background. Nrf2 augmented hepatic steatosis and increased lipid deposition in liver. Next, C57Bl/6J and Keap1-KD mice were fed a high-fat diet (HFD) to determine whether Keap1 and Nrf2 impact HFD-induced obesity. HFD-induced obesity and lipid accumulation in white adipose tissue was decreased in Keap1-KD mice. Nrf2 activation via Keap1-KD or sulforaphane suppressed hormone-induced differentiation and decreased peroxisome proliferator-activated receptor-γ, CCAAT/enhancer-binding protein α, and fatty acid-binding protein 4 expression in mouse embryonic fibroblasts. Constitutive Nrf2 activation inhibited lipid accumulation in white adipose tissue, suppressed adipogenesis, induced insulin resistance and glucose intolerance, and increased hepatic steatosis in Lep(ob/ob) mice.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Animals; Cytoskeletal Proteins; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Liver; Insulin Resistance; Kelch-Like ECH-Associated Protein 1; Leptin; Mice; Mice, Knockout; NF-E2-Related Factor 2; Obesity

Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans.. We measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.. Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients' insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.. PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.).

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Haploinsufficiency; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Neoplasms; Obesity; PTEN Phosphohydrolase

Adipose tissue inflammation plays a role in cardiovascular (CV) and metabolic diseases associated with obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The interactive effects of exercise training and metformin, two first-line T2DM treatments, on adipose tissue inflammation are not known. Using the hyperphagic, obese, insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, we tested the hypothesis that treadmill training, metformin, or a combination of these reduces the secretion of proinflammatory cytokines from adipose tissue. Compared with Long-Evans Tokushima Otsuka (LETO) control rats (L-Sed), sedentary OLETF (O-Sed) animals secreted significantly greater amounts of leptin from retroperitoneal adipose tissue. Conversely, secretion of interleukin (IL)-10 by O-Sed adipose tissue was lower than that in L-Sed animals. Examination of leptin and IL-10 secretion from adipose tissue in OLETF groups treated with endurance exercise training (O-EndEx), metformin treatment (O-Met), and a combination of these (O-E+M) from 20 to 32 wk of age indicated that 1) leptin secretion from adipose tissue was reduced in O-Met and O-E+M, but not O-EndEx animals; 2) adipose tissue IL-10 secretion was increased in O-EndEx and O-E+M but not in O-Met animals; and 3) only the combined treatment (O-E+M) displayed both a reduction in leptin secretion and an increase in IL-10 secretion. Leptin and IL-10 concentrations in adipose tissue-conditioned buffers were correlated with their plasma concentrations, adipocyte diameters, and total adiposity. Overall, this study indicates that exercise training and metformin have additive influences on adipose tissue secretion and plasma concentrations of leptin and IL-10.

Topics: Adipose Tissue; Animals; Combined Modality Therapy; Diabetes Mellitus, Type 2; Interleukin-10; Leptin; Male; Metformin; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Inbred OLETF; Treatment Outcome

Youth with diabetes are at increased risk for depression. The objectives of this study were to provide preliminary evidence that this at-risk status for depression is associated with metabolic and inflammatory markers and to inform future, more stringent examinations of the directionality of these associations.. Data from SEARCH for Diabetes in Youth (SEARCH), an observational study of U.S. children diagnosed with diabetes at <20 years of age, were used for these analyses. SEARCH participants were drawn from four geographically defined populations in Ohio, Washington, South Carolina, and Colorado; health plan enrollees in Hawaii and California; and Indian Health Service beneficiaries from four Native American populations. Participants were 2,359 youth with diabetes from the 2001 prevalent and 2002-2004 incident SEARCH cohorts. Depression was measured with the Center for Epidemiologic Studies Depression scale. Eight metabolic and inflammatory markers were measured: adiponectin, leptin, C-reactive protein, serum amyloid A, apolipoprotein B (apoB), lipoprotein A, interleukin-6, and LDL.. Six of eight markers were significantly (P < 0.006) associated with depression in youth with diabetes in bivariate analyses. In general, higher levels of depression were associated with indicators of worse metabolic or inflammatory functioning. In regression models stratified by diabetes type and accounting for demographic and clinical characteristics, only higher levels of apoB remained associated with higher levels of depression in youth with type 1 diabetes.. These data suggest that depression reported by youth with diabetes is partially associated with metabolic abnormalities and systemic inflammation.

Topics: Adiponectin; Adolescent; Apolipoproteins B; C-Reactive Protein; Child; Depression; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Inflammation; Interleukin-6; Leptin; Male

Inherent mechanisms leading to vascular smooth muscle cells (VSMC) alterations in obesitylinked type 2 diabetes (T2D) situation remain to be clarified. This study evaluates the impact of supernatant of adipocytes extracted from mice fed high-fat-diets (HFD) on the proliferation and apoptosis of VSMC.. Adipocytes were extracted from visceral white fat pads of male and female C57Bl6 mice showing different stages of metabolic alterations after 20 weeks of vegetal or animal HFD feeding. These cells were stimulated or not with insulin or glucose to condition VSMC media. After 24h of stimulation with adipocyte supernatants (AdS), VSMC proliferation and sustainability were assessed in the absence and presence of AdS. CD36 and insulin receptor mRNA levels were also evaluated.. Proliferation and viability of VSMC were significantly modulated by the nature of the AdS used and the gender of mice from which adipocytes have been extracted. The most extensive effects on VSMC were triggered by adipocytes from males fed animal HFD and females fed vegetal HFD. These effects were concurrent with increased leptin concentration and decreased adiponectin levels in AdS. In addition, adipocytes of HFD-fed mice increased caspase-3 activity and apoptosis in VSMC. Significant up-regulation of CD36 mRNA was also found in these cells.. Adipocytes of HFD-fed mice induce VSMC alterations. These changes involved mouse gender, most probably correlated to the diet-induced adipocyte secretion profile. Greater sensitivity to AdS effects in VSMC raises concerns about the more frequent cardiovascular events associated with obesity in the presence of T2D, which impairs adipocyte activity.

Topics: Adipocytes; Adipokines; Animal Feed; Animals; Apoptosis; Atherosclerosis; Caspase 3; CD36 Antigens; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Female; Glucose; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; RNA, Messenger

Studies investigating serum ghrelin level in atherosclerosis yielded contradictory results. Interaction of ghrelin with adipocytokines is obscure in cardiovascular diseases. We undertook this study to determine which molecules influence ghrelin level and to see whether post-myocardial infarction (MI) patients have decreased ghrelin levels.. In this cross-sectional study, acyl-ghrelin concentration was determined by radioimmunoassay in sera of 171 patients (ages 62 ± 6 years, mean ± SD) with previous MI and 81 age-matched referent subjects. We evaluated the associations of ghrelin with insulin, adiponectin, leptin, resistin, fetuin-A and tumor necrosis factor-alpha (TNF-α).. Patients had lower ghrelin levels compared to referent subjects (240.55 ± 59.33 vs. 337.96 ± 30.75 pg/mL, p <0.001) even after excluding diabetic and obese patients (240.63 ± 54.08 vs. 337.96 ± 30.75, p <0.001). In multivariate analysis, insulin (β = -0.327, p <0.001) and adiponectin (β = 0.301, p <0.001) determined ghrelin level (R(2) = 0.199, p <0.001). There was no association between ghrelin and TNF-α levels. In discriminant analysis using ghrelin, adiponectin, leptin, fetuin-A, resistin and TNF-α, the structure matrix revealed ghrelin and TNF-α as strongest predictors for belonging to the patient group (0.760 and -0.569, respectively). Using these two parameters, 89.7% of cases were correctly classified. Subjects with high TNF-α/ghrelin ratio had 11.25 times higher chance for belonging to the patient group (95% CI 5.80-21.80; χ(2) (1) = 215.6, p <0.001). Acylated ghrelin levels are decreased in patients with coronary atherosclerosis, independently of body weight and the presence of type 2 diabetes mellitus. Ghrelin level is determined by elevated insulin and decreased adiponectin levels. Ghrelin alone or in combination with TNF-α may prove to be a novel indicator of coronary atherosclerosis.

Topics: Adiponectin; Aged; alpha-2-HS-Glycoprotein; Atherosclerosis; Blood Glucose; Body Weight; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Insulin; Leptin; Male; Middle Aged; Myocardial Infarction; Resistin; Tumor Necrosis Factor-alpha

This study aimed to determine whether taurine supplementation improves metabolic disturbances and diabetic complications in an animal model for type 2 diabetes. We investigated whether taurine has therapeutic effects on glucose metabolism, lipid metabolism, and diabetic complications in Otsuka Long- Evans Tokushima fatty (OLETF) rats with long-term duration of diabetes. Fourteen 50-week-old OLETF rats with chronic diabetes were fed a diet supplemented with taurine (2%) or a non-supplemented control diet for 12 weeks. Taurine reduced blood glucose levels over 12 weeks, and improved OGTT outcomes at 6 weeks after taurine supplementation, in OLETF rats. Taurine significantly reduced insulin resistance but did not improve β-cell function or islet mass. After 12 weeks, taurine significantly decreased serum levels of lipids such as triglyceride, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Taurine significantly reduced serum leptin, but not adiponectin levels. However, taurine had no therapeutic effect on damaged tissues. Taurine ameliorated hyperglycemia and dyslipidemia, at least in part, by improving insulin sensitivity and leptin modulation in OLETF rats with long-term diabetes. Additional study is needed to investigate whether taurine has the same beneficial effects in human diabetic patients.

Topics: Adipokines; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Supplements; Dyslipidemias; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Lipid Metabolism; Lipids; Male; Organ Specificity; Rats; Rats, Long-Evans; Taurine

Ghrelin is a polypeptide that is excreted by the secretory cells of the gastric and intestinal mucosa, the arcuate nucleus of the hypothalamus as well as by the epsilon cells (ε) located in the pancreatic islets. It plays an important role in maintaining the energy balance of the organism and influences the endocrine function of the pancreas and glucose metabolism. It takes part in the regulation of glucose homeostasis through the modulation of insulin secretion and insulin sensitivity. Due to the broad spectrum of ghrelin's biological effects, ways to modify them are presently being investigated. Much attention is focused on the enzyme called ghrelin O-acyl transferase (GOAT), which mediates the physiological functions of ghrelin. Acyl-ghrelin and des-acyl-ghrelin appear to have opposite glucoregulatory effects. The regulation of acylation by GOAT seems therefore to play a role in mediating glucose metabolism. The modulation of GOAT or ghrelin signaling may be a clinically relevant strategy to treat obesity and metabolic diseases such as type 2 diabetes.  

Topics: Acylation; Acyltransferases; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Energy Metabolism; Gastric Mucosa; Ghrelin; Humans; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Intestinal Mucosa; Islets of Langerhans; Leptin; Obesity; Receptors, Ghrelin; Signal Transduction

In view of the noteworthy role of adipocytokines in the onset of insulin resistance and diabetes in gene-knockout-rat-model-cell-line studies we aimed to study the influence of genetic predisposition for diabetes on adipocytokine levels and their role in building insulin-resistance-like environment well before the onset of diabetes; thus a hypothesis can be drawn on their role in developing diabetes in high risk population.. Ages between 18 and 22 years were selected and divided into three groups. Group I (n = 81): control group with no family history of diabetes. Group II (n = 157): with one of their parents with history of type 2 diabetes. Group III (n = 47): with both parents having history of type 2 diabetes. In all the groups we estimated fasting plasma glucose, insulin and adipocytokines like adiponectin, leptin, TNF-α, and IL-6.. Of all adipocytokines we observed significantly lower levels of adiponectin (8.7 ± 1 μg/mL in group III and 9.5 ± 1.3 μg/mL group II) when compared to control (11.0 ± 1.2 μg/mL; P < 0.01) and it has strong correlation with family history of diabetes with Pearson's coefficient of -0.502. Linear regression analysis showed significant negative association with HOMA-IR (P < 0.01) and logistic regression analysis showed highest association with parental diabetes (P < 0.01; OR .260, 95% CI .260-.468).. Genetic predisposition for diabetes may influence adiponectin gene expression leading to decrease in its plasma concentration, which might play a key role in developing diabetes in near future.

Topics: Adipokines; Adiponectin; Adolescent; Biomarkers; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Humans; India; Insulin; Interleukin-6; Leptin; Linear Models; Logistic Models; Male; Multivariate Analysis; Odds Ratio; Parents; Pedigree; Phenotype; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha; Young Adult

Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptin(ob/ob) mutation (Lep(ob)). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

Topics: Adipose Tissue; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gene Expression Profiling; Gene Regulatory Networks; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Mice, Obese; Protein Interaction Maps

Hypoglycemic effects of berberine (BBR) have been reported in several studies in cell and animal models. However, the mechanisms of action are not fully understood. The present study was therefore aimed at determining the effect and underlying mechanisms of action of BBR on diabetes in a high-fat diet- and streptozotocin-induced diabetic rat model. Ninety male Sprague-Dawley rats, 150 to 170 g, were housed individually in cages. Two groups (n = 12 each) were fed the AIN-93G diet (normal control) and the same diet modified to contain 33% fat and 2% cholesterol (high-fat control), respectively. The third group (n = 66) was fed the high-fat diet and injected intraperitoneally 2 weeks later with 35 mg/kg body weight of streptozotocin in citrate buffer (pH 4.5). The rats in both control groups were injected with the vehicle. After 12 days, rats with semifasting (5 hours) blood glucose levels between 14 and 25 mmol/L were divided into 4 groups (n = 12 each) and treated with 0 (diabetic control), 50, 100, and 150 mg/kg/d of BBR for 6 weeks while continuing on the high-fat diet. Hypoglycemic effects of BBR were consistently demonstrated by semifasting and fasting blood glucose levels, and insulin-sensitizing effects were seen during oral glucose tolerance testing. Berberine also reduced food intake while having no effect on body weight in diabetic rats. No effect of BBR was observed on plasma levels of insulin, adipokines (leptin and adiponectin), or inflammatory cytokines (tumor necrosis factor-α and C-reactive protein). Berberine did not affect the state of oxidative stress as assessed by the activity of superoxide dismutase and the concentrations of malondialdehyde and reduced and oxidized glutathione in the liver. These findings demonstrated the hypoglycemic and insulin-sensitizing capabilities of BBR, with the underlying mechanisms awaiting further investigation.

Topics: Adiponectin; Animals; Berberine; Blood Glucose; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Glucose Tolerance Test; Glutathione; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liver; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The objective of this study was to assess the association of serum leptin levels with insulin resistance (IR), metabolic syndrome (MetS), lipid levels, and glucose control in an Iranian type 2 diabetic population.. In this cross-sectional analysis, 132 type 2 diabetic patients (79 women) and 71 healthy non-diabetic and non-hypertensive individuals (40 women; as control subjects) were included. Homeostasis model assessment (HOMA) of insulin values ≥ 1.8 for females and 1.7 for males was regarded as the cut-point of IR. MetS was defined according to updated 2005 NCEP ATP III criteria. The leptin correlated with HOMA-IR values without adjustment (r = 0.24; p < 0.005) and with adjustment for sex and diabetes (r = 0.44; p < 0.005). Sex had significant effect on the BMI adjusted association of HOMA-IR (quintiles) and leptin (df = 4 F(12.7) = 3.5; p = 0.011). In diabetic women (but not men), leptin levels were different between those with and without IR (27.3 ± 1.9 vs. 18.2 ± 3.3; p < 0.05). BMI adjusted leptin values were different between subjects with and without MetS (22.2 ± 1.7 vs.14.8 ± 1.2; p < 0.001). No association was noticed between BMI-adjusted leptin with glycated hemoglobin or blood lipid levels.. In this study, plasma leptin concentration correlated with IR independent of the effect of obesity in female but not male diabetic subjects.

Topics: Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Iran; Leptin; Lipids; Male; Metabolic Syndrome; Obesity; Sex Factors; Triglycerides; Waist Circumference

The aim of this study was to analyze the relationship of serum leptin as well as adiponectin and the manifestation of pancreatic cancer (PC). Serum leptin, adiponectin, glucose homeostasis and insulin resistance (expressed as HOMA-IR) were investigated in 64 patients with newly diagnosed PC and compared with 64 healthy controls (CON group) and 75 patients with type 2 diabetes (DM2). Seventy percent of newly diagnosed PC patients had DM2. The levels of leptin were lower, whilst adiponectin/leptin ratio was higher in PC patients (both with and without DM2), in comparison with CON and DM2 groups (P < 0.001) independently of age, BMI and waist circumference. Newly diagnosed PC is characterized with lower leptin concentrations and higher adiponectin/leptin ratio in comparison with CON or DM2 individuals. Analysis of these parameters could help in the screening of persons in high risk for PC, especially in those with DM2.. adiponectin, leptin, pancreatic cancer, type 2 diabetes mellitus.

Topics: Adiponectin; Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Pancreatic Neoplasms; Pilot Projects

The aim of this study was to evaluate the association of serum visfatin, adiponectin and leptin with 2 diabetes mellitus (T2DM) in the context of the role of obesity or insulin resistance, which is not well understood.. A total of 76 newly-diagnosed T2DM patients and 76 healthy control subjects, matched for age, body mass index (BMI) and sex ratio, were enrolled. Anthropometric parameters, glycemic and lipid profile, insulin resistance (measured by homeostasis model assessment of insulin resistance index [HOMA-IR]), leptin, adiponectin, and visfatin were assessed.. On the contrary to adiponectin, serum leptin and visfatin levels were higher in T2DM patients compared with controls (10.07 ± 4.5, 15.87 ± 16.4, and 5.49 ± 2.4 vs. 12.22 ± 4.9 μg/ml, 8.5 ± 7.8 ng/ml and 3.58 ± 2.2 ng/ml, respectively, P<0.01). Waist circumference and BMI were correlated with leptin and adiponectin but not with visfatin. Leptin, adiponectin and visfatin all were associated with T2DM following adjusting for obesity measures. After controlling for HOMA-IR, visfatin remained as an independent predictor of T2DM (odds ratio=1.32, P<0.05). In a multiple regression analysis to determine visfatin only triglycerides and fasting glucose remained in the model (P<0.05).. Elevation of visfatin in T2DM is independent of obesity and insulin resistance and is mainly determined by fasting glucose and triglycerides.

Topics: Adiponectin; Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity

Insulin resistance and type 2 diabetes (T2D) are commonly seen in human immunodeficiency virus (HIV) infection and are related to antiretroviral therapy. Adiponectin and leptin secreted by adipocytes are both linked to body-fat distribution and insulin sensitivity. The present study aimed to assess the prevalence of insulin resistance and T2D, and their association with adiponectin and leptin, in Afro-Caribbean men and women with HIV infection.. This cross-sectional study was conducted in an unselected sample of 237 HIV-1-infected patients. Clinical and metabolic parameters were measured, including fasting and postload plasma insulin, and circulating adiponectin and leptin levels. Insulin resistance was estimated by homoeostasis model assessment (HOMA-IR). Adjusted multiple logistic regressions were used to estimate the association of insulin resistance with adipokine levels and patients' characteristics.. A total of 132 men (mean age: 49 years) and 105 women (mean age: 48 years) were included in the study. Prevalences of T2D and insulin resistance were higher in women than in men [16.2% vs 8.3% (P = 0.06) and 24% vs 9.9% (P < 10⁻³), respectively]. Abdominal obesity was found in 47% of women and in 7% of men (P < 10⁻⁴). Insulin resistance was independently associated with adiponectin in women and with leptin in men.. Insulin resistance is frequent in Afro-Caribbean women with HIV infection. Overweight and obesity are major risk factors in such a population. Systematic screening for insulin resistance should be carried out in this population, which has a high prevalence of T2D.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Anti-Retroviral Agents; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Guadeloupe; HIV Infections; Humans; Insulin Resistance; Leptin; Logistic Models; Male; Middle Aged; Obesity, Abdominal

The kinase suppressor of ras 2 (KSR2) gene resides at human chromosome 12q24, a region linked to obesity and type 2 diabetes (T2D). While knocking out and phenotypically screening mouse orthologs of thousands of druggable human genes, we found KSR2 knockout (KSR2(-/-)) mice to be more obese and glucose intolerant than melanocortin 4 receptor(-/-) (MC4R(-/-)) mice. The obesity and T2D of KSR2(-/-) mice resulted from hyperphagia which was unresponsive to leptin and did not originate downstream of MC4R. The kinases AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are each linked to food intake regulation, but only mTOR had increased activity in KSR2(-/-) mouse brain, and the ability of rapamycin to inhibit food intake in KSR2(-/-) mice further implicated mTOR in this process. The metabolic phenotype of KSR2 heterozygous (KSR2(+/minus;)) and KSR2(-/-) mice suggests that human KSR2 variants may contribute to a similar phenotype linked to human chromosome 12q24.

Topics: Adipose Tissue; AMP-Activated Protein Kinase Kinases; Animals; Diabetes Mellitus, Type 2; Eating; Hyperphagia; Leptin; Mice; Mice, Knockout; Obesity; Protein Kinases; Protein Serine-Threonine Kinases; TOR Serine-Threonine Kinases

Type 2 diabetes (T2D) resolves rapidly after bariatric surgery, even before substantial weight is lost. However, the molecular pathways underlying this phenomenon remain unclear. Microarray data has shown that numerous genes are differentially expressed in blood after bariatric surgery, including resistin and leptin. Resistin and leptin are circulating hormones derived from adipose tissue, which are associated with obesity and insulin resistance. This study examined expression of these genes before and after bariatric surgery in diabetic and nondiabetic obese patients.. The study included 16 obese patients who underwent bariatric surgery, either Roux-en-Y gastric bypass (RYGB) or adjustable gastric banding. Eight patients had T2D. Preoperative blood samples were collected in PAXgene tubes to stabilize mRNA. Postoperative samples were collected 3 months after surgery. Total RNA was isolated and cDNA was synthesized. Real-time quantitative PCR was used to quantify mRNA. Results were analyzed using Student's t test with a P<0.05 considered significant.. Postoperatively, five diabetic patients had discontinued hypoglycemic medications and one showed improved glycemic control. Both leptin and resistin mRNA levels were elevated in the diabetic group but decreased after surgery to levels near those of the nondiabetic group. Greater downregulation of resistin and leptin expression occurred in patients who lost more excess body weight (EBW), while patients who lost less than 10% EBW had a mean increase in expression of the two genes. Downregulation of both genes was more pronounced after RYGB compared to gastric banding.. Downregulation of resistin and leptin gene expression after bariatric surgery may play a role in normalizing obesity-associated insulin resistance. Interestingly, downregulation is greater after RYGB and in patients who lose a greater proportion of EBW. Targeted therapies for obesity and diabetes may be developed by understanding the pathways by which these adipocytokines contribute to obesity and T2D.

Topics: Diabetes Mellitus, Type 2; Down-Regulation; Gene Expression Regulation; Humans; Insulin Resistance; Leptin; Microarray Analysis; Obesity, Morbid; Polymerase Chain Reaction; Postoperative Period; Resistin; Weight Loss

The Chinese formula Tang-Min-Ling (TML), an improved product of the decoction of Dachaihu which has a history of more than 2000 years, has main constituents of Coptis chinensis Franch, Scutellaria baicalensis Georgi, Rheum officinale Baill and Bupleurum chinense DC. A multi-central randomized controlled investigation performed previously by us has showed that TML has positive effects on regulating glycometabolism in type 2 diabetes (T2DM) patients, but the mechanisms remain unclear. Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats as an animal model with rosiglitazone as a positive control, we were able to detect TML's effect on the serum glucose, serum lipid, serum leptin and adiponcetin after oral administration for 12 weeks. We were also able to detect the insulin resistance level by a glucose clamp test and study the mechanisms of TML in improving insulin resistance by detecting skeletal muscle AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT4). Results showed that TML significantly reduced the glucose area under a curve of the oral glucose tolerance test, and had a positive effect in regulating serum lipid metabolism. TML treatment also significantly reduced the serum leptin level, but it had no effect on the serum adiponectin level. The AMPK enzymatic activity and GLUT4 expression in Skeletal Muscle were also upregulated in the TML group. The results suggest that the Chinese medicine TML, which contains Coptis chinensis Franch as one of its components, improves glycometabolism and its possible mechanisms may involve in improvement of insulin resistance of OLETF rats.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Area Under Curve; Blood Glucose; Bupleurum; Coptis; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Glucose Tolerance Test; Glucose Transporter Type 4; Hyperlipidemias; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Muscle, Skeletal; Phytotherapy; Rats; Rats, Inbred OLETF; Rheum; Rosiglitazone; Scutellaria baicalensis; Thiazolidinediones

The aim of the study was to assess the association between visceral and subcutaneous fat with glucose intolerance, adipocytokines, inflammatory markers and carotid IMT in Asian Indians.. Subjects with NGT (n=85), IGT (n=49) and T2DM (n=93) were randomly selected from CURES. Total abdominal, visceral and subcutaneous fat were measured using Helical CT scan. Adiponectin, hs-CRP, TNF-alpha, oxidized LDL, visfatin and leptin and IMT and insulin resistance were assessed.. Total abdominal fat (p=0.041) and the visceral fat (p=0.039) but not subcutaneous fat progressively increased from NGT, IGT and T2DM subjects. With increasing quartiles of visceral fat, there was a significant increase in insulin resistance (p=0.040); significant decrease in adiponectin (p=0.043) and increase in TNF-alpha (p=0.028), hs-CRP (p=0.043), OX-LDL (p=0.034) and visfatin (p=0.040), and carotid IMT (p=0.047) was observed.. Visceral fat levels increased with increasing glucose intolerance and are associated with decreased levels of adiponectin and increased levels of hs-CRP, TNF-alpha, oxidized LDL, visfatin, HOMA-IR and IMT.

Topics: Abdominal Fat; Adipokines; Adiponectin; Adiposity; Adult; Asian People; Biomarkers; Blood Glucose; C-Reactive Protein; Causality; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; India; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipoproteins, LDL; Male; Nicotinamide Phosphoribosyltransferase; Subcutaneous Fat; Tumor Necrosis Factor-alpha

We aimed to examine whether circulating levels of osteocalcin, bone formation marker secreted from osteoblast, are changed in glucose-intolerant subjects without taking glucose lowering agent, because bone metabolism is reportedly related to glucose metabolism in animal and human studies. According to 75 g oral glucose tolerance test (75 g-OGTT), all subjects (47.6 ± 10.2 years of age; 45 men and 10 women) were divided into three categories: normal glucose tolerance (NGT, n = 39), prediabetes (PDM, n = 11) that included impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and diabetes (T2DM, n = 5). Serum osteocalcin levels were increased in T2DM as compared to NGT. In all the participants, simple regression analysis model revealed positive correlation of osteocalcin with plasma glucose at 120 min, G(120), on 75 g-OGTT, negative with both creatinine and Ln(CRP), but not significantly with fasting plasma glucose. Osteocalcin and leptin were independent variables for G(120) (P = 0.026 and 0.035, respectively). In multinomial logistic analysis leptin (PDM vs. NGT: P = 0.02 Odds ratio (OR) of 1.05, 95% confidence intervals, 1.007-1.084) and osteocalcin (T2DM vs. NGT: P = 0.038, OR 10.8, 1.13-102.4) were independently associated. We conclude that circulating osteocalcin and leptin are related to glucose intolerant state.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Osteocalcin

There have been lots of studies about the relationship between chronic use of alcohol and the development of type 2 diabetes mellitus (T2DM). Chronic use of alcohol can be affected by the altered level of ghrelin and leptin which regulate food-seeking behavior having similar mechanism of controlling alcohol-craving behavior. Those peptides are known to be correlated with T2DM. Ghrelin and leptin also have been regarded as possible regulators of glucose metabolism and insulin function. Hence, there is the possibility that ghrelin and leptin can be related with deteriorated pathophysiology of T2DM in alcoholic patients.. Patients with alcohol dependence diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) underwent an 75 g oral glucose-tolerance test (OGTT), to classify them to normal glucose tolerance (NGT, n = 52), pre-diabetes including impaired glucose tolerance (IGT), impaired fasting glucose level (IFG) and combination of IGT and IFG (Pre-DM, n = 26) and T2DM (n = 24) groups. Fasting plasma ghrelin and leptin levels were compared among groups.. There was no difference of ghrelin concentration among the groups but the leptin concentration was significantly different between NGT and T2DM group (p < 0.05). Increased leptin levels were significantly correlated with body mass index (BMI), insulin level, and insulin resistance.. Chronic alcohol drinking might produce leptin resistance which makes leptin significantly correlated with fasting insulin concentration and insulin resistance. Therefore, we suppose that increased level of leptin by chronic alcohol use could be one of the main mechanisms that develop insulin resistance in alcoholic patients.

Topics: Alcoholism; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Ghrelin; Humans; Insulin Resistance; Leptin; Male; Middle Aged

Ketogenic diets (KTD) are reported to have beneficial effects on the regulation of energy and glucose homeostasis, but remain controversial. We investigated the effects of KTD and ketones on insulin resistance and secretion in non-obese type 2 diabetic rats and their mechanism. KTD (82% energy as fat), intraperitoneal injection of β-hydroxybutyrate (IHB; 150 mg/kg bw/12 h) with a control diet (COD; 20% energy as fat) or saline injection with COD was given to 90% pancreatectomized (Px) diabetic rats for five weeks. KTD increased epididymal fat pads and serum leptin levels without increasing energy intake, but IHB decreased them. KTD, but not IHB, attenuated hypothalamic signal transducer and activator of transcription 3 and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in KTD. Serum glucagon levels were markedly higher in the KTD group than in other groups. During an oral glucose tolerance test, serum glucose levels slowly increased until 80 min in the KTD group and then decreased very slowly. Insulin secretion capacity during a hyperglycemic clamp was significantly lower in the IHB group than in other groups. However, a euglycemic hyperinsulinemic clamp revealed that KTD decreased glucose infusion rates and increased hepatic glucose output in hyperinsulinemic states while IHB had opposite effects to KTD. The increased hepatic glucose output in KTD was associated with increased hepatic phosphoenolpyruvate carboxykinase expression through attenuated tyrosine phosphorylation of IRS2 and phosphorylation of Akt(Ser473). Hepatic AMPK(Thr172) phosphorylation was reduced in KTD. In conclusion, KTD impairs energy and glucose homeostasis by exacerbating insulin resistance and attenuating hypothalamic leptin signaling in non-obese type 2 diabetic rats. These changes are not associated with increased serum ketone levels.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, Ketogenic; Disease Models, Animal; Energy Metabolism; Glucose; Homeostasis; Insulin; Leptin; Rats; Signal Transduction

To investigate the possible relationship of leptin to bone mineral density (BMD) in men with type 2 diabetes mellitus (T2DM), we screened 168 Belarusian men aged 45-65 years. Plasma total cholesterol (TC), high-density lipoprotein cholesterol, and triglyceride concentrations were assessed, and low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol (LDL-C) were calculated. Hemoglobin A(1c), immune-reactive insulin (IRI), serum total testosterone, and sex hormone-binding globulin were also evaluated. BMD was evaluated using dual-energy X-ray absorptiometry. By univariate linear regression analysis, BMD was significantly correlated with body mass index (r = 0.23, P = 0.002) and leptin (r = 0.21, P = 0.006). By multivariate regression analysis adjusting for confounding factors, log leptin was independently correlated with BMD (β = 0.058, P = 0.001). Our study revealed that leptin is an independent determinant of BMD in patients with T2DM. Further research is necessary to confirm this association and to develop ways to correct abnormalities of bone metabolism in patients with T2DM.

Topics: Aged; Bone Density; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged

We have previously demonstrated that running-wheel access normalizes the food intake and body weight of Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Following 6 wk of running-wheel access beginning at 8 wk of age, the body weight of OLETF rats remains reduced, demonstrating a lasting effect on their phenotype. In contrast, access to a high-fat diet exacerbates the hyperphagia and obesity of OLETF rats. To determine whether diet modulates the long-term effects of exercise, we examined the effects of high-fat diet on food intake and body weight in OLETF rats that had prior access to running wheels for 4 wk. We found that 4 wk of running exercise significantly decreased food intake and body weight of OLETF rats. Consistent with prior results, 4 wk of exercise also produced long-lasting effects on food intake and body weight in OLETF rats fed a regular chow. When running wheels were relocked, OLETF rats stabilized at lower levels of body weight than sedentary OLETF rats. However, access to a high-fat diet offset these effects. When OLETF rats were switched to a high-fat diet following wheel relocking, they significantly increased food intake and body weight, so that they reached levels similar to those of sedentary OLETF rats fed a high-fat diet. Gene expression determination of hypothalamic neuropeptides revealed changes that appeared to be appropriate responses to the effects of diet and running exercise. Together, these results demonstrate that high-fat diet modulates the long-lasting effects of exercise on food intake and body weight in OLETF rats.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Body Weight; Corticotropin-Releasing Hormone; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Glucose Intolerance; Hypothalamus; Leptin; Male; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Time Factors

MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Glucose; Homeostasis; Infusions, Intraventricular; Leptin; Liver; Male; Mice; Mice, Knockout; Receptor, IGF Type 1; Signal Transduction; Thinness; Vagus Nerve

The role of the gaseous messengers NO and CO for β-cell function and survival is controversial. We examined this issue in the hyperglycemic-hyperinsulinemic ob/ob mouse, an animal model of type 2 obese diabetes, by studying islets from obese vs lean mice regarding glucose-stimulated insulin release in relation to islet NO and CO production and the influence of modulating peptide hormones. Glucose-stimulated increase in ncNOS-activity in incubated lean islets was converted to a decrease in ob/ob islets associated with markedly increased insulin release. Both types of islets displayed iNOS activity appearing after ~60 min in high-glucose. In ob/ob islets the insulinotropic peptides glucagon, GLP-1 and GIP suppressed NOS activities and amplified glucose-stimulated insulin release. The insulinostatic peptide leptin induced the opposite effects. Suppression of islet CO production inhibited, while stimulation amplified glucose-stimulated insulin release. Nonincubated isolated islets from young and adult obese mice displayed very low ncNOS and negligible iNOS activity. In contrast, production of CO, a NOS inhibitor, was impressively raised. Glucose injections induced strong activities of islet NOS isoforms in lean but not in obese mice and confocal microscopy revealed iNOS expression only in lean islets. Islets from ob/ob mice existing in a hyperglycemic in vivo milieu maintain elevated insulin secretion and protection from glucotoxicity through a general suppression of islet NOS activities achieved by leptin deficiency, high CO production and insulinotropic cyclic-AMP-generating hormones. Such a beneficial effect on islet function and survival might have its clinical counterpart in human leptin-resistant type 2 obese diabetes with hyperinsulinemia.

Topics: Animals; Blood Glucose; Carbon Monoxide; Diabetes Mellitus, Type 2; Enzyme Assays; Female; Glucagon; Glucose; Humans; Hyperinsulinism; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II

Although the effects of ketogenic diets on energy and glucose homeostasis have been controversial, elevation of serum ketone levels by subcutaneous injection of β-hydroxybutyrate (BHB) can improve glucose homeostasis. Ketones may work through the brain; therefore, we evaluated whether the intracerebroventricular (ICV) infusion of β-hydroxybutyrates would also modulate peripheral energy and glucose homeostasis, and through what mechanisms, in diabetic rats fed a high fat diet in short- and long-term studies. Short-term (3h) central injection of BHB (50 μg/h) improved serum glucose levels and peripheral insulin sensitivity compared to the artificial cerebrospinal fluid (CSF) group among 90% pancreatectomized (Px) diabetic rats, but not in non-diabetic Sham rats. In addition to short-term infusion, long-term (28 days) central infusion of BHB (12 μg/h) elevated serum BHB levels. Long-term infusion of BHB potentiated leptin and insulin signaling in the hypothalamus to slightly decrease body weight in Px rats. Central BHB infusion had a greater effect on peripheral glucose metabolism than overall energy metabolism. Hepatic insulin signaling (tyrosine phosphorylation of IRS2→serine phosphorylation of Akt→reduced expression of PEPCK) was potentiated and hepatic glucose production in the hyperinsulinemic state was suppressed in the diabetic rats. In addition, glucose tolerance was improved by central BHB infusion through enhanced whole body glucose disposal rates, but insulin secretion was not affected in the diabetic rats. In conclusion, mild ketosis by central infusion of ketones improves energy and glucose metabolism through the potentiation of leptin and insulin signaling in the hypothalamus of diabetic rats.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Infusions, Intraventricular; Insulin; Insulin Resistance; Ketone Bodies; Leptin; Liver; Male; Rats; Rats, Sprague-Dawley; Signal Transduction

The aim of this study was to test the hypothesis that a lower birth weight, as an indicator of adverse intrauterine environment, is associated with higher serum leptin levels in European adolescents. We also examined the possible sexual dimorphism in this relationship.. Fasting serum leptin was measured in 757 European born at term adolescents (429 females) aged 14.6 ± 1.2 yr. We measured weight and height, and body mass index was calculated. Birth weight, duration of pregnancy, and duration of breast-feeding were obtained from parental records. Duration of pregnancy and breast-feeding, pubertal status, center, body mass index, and physical activity were entered as confounders in the analyses.. There was a significant interaction effect between sex and birth weight on serum leptin levels (P = 0.044). We observed that body weight at birth was negatively and significantly associated with serum leptin levels only in female adolescents (β = -0.109; adjusted P = 0.008). The association persisted after further controlling for physical activity (β = -0.115; adjusted P = 0.016).. These findings provide further evidence for a sex-specific programming effect of birth weight on serum leptin levels. Our results also contribute to explain the detrimental health effects associated with lower birth weight, such as long-term increased risk of developing obesity and type 2 diabetes.

Topics: Adolescent; Body Mass Index; Diabetes Mellitus, Type 2; Europe; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Leptin; Male; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors; Sex Characteristics; Sex Distribution

Recently, YKL-40 has been identified as a new inflammatory marker of type 2 diabetes mellitus (T2DM), while leptin is one of the most important adipose derived hormones. However, the relationship between them has not been elucidated. Therefore this study aimed to study their correlation in obese T2DM patients.

Topics: Adipokines; Adult; Chitinase-3-Like Protein 1; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Lectins; Leptin; Male; Middle Aged; Obesity

Despite the higher prevalence of diabetes and hypertension in populations residing at moderate altitudes, mortality in these populations is lower than in populations residing at low altitudes. To examine whether metabolic and hemodynamic differences can explain this apparent paradox, we performed a cross-sectional study of a general population sample recruited in the Canary Islands, Spain (n=6729). We recorded altitude of residence, age, heart rate, blood pressure, body mass index, social class, physical activity, energy intake, alcohol intake, smoking habit, prevalence of type 2 diabetes mellitus and hypertension. In a subsample (n=903), we recorded serum concentration of cholesterol, triglycerides, glucose, C peptide, leptin, soluble leptin receptor (sObR), C-reactive protein, resistin, soluble CD40 ligand (sCD40L), and paraoxonase activity (PON), and we estimated insulin resistance and free leptin index. We found an inverse association between altitude and heart rate (p<0.001), leptin (p<0.001), free leptin index (p<0.001), resistin (p<0.001), and sCD40L (p<0.05) and a direct association between altitude and hypertension (odds ratio=1.29 for altitude >600 m; 95% confidence interval=1.03-1.62), glycemia (p<0.05), C peptide (p<0.001), insulin resistance (p<0.001), sObR (p<0.05), and PON (p<0.05). When social class was included in the multivariate model, the association with PON was no longer significant. In conclusion, individuals residing at moderate altitudes have a lower heart rate and lower serum concentration of total leptin, free leptin, and sCD40L. These differences may partially explain the lower mortality in these populations.

Topics: Adolescent; Adult; Aged; Altitude; Blood Pressure; CD40 Ligand; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Male; Middle Aged; Young Adult

In recent years, the number of patients suffering from diseases, such as cancer, apoplexy, osteoporosis, hypertension, and type 2 diabetes mellitus is increasing worldwide. Type 2 diabetes, a lifestyle-related disease, is recognized as a serious disease. Various types of pharmaceutics for diabetes have been used. Since the relationship between diabetes and biometals such as vanadium, copper, and zinc ions has been recognized for many years, we have been developing the anti-diabetic metal complexes as new candidates. We found that several zinc(II) (Zn) complexes exhibit glucose-lowering activity for treating type 2 diabetes. High doses of salicylates have been known to reverse hyperglycemia and hyperinsulinemia in type 2 diabetic patients. These findings strongly suggest that the combined use of Zn and salicylates achieves the synergism in treating type 2 diabetes. Because aspirin, acetyl salicylic acid, has a chelating ability, we used it as a ligand to Zn. Several Zn-salicylate complexes were prepared and their biological activities were examined in this study. The complexes with an electron-withdrawing group in the ligand exhibited higher in vitro insulinomimetic activity than those of Zn complexes with an electron-donating group in the ligand. When bis(aspirinato)Zn (Zn(asp)₂) complex was orally administered on KK-A(y) mice with hereditary type 2 diabetes, the diabetic state was improved. In addition, this complex exhibited normalizing effects on serum adiponectin level and high blood pressure in metabolic syndrome. In conclusion, Zn(asp)₂ complex is newly proposed as a potent anti-diabetic and anti-metabolic syndrome agent.

Topics: Adiponectin; Administration, Oral; Animals; Aspirin; Blood Pressure; Coordination Complexes; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Mice; Structure-Activity Relationship

Obesity is more common in African than Asian-Indian populations and yet type 2 diabetes and cardiovascular diseases are more common in the latter populations. The main purpose of the current study was therefore to determine whether ethnic differences in body fat distribution, adipokine levels, and socio-economic status may explain population differences in the prevalence of these metabolic disorders. Leptin, IL-6, CRP, visceral fat, education level, and socio-economic status were measured in 50 African and the same number of Indian women residing in Johannesburg, South Africa. Serum leptin levels were significantly higher in Indian than African subjects (41.3±2.0 and 34.2±2.9 ng/ml, respectively; p<0.05). TNF-α levels were significantly higher in the African group, (5.22±0.86 vs. 2.54±0.52 pg/ml; p<0.05), whilst visceral fat levels were significantly lower (56.1±5.5 vs. 77.9±6.5 cm(2); p<0.05). The CRP and IL-6 levels were not different between groups. Education levels (p<0.005) and socio-economic status (p<0.0001) were both lower in the African subjects, however, adjusting for these variables in ANCOVA did not attenuate differences in adipokine or visceral fat levels. We hypothesise that one of the reasons for the higher prevalence of obesity in the African than Indian population may be related to lower leptin levels, whilst ethnic differences in the prevalence of metabolic disorders cannot be explained by differences in adipokine levels, but maybe related to higher visceral adiposity in the Indian group.

Topics: Adipokines; Adult; Anthropometry; Asian People; Black People; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Education; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Prevalence; Socioeconomic Factors

Maternal diabetes is a common complication of pregnancy, and the offspring of diabetic mothers have a higher risk of developing obesity and type 2 diabetes later in life. Despite these observations, the precise biological processes mediating this metabolic programming are not well understood. Here, we explored the consequences of maternal diabetes on the organization of hypothalamic neural circuits involved in the regulation of energy balance. To accomplish this aim, we used a mouse model of maternal insulin deficiency induced by streptozotocin injections. Maternal diabetes was found to be associated with changes in offspring growth as revealed by a significantly higher pre- and postweaning body weight in the offspring of insulin-deficient dams relative to those of control mice. Mice born to diabetic dams also showed increased fasting glucose levels, increased insulin levels, and increased food intake during their adult lives. These impairments in metabolic regulation were associated with leptin resistance during adulthood. Importantly, the ability of leptin to activate intracellular signaling in arcuate neurons was also significantly reduced in neonates born to diabetic dams. Furthermore, neural projections from the arcuate nucleus to the paraventricular nucleus were markedly reduced in the offspring of insulin-deficient dams. Together, these data show that insulin deficiency during gestation has long-term consequences for metabolic regulation. They also indicate that animals born to diabetic dams display abnormally organized hypothalamic feeding pathways that could result from the attenuated responsiveness of hypothalamic neurons to the neurotrophic actions of leptin during neonatal development.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Diabetes, Gestational; Eating; Female; Hypothalamus; Insulin; Leptin; Maternal Nutritional Physiological Phenomena; Mice; Nerve Net; Neurons; Obesity; Phosphorylation; Pregnancy; STAT3 Transcription Factor

Leptin has been shown to reduce hyperglycemia in rodent models of type 1 diabetes. We investigated the effects of leptin administration in University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rats, which develop adult-onset polygenic obesity and type 2 diabetes. Animals that had been diabetic for 2 mo were treated with s.c. injections of saline (control) or murine leptin (0.5 mg/kg) twice daily for 1 mo. Control rats were pair-fed to leptin-treated animals. Treatment with leptin normalized fasting plasma glucose and was accompanied by lowered HbA1c, plasma glucagon, and triglyceride concentrations and expression of hepatic gluconeogenic enzymes compared with vehicle (P < 0.05), independent of any effects on body weight and food intake. In addition, leptin-treated animals exhibited marked improvement of insulin sensitivity and glucose homeostasis compared with controls, whereas pancreatic insulin content was 50% higher in leptin-treated animals (P < 0.05). These effects coincided with activation of leptin and insulin signaling pathways and down-regulation of the PKR-like endoplasmic reticulum (ER) kinase/eukaryotic translation inhibition factor 2α (PERK-eIF2α) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased pro-opiomelanocortin and decreased agouti-related peptide in the hypothalamus. In contrast, several markers of inflammation/immune function were elevated with leptin treatment in the same tissues (P < 0.05), suggesting that the leptin-mediated increase of insulin sensitivity was not attributable to decreased inflammation. Thus, leptin administration improves insulin sensitivity and normalizes fasting plasma glucose in diabetic UCD-T2DM rats, independent of energy intake, via peripheral and possibly centrally mediated actions, in part by decreasing circulating glucagon and ER stress.

Topics: Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; Eating; eIF-2 Kinase; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Glucagon; Gluconeogenesis; Glycated Hemoglobin; Injections, Subcutaneous; Insulin; Insulin-Like Growth Factor I; Janus Kinase 2; Leptin; Lipid Metabolism; Male; Rats; Signal Transduction

We have previously shown that chronic exposure to ambient fine particulate matter (less than 2.5 μm in aerodynamic diameter, PM₂.₅) pollution in conjunction with high-fat diet induces insulin resistance through alterations in inflammatory pathways. In this study, we evaluated the effects of PM₂.₅ exposure over a substantive duration of a rodent's lifespan and focused on the impact of long-term exposure on adipose structure and function. C57BL/6 mice were exposed to PM₂.₅ or filtered air (FA) (6 h/day, 5 days/week) for duration of 10 months in Columbus, OH. At the end of the exposure, PM₂.₅-exposed mice demonstrated insulin resistance (IR) and a decrease in glucose tolerance compared with the FA-exposed group. Although there were no significant differences in circulating cytokines between PM₂.₅- and FA-exposed groups, circulating adiponectin and leptin were significantly decreased in PM₂.₅-exposed group. PM₂.₅ exposure also led to inflammatory response and oxidative stress as evidenced by increase of Nrf2-regulated antioxidant genes. Additionally, PM₂.₅ exposure decreased mitochondrial count in visceral adipose and mitochondrial size in interscapular adipose depots, which were associated with reduction of uncoupling protein 1 (UCP1) expression and downregulation of brown adipocyte-specific gene profiles. These findings suggest that long-term ambient PM₂.₅ exposure induces impaired glucose tolerance, IR, inflammation, and mitochondrial alteration, and thus, it is a risk factor for the development of type 2 diabetes.

Topics: Adiponectin; Adipose Tissue; Air Pollutants; Animals; Biomarkers; Blotting, Western; Diabetes Mellitus, Type 2; Gene Expression Profiling; Gene Expression Regulation; Immunohistochemistry; Inhalation Exposure; Insulin Resistance; Ion Channels; Leptin; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria; Mitochondrial Proteins; Mitochondrial Size; NF-E2-Related Factor 2; Organ Specificity; Oxidative Stress; Particle Size; Particulate Matter; Real-Time Polymerase Chain Reaction; Risk Factors; Time Factors; Uncoupling Protein 1

Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance. Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure. Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle. Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin. Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity. Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Fats; Energy Metabolism; Female; Gene Expression; Gene Knockdown Techniques; Hypothalamus; Immunohistochemistry; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Transgenic; Motor Activity; Neurons; Neuropeptides; Obesity; Orexins; Patch-Clamp Techniques; Sirtuin 1; Steroidogenic Factor 1

This case control study aimed to investigate relationship between appetite hormones (ghrelin and leptin) and body mass index (BMI), insulin and oxidative stress in simple obese and type 2 diabetes (T2DM) obese patients.. Thirty healthy controls; 30 simple obese and 30 T2DM obese patients were enrolled. Demographic and clinical data of all participants were reported. Serum levels of fasting blood glucose (FBG), postprandial blood glucose (PBG), lipid peroxide (LPO) and nitric oxide (NO) were measured by chemical methods while, insulin, leptin and ghrelin by ELISA kits.. Serum levels of insulin, leptin, LPO were significantly higher while, ghrelin was significantly lower in simple obese and obese patients with diabetes versus controls. Insulin resistance was found in 76.67% simple obese and 93.33% obese patients with diabetes. Ghrelin showed a positive correlation with PBG in controls; but negative correlation with BMI in simple obese and with NO in obese patients with diabetes. Positive correlations were found between LPO and FBG, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and between leptin and FBG in obese patients with diabetes.. Our results suggested that hyperinsulinemia and hyperleptinemia may be most important mechanisms in decreasing ghrelin and inducing oxidative stress in simple obese and T2DM obese patients.

Topics: Adult; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Oxidative Stress

Topics: Animals; Awards and Prizes; Circadian Rhythm; Diabetes Mellitus, Type 2; Endocrinology; Endoplasmic Reticulum Stress; History, 20th Century; History, 21st Century; Humans; Insulin-Like Growth Factor I; Leptin; Neoplasms; Pediatrics; Retinoid X Receptors; Societies, Medical; Stress, Physiological; Unfolded Protein Response

To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.. Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.. In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat-fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.. We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

Topics: Animals; Cecum; Colon; Diabetes Mellitus, Type 2; Dietary Fats; Enteroendocrine Cells; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Intolerance; Gram-Negative Bacteria; Gram-Positive Bacteria; Hyperglycemia; Hyperlipidemias; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Typing; Obesity; Prebiotics; Proglucagon; RNA, Messenger

To clarify the association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes (T2D).. This was an observational cohort study of 668 patients with T2D. Patients were classified into three groups by sex-specific tertile of leptin levels. Outcome measurements were the rate of change in estimated glomerular filtration rate (eGFR) and progression to a more advanced stage of albuminuria.. Patients with low or high leptin levels had a steeper eGFR decline (-2.07 and -2.14 mL/min/1.73 m(2)/year) than those with midrange leptin levels (-0.82 mL/min/1.73 m(2)/year; P < 0.01), whereas patients with low leptin levels had an elevated risk of progression of albuminuria as compared with those with high leptin levels (hazard ratio 3.125 [95% CI 1.302-7.499]).. Both low and high serum leptin levels were risk factors for kidney function decline. Meanwhile, lower serum leptin levels were associated with progression of albuminuria.

Topics: Aged; Albuminuria; Asian People; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Glomerular Filtration Rate; Humans; Leptin; Male; Middle Aged; Risk Factors

We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lep(ob/ob) and C57BL/6 (B6) Lep(ob/ob) mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We derived a panel of sub-congenic mice and narrowed the diabetes susceptibility locus to a 1.6 Mb region. Introgression of this 1.6 Mb fragment of the BTBR Chr 16 into lean B6 mice (B6.16(BT36-38)) replicated the phenotypes of the consomic mice. Pancreatic islets from the B6.16(BT36-38) mice were defective in the second phase of the insulin secretion, suggesting that the 1.6 Mb region encodes a regulator of insulin secretion. Within this region, syntaxin-binding protein 5-like (Stxbp5l) or tomosyn-2 was the only gene with an expression difference and a non-synonymous coding single nucleotide polymorphism (SNP) between the B6 and BTBR alleles. Overexpression of the b-tomosyn-2 isoform in the pancreatic β-cell line, INS1 (832/13), resulted in an inhibition of insulin secretion in response to 3 mM 8-bromo cAMP at 7 mM glucose. In vitro binding experiments showed that tomosyn-2 binds recombinant syntaxin-1A and syntaxin-4, key proteins that are involved in insulin secretion via formation of the SNARE complex. The B6 form of tomosyn-2 is more susceptible to proteasomal degradation than the BTBR form, establishing a functional role for the coding SNP in tomosyn-2. We conclude that tomosyn-2 is the major gene responsible for the T2D Chr 16 quantitative trait locus (QTL) we mapped in our mouse cross. Our findings suggest that tomosyn-2 is a key negative regulator of insulin secretion.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adaptor Proteins, Vesicular Transport; Animals; Chromosome Mapping; Cloning, Molecular; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Predisposition to Disease; Glucose; HEK293 Cells; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Polymorphism, Single Nucleotide; Qa-SNARE Proteins; Quantitative Trait Loci; R-SNARE Proteins; Rats; SNARE Proteins; Syntaxin 1

Topics: Animals; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Hypothalamus; Leptin; Maternal Nutritional Physiological Phenomena; Nerve Net; Neurons; Pregnancy

Our aim is to identify the relation of leptin, adiponectin and insulin resistance to bone mineral density (BMD) in type 2 diabetic postmenopausal women and compare it with that experienced by nondiabetics.. Seventy six postmenopausal female patients were included in the study. Postmenopausal type 2 diabetic (n = 19) and nondiabetic patients (n = 19) with spine and/or hip BMD T score lower than -2 were included in the study, and postmenopausal type 2 diabetic (n = 20) and nondiabetic women (n = 18) with normal BMD (T score > -1) were selected as control groups. Those receiving therapy for osteoporosis, over the age of 65, those who had a disease and were taking a medication that could affect bone metabolism were excluded. Biochemical tests, as well as leptin, adiponectin and insulin levels, were measured and insulin resistance was calculated using the HOMA test.. There was no correlation between low BMD and leptin, adiponectin and insulin resistance. There was only a negative correlation between leptin and femur Ward's triangle BMD.. Further large-scale studies must to be performed in order to analyse the effects of leptin, adiponectin and insulin resistance on bone metabolism in type 2 diabetic patients.

Topics: Adiponectin; Body Mass Index; Bone Density; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Postmenopause; Statistics as Topic

The aim of this study was to explore the relationship of serum profile of adipokines with cardiovascular risk factors and anthropometric parameters in patients with diabetes mellitus type 2.. A population of 108 obese patients with DM2 was analyzed. A complete biochemical anthropometric and nutritional evaluation was performed.. In the analysis with leptin as a dependent variable, the IL-6 and glucose levels remained in the model (F = 6.2; P<0.05), with an increase of 5.8 (CI 95%:2.7-7.6) ng/ml with each 1 pg/ml of IL-6 and of 5.2 (CI95%:2.5-5.8) ng/ml with each 1 mg/dl of glucose. In a second model with adiponectin as a dependent variable, the BMI remained in the model (F = 3.77;P<0.05), with an decrease of -3.77 (CI 95%:0.53-7.1) ng/ml with each 1 point of BMI. In the third multivariate analysis with IL-6 as a dependent variable, the glucose level remained in the model (F = 10.1; P<0.01), with an increase of 0.09 (CI95%:0.06-0.12) pg/ml with each 1 mg/dl of glucose. In the fourth multivariate analysis with resistin as a dependent variable, the CRP remained in the model (F = 2.51; P<0.05), with an increase of 0.28 (CI 95%:0.08-0.48) pg/ml with each 1 mg/dl of CRP.. Serum profile of adipokines is associated with different risk factors in diabetic obese patients.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Cardiovascular Physiological Phenomena; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Resistin; Risk Factors

Leptin regulates gastric and intestinal motility, but its effect on oesophageal motility is unknown. We analyzed oesophageal manometric characteristics in diabetics with elevated leptin.. Fasting blood leptin levels were measured in 32 type 2 individuals aged from 39-81 years. An oesophageal stationary manometry was then performed. Each manometric door (P) registered one third of the oesophageal activity. Results are presented as mean +/- SD.. Twenty-one subjects had elevated leptin (HLL) while 11 displayed normal levels (NLL). Peristaltic wave distributions (%) in NLL vs. HLL were 79.4 +/- 26.3 vs. 88.6 +/- 8.3 (p = 0.2). Simultaneous and retrograde waves showed similar trends. Non-transmitted waves were 16.1 +/- 26.5 vs. 4.6 +/- 4.5% (p < 0.05). Amplitudes in NLL vs. HLL (in mm Hg) were P1: 30.2 +/- 10.8 vs. 33.2 +/- 11.7 (p = 0.4), P2: 38.4 +/- 14.4 vs. 58.0 +/- 21.2 (p = 0.01), P3: 42.4 +/- 14.4 vs. 64.7 +/-2 8.3 (p < 0.006), and average amplitudes: 37.1 +/- 12.1 vs. 52.1 +/- 17.6 (p = 0.01). Wave average upstroke (in mm Hgs) was P1: 25.6 +/- 19.1 vs. 23.3 +/- 10.1 (p = 0.6), P2: 26.8 +/- 10.7 vs. 36.2 +/- 11.6 (p < 0.03), and P3: 25.5 +/- 9.1 vs. 34.1 +/- 16.3, (p < 0.06). Wave maximum upstroke was P1: 39.0 +/- 18.6 vs. 40.5 +/- 13.8, (p = 0.8), P2: 45.5 +/- 15.5 vs. 63.8 +/- 19.2 (p = 0.01), P3: 46.6 +/- 17.8 vs. 65.0 +/- 29.1 (p <0.03). Wave duration in distal oesophagus was 4.5 +/- 0.7 vs. 5.5 +/- 1.1 s (p = 0.01), and velocity 3.3 +/- 3.3 vs. 2.96 +/- 3.7 cm/s (p = 0.6).. 1--Non-transmitted waves were slightly higher in NLL. 2--In medium and distal oesophagus, the wave amplitude, medium and maximum upstroke, and duration in distal oesophagus were increased in HLL.

Topics: Adult; Aged; Aged, 80 and over; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Esophageal Motility Disorders; Esophagus; Female; Humans; Leptin; Male; Manometry; Middle Aged

The inflammatory marker, C-reactive protein (CRP) is associated with long-term cardiovascular events. The aim of the study was to investigate the factors contributing to serum CRP, assess the relationship between CRP level and the parameters of visceral obesity, and examine the association between leptin and CRP level in type 2 diabetic patients. 150 patients with type 2 diabetes were enrolled. These patients were recently diagnosed (< or =3 years) with type 2 diabetes and were drug naive or taking sulfonylureas only. BMI, WC, and serum concentration of CRP, glycosylated hemoglobin (HbA1c), glucose, lipids, plasminogen activator-1 (PAI-1) and leptin were measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). We measured the carotid intima-media thickness (IMT). Fat mass assessed by dual-energy X-ray absorptionmetry and abdominal fat distribution was determined by CT scan. Serum concentration of CRP was significantly correlated with BMI (gamma = 0.257, P < 0.01), WC (gamma = 0.293, P < 0.01), fat mass (gamma = 0.213, P < 0.01), total adipose tissue (gamma = 0.263, P < 0.01), visceral adipose tissue (gamma = 0.296, P < 0.01), insulin (gamma = 0.189, P = 0.047), PAI-1 (gamma = 0.206, P < 0.01), leptin (gamma = 0.322, P < 0.01), mean IMT (gamma = 0.132, P = 0.042), and HOMA-IR (gamma = 0.172, P = 0.045). After adjustment for age and gender, multiple regression analysis showed that serum CRP was significantly associated with leptin (beta = 0.326, P = 0.01) and visceral adipose tissue (beta = 0.265, P = 0.035). In conclusion, serum CRP level is significantly associated with obesity, especially the visceral adipose tissue, and serum leptin is another important independent factor associated with CRP in Korean type 2 diabetic patients.

Topics: Absorptiometry, Photon; Adiposity; Adult; Blood Glucose; Blood Pressure; Body Mass Index; C-Reactive Protein; Carotid Arteries; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Intra-Abdominal Fat; Korea; Leptin; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Regression Analysis; Tunica Intima; Tunica Media; Ultrasonography

To determine whether multiparity is associated with type 2 diabetes, independent of visceral adipose tissue (VAT) and adipokines.. Participants were from the University of California San Diego Filipino Women's Health Study with at least one live birth. A 2-h 75-g oral glucose tolerance test was administered; adiponectin, leptin, ghrelin, reproductive history, family history of diabetes, VAT, and lifestyle behaviors were measured between 1995 and 2002.. Among 152 women, mean age was 59.5 years (range 48-73 years) and mean parity was 4.3 (range 1-12 births). Type 2 diabetes prevalence increased by parity group (low parity, 1-2 births, 25%; medium parity, 3-5 births, 30.3%; and grand multiparity: 6-12 births, 50%; P = 0.048). Family history of diabetes, exercise, insulin resistance, and leptin and ghrelin levels did not differ by parity group. Compared with women in the low parity group, women with > or =6 births were significantly older (62 vs. 57 years), had lower college completion (22 vs. 58%, P = 0.006), more hypertension (72 vs. 55%), higher VAT (74.9 vs. 58.4 cm(3)), and lower adiponectin concentration (5.79 vs. 7.61 microg/ml). In multivariate analysis adjusting for adiponectin, VAT, family history of diabetes, age, education, hypertension, and estrogen use, grand multiparous women had a threefold higher odds of type 2 diabetes (adjusted odds ratio 3.40 [95% CI 1.13-10.2]) compared with low parity women. No differences were observed in the odds of diabetes between women in the medium (1.10 [0.41-2.91]) and low parity groups.. Having > or =6 children was associated with type 2 diabetes, independent of adiponectin, VAT, family history, and other measured diabetes risk factors.

Topics: Adiponectin; Adipose Tissue; Aged; Body Size; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucose Tolerance Test; Humans; Leptin; Life Style; Medical History Taking; Middle Aged; Multivariate Analysis; Parity; Philippines; Pregnancy; Prevalence; Risk Factors; Viscera

The postpartum phase following gestational diabetes (GDM) is characterised by subtle metabolic defects, including the beta cell dysfunction that is believed to mediate the increased future risk of type 2 diabetes in this patient population. Low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have recently emerged as novel diabetic risk factors, although their relevance to GDM and subsequent diabetes has not been characterised. Thus, we sought to determine whether adiponectin, leptin and CRP levels during pregnancy relate to the postpartum metabolic defects linking GDM with type 2 diabetes.. Metabolic characterisation, including oral glucose tolerance testing, was undertaken in 487 women during pregnancy and at 3 months postpartum. Based on the antepartum OGTT, there were 137 women with GDM, 91 with gestational impaired glucose tolerance and 259 with normal glucose tolerance.. Adiponectin levels were lowest (p < 0.0001) and CRP levels highest (p = 0.0008) in women with GDM. Leptin did not differ between the glucose tolerance groups (p = 0.4483). Adiponectin (r = 0.41, p < 0.0001), leptin (r = -0.36, p < 0.0001) and CRP (r = -0.30, p < 0.0001) during pregnancy were all associated with postpartum insulin sensitivity (determined using the insulin sensitivity index of Matsuda and DeFronzo [IS(OGTT)]). Intriguingly, adiponectin levels were also related to postpartum beta cell function (insulinogenic index/HOMA of insulin resistance; r = 0.16, p = 0.0009). Indeed, on multiple linear regression analyses, adiponectin levels during pregnancy independently predicted both postpartum insulin sensitivity (t = 3.97, p < 0.0001) and beta cell function (t = 2.37, p = 0.0181), even after adjustment for GDM. Furthermore, adiponectin emerged as a significant negative independent determinant of postpartum fasting glucose (t = -3.01, p = 0.0027).. Hypoadiponectinaemia during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia, and hence may be relevant to the pathophysiology relating GDM with type 2 diabetes.

Topics: Adiponectin; Adult; Blood Glucose; Breast Feeding; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetes, Gestational; Ethnicity; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Parity; Postpartum Period; Pregnancy; Racial Groups; Risk Factors; Weight Gain

We prospectively examined plasma levels of leptin and soluble leptin receptor (sOB-R), as well as their interactions with other diabetes risk factors, in relation to type 2 diabetes to elucidate the complex relation between these two biomarkers and diabetes risk.. Of 32,826 Nurses' Health Study participants who provided blood samples during 1989-1990, 1,054 incident case subjects of type 2 diabetes were identified and confirmed during 1990-2004 and 1,254 matched control subjects were selected. Plasma leptin and sOB-R levels were measured among these participants.. After multivariate adjustment for BMI, lifestyle practices, and dietary factors, sOB-R levels were significantly associated with a lower risk of type 2 diabetes. In comparison with women in the lowest quintile, the ORs (95% CI) of developing type 2 diabetes were 0.73 (0.55-0.96), 0.51 (0.38-0.68), 0.42 (0.31-0.57), and 0.39 (0.28-0.54; P for trend < 0.0001) for women in the second to fifth quintiles of sOB-R levels, respectively. In contrast, plasma leptin levels were not significantly associated with the risk of type 2 diabetes: The OR (95% CI) was 0.82 (0.62-1.10; P for trend = 0.46) comparing the highest with the lowest quintile of leptin levels. sOB-R levels were consistently associated with a decreased risk of type 2 diabetes at various levels of leptin or high-molecular-weight adiponectin.. These data suggest a strong inverse association between plasma sOB-R levels and risk of type 2 diabetes, independent of BMI, leptin, and adiponectin levels.

Topics: Adiponectin; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Leptin; Middle Aged; Multivariate Analysis; Prospective Studies; Receptors, Leptin; Risk Factors; Solubility; United States

Discovery of protein biomarkers in different diseases is an important area of research in the field of proteomics. We have described the levels of protein biomarkers specific to diabetes mellitus type 2 in the local population of Pakistan using proteomic technology. Type 2 diabetic patients, age and sex-matched normal healthy controls were recruited from Sheikh Zayed Hospital, Lahore, Pakistan. Plasma proteins were analysed by 2D liquid chromatographic system in which samples were initially fractionated by chromatofocusing and the selected fractions were further analysed by reverse-phase high performance liquid chromatography. The proteins which showed variation between test and control samples were identified by MALDI-TOF analysis. All the samples belonging to the control and diabetic groups were then analyzed by ELISA and estimated four proteins which were found to vary. Levels of apolipoprotein A-I was found to decrease by -6.4% while apolipoprotein E, leptin and C reactive protein (CRP) were increased by +802, +842 and +872%, respectively, in the diabetic patients as compared to the controls. The discovery of these marker proteins might thus provide an adjunctive method for early detection of risk for this disease.

Topics: Adult; Aged; Apolipoprotein A-I; Apolipoproteins E; Asian People; Biomarkers; Blood Proteins; C-Reactive Protein; Case-Control Studies; Chemical Fractionation; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Pakistan; Predictive Value of Tests; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

To determine the potential role of the transcriptional factor-activating enhancer-binding protein-2beta (TFAP2B) in the regulation of expression of adipokines, adiponectin, leptin, and interleukin-6 (IL-6) in vivo, we quantified the mRNA expression levels of these adipokines and TFAP2B in visceral (omental) and abdominal subcutaneous adipose tissues of 66 individuals with variable degree of adiposity and studied their correlations with BMI and their plasma concentrations. We found that BMI correlated negatively with plasma adiponectin levels and positively with those of leptin. Adiponection mRNA expression in subcutaneous fat correlated negatively with BMI, whereas leptin mRNA levels in the omentum correlated with plasma leptin levels and BMI. In contrast, IL-6 mRNA levels in subcutaneous and omental fat did not correlate with BMI. IL-6 mRNA levels in the omental fat correlated with plasma IL-6 levels. Whereas TFAP2B mRNA expression did not correlate with BMI, it correlated negatively with adiponectin expression in the subcutaneous adipose tissue. Furthermore, TFAP2B mRNA expression correlated negatively with leptin and positively with IL-6 expression in both subcutaneous and omental adipose tissues. These relationships are consistent with our in vitro observations and indicate that TFAP2B seems to regulate the expression of various adipokines in vivo.

Topics: Abdominal Fat; Adiponectin; Aged; Aged, 80 and over; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-6; Leptin; Male; Metabolic Syndrome; Middle Aged; Omentum; RNA, Messenger; Subcutaneous Fat; Transcription Factor AP-2

China has experienced a rapid increase in diabetes. In this study, we assessed whether the associations of two adipocyte-derived hormones, leptin and adiponectin, with type 2 diabetes are independent of obesity in older Chinese adults.. In this matched case-control study, each of the 619 diabetes and impaired fasting glucose (IFG) cases aged 60-96 years was matched to a control by age, sex, waist circumference and body mass index (BMI).. Before matching, IFG and diabetes cases had significantly lower adiponectin and higher leptin concentrations than the participants with normal glucose. After matching for age, sex, waist circumference and BMI, the differences between cases and controls remained significant (p < 0.001) in adiponectin but not in leptin (p = 0.77). Adjusted odds ratios for the combined outcome of diabetes and IFG were 1.03 (95% confidence interval: 0.88, 1.21; p = 0.71) for one standard deviation increase in plasma leptin and 0.79 (95% confidence interval: 0.69, 0.91; p < 0.001) for one standard deviation increase in plasma adiponectin.. Without adjustment for obesity related body size measurements of waist circumference and BMI, both adiponectin and leptin are associated with diabetes and IFG. After adjustment, adiponectin is independently associated with diabetes and IFG, but there is no independent association between leptin and either diabetes or IFG. Our findings suggest that adiponectin provides extra-predictive power beyond obesity while leptin does not independently predict the risk of diabetes and IFG in older Chinese adults.

Topics: Adiponectin; Aged; Aged, 80 and over; Asian People; Case-Control Studies; China; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity

This study was performed to evaluate the effects of initial periodontal treatment on clinical periodontal measurements, glycemic control, and systemic inflammatory mediator levels in patients with type 2 diabetes and chronic periodontitis.. Thirteen well-controlled (glycated hemoglobin [HbA1c] <7%) and 12 poorly controlled (HbA1c > or =7%) patients with type 2 diabetes and chronic periodontitis and 15 systemically healthy patients with chronic periodontitis were enrolled. Blood samples were collected at baseline from all patients and 1 and 3 months after the initial periodontal treatment from patients with diabetes. Serum levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, C-reactive protein (CRP), soluble intercellular adhesion molecule-1, adiponectin, and leptin were analyzed by enzyme-linked immunosorbent assay.. The study groups showed similar improvements in clinical periodontal variables at all evaluation times (P <0.05). HbA1c levels in the poorly controlled group with diabetes decreased significantly at 3 months after completion of the initial periodontal treatment (P <0.05), whereas no significant changes were evident in the well-controlled group. There were insignificant decreases in TNF-alpha and CRP levels (P >0.05). IL-6 levels decreased in well-controlled patients with diabetes and in the systemically healthy group (P <0.05). Adiponectin levels increased in the systemically healthy group (P <0.05). Leptin levels increased at 1 month in well-controlled patients with diabetes (P <0.05).. Within the limits of this study, patients with type 2 diabetes and chronic periodontitis exhibited similar clinical periodontal improvements as their systemically healthy counterparts. Initial periodontal treatment appeared to improve glycemic control in poorly controlled patients with diabetes. Decreases in levels of IL-6, TNF-alpha, CRP, and leptin and an increase in adiponectin levels after periodontal therapy may be a function of glycemic control in patients with type 2 diabetes.

Topics: Adipokines; Adiponectin; Adult; Analysis of Variance; C-Reactive Protein; Case-Control Studies; Chronic Periodontitis; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Male; Middle Aged; Reference Values; Statistics, Nonparametric; Treatment Outcome; Tumor Necrosis Factor-alpha

Adipocytes synthesize galectin-3 whose deficiency protects from inflammation associated with metabolic diseases. We aimed to study circulating galectin-3 in obesity and type 2 diabetes (T2D).. Galectin-3 was measured by ELISA in the serum of male normal-weight and overweight controls and T2D patients and in T2D patients of both sexes. Because visceral fat contributes to systemic inflammation, galectin-3 was analyzed in paired samples of human and rodent sc and visceral adipose tissue. Visceral adipose tissue adipokines are released to the portal vein, and galectin-3 was analyzed in portal, hepatic, and systemic venous serum (PVS, HVS, and SVS, respectively) of patients with liver cirrhosis and in patients who underwent surgery for nonhepatic diseases. The effect of metformin on adipocyte galectin-3 was analyzed by immunoblot.. Circulating galectin-3 was similarly elevated in T2D and obesity compared with normal-weight individuals and revealed a body mass index-dependent positive correlation with leptin, resistin, IL-6, and age. In T2D patients, galectin-3 was increased in serum of patients with elevated C-reactive protein and negatively correlated with glycated hemoglobin. Metformin treatment was associated with lower systemic galectin-3. Reduced galectin-3 in metformin-incubated human adipocytes indicated that low galectin-3 may be a direct effect of this drug. Galectin-3 was higher in PVS compared with HVS and SVS, suggesting that the splanchnic region is a major site of galectin-3 synthesis. Low galectin-3 in HVS compared with PVS demonstrated hepatic removal.. Systemic galectin-3 is elevated in obesity and negatively correlates with glycated hemoglobin in T2D patients, pointing to a modifying function of galectin-3 in human metabolic diseases.

Topics: Adipocytes; Adult; Aged; Animals; Blotting, Western; Body Mass Index; Cells, Cultured; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Galectin 3; Glycated Hemoglobin; Humans; Intra-Abdominal Fat; Leptin; Male; Metformin; Mice; Middle Aged; Obesity; Resistin; Statistics, Nonparametric

Leptin predicts cardiovascular diseases and type 2 diabetes, diseases to which Asian Indians are highly susceptible. As a risk marker, leptin's intra-individual and seasonal stability is unstudied and only small studies have compared leptin levels in Asian Indians with other populations. The aim of this study was to explore ethnicity related differences in leptin levels and its intra-individual and seasonal stability.. Leptin and anthropometric data from the northern Sweden MONICA (3513 Europids) and the Mauritius Non-communicable Disease (2480 Asian Indians and Creoles) studies were used. In both studies men and women, 25- to 74-year old, participated in both an initial population survey and a follow-up after 5-13 years. For the analysis of seasonal leptin variation, a subset of 1780 participants, 30- to 60-year old, in the Västerbotten Intervention Project was used.. Asian Indian men and women had higher levels of leptin, leptin per body mass index (BMI) unit (leptin/BMI) or per cm in waist circumference (WC; leptin/waist) than Creoles and Europids when adjusted for BMI (all P<0.0005) or WC (all P<0.005). In men, Creoles had higher leptin, leptin/BMI and leptin/waist than Europids when adjusted for BMI or WC (all P<0.0005). In women, Creoles had higher leptin/BMI and leptin/waist than Europids only when adjusted for WC (P<0.0005). Asian Indian ethnicity in both sexes, and Creole ethnicity in men, was independently associated with high leptin levels. The intra-class correlation for leptin was similar (0.6-0.7), independently of sex, ethnicity or follow-up time. No seasonal variation in leptin levels was seen.. Asian Indians have higher levels of leptin, leptin/BMI and leptin/waist than Creoles and Europids. Leptin has a high intra-individual stability and seasonal leptin variation does not appear to explain the ethnic differences observed here.

Topics: Adult; Aged; Asian People; Blood Glucose; Body Composition; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Mauritius; Middle Aged; Obesity; Risk Factors; Seasons; Sex Factors; Sweden; Waist Circumference

Elevated plasma free fatty acid (FFA), inflammatory marker, and altered adipokine concentrations have been observed in obese type 2 diabetes patients. It remains unclear whether these altered plasma concentrations are related to the diabetic state or presence of obesity. In this cross-sectional observational study, we compare basal plasma FFA, inflammatory marker, and adipokine concentrations between obese and non-obese type 2 diabetes patients and healthy, non-obese controls. A total of 20 healthy, normoglycemic males (BMI <30 kg/m(2)), 20 non-obese (BMI <30 kg/m(2)) and 20 obese (BMI >35 kg/m(2)) type 2 diabetes patients were selected to participate in this study. Groups were matched for age and habitual physical activity level. Body composition, glycemic control, and exercise performance capacity were assessed. Basal blood samples were collected to determine plasma leptin, adiponectin, resistin, tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and FFA concentrations. Plasma FFA, inflammatory marker (hsCRP, IL-6, TNFalpha), adipokine (adiponectin, resistin, leptin), and triglyceride concentrations did not differ between non-obese diabetes patients and healthy, normoglycemic controls. Plasma FFA, IL-6, hsCRP, leptin, and triglyceride levels were significantly higher in the obese diabetes patients when compared with the healthy normoglycemic controls (P < 0.05). Furthermore, plasma hsCRP and leptin levels were significantly higher in the obese versus non-obese diabetes patients (P < 0.05). Significant correlations between plasma parameters and glycemic control were observed, but disappeared after adjusting for trunk adipose tissue mass. Elevated plasma leptin, hsCRP, IL-6, and FFA concentrations are associated with obesity and not necessarily with the type 2 diabetic state.

Topics: Adipokines; Adiponectin; Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Exercise Tolerance; Fatty Acids, Nonesterified; Humans; Inflammation Mediators; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Regression Analysis; Resistin; Triglycerides; Tumor Necrosis Factor-alpha

Sustained fructose consumption has been shown to induce insulin resistance and glucose intolerance, in part, by promoting oxidative stress. Alpha-lipoic acid (LA) is an antioxidant with insulin-sensitizing activity. The effect of sustained fructose consumption (20% of energy) on the development of T2DM and the effects of daily LA supplementation in fructose-fed University of California, Davis-Type 2 diabetes mellitus (UCD-T2DM) rats, a model of polygenic obese T2DM, was investigated. At 2 mo of age, animals were divided into three groups: control, fructose, and fructose + LA (80 mg LA.kg body wt(-1).day(-1)). One subset was followed until diabetes onset, while another subset was euthanized at 4 mo of age for tissue collection. Monthly fasted blood samples were collected, and an intravenous glucose tolerance test (IVGTT) was performed. Fructose feeding accelerated diabetes onset by 2.6 +/- 0.5 mo compared with control (P < 0.01), without affecting body weight. LA supplementation delayed diabetes onset in fructose-fed animals by 1.0 +/- 0.7 mo (P < 0.05). Fructose consumption lowered the GSH/GSSG ratio, while LA attenuated the fructose-induced decrease of oxidative capacity. Insulin sensitivity, as assessed by IVGTT, decreased in both fructose-fed and fructose + LA-supplemented rats. However, glucose excursions in fructose-fed LA-supplemented animals were normalized to those of control via increased glucose-stimulated insulin secretion. Fasting plasma triglycerides were twofold higher in fructose-fed compared with control animals at 4 mo, and triglyceride exposure during IVGTT was increased in both the fructose and fructose + LA groups compared with control. In conclusion, dietary fructose accelerates the onset of T2DM in UCD-T2DM rats, and LA ameliorates the effects of fructose by improving glucose homeostasis, possibly by preserving beta-cell function.

Topics: Adiponectin; Animal Feed; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Fats; Dyslipidemias; Energy Metabolism; Fructose; Glucose Intolerance; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Intercellular Adhesion Molecule-1; Kaplan-Meier Estimate; Leptin; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rats, Zucker; Thioctic Acid; Tocopherols; Triglycerides

Epicardial adipose tissue (EAT) is an interesting visceral fat pad with a particular location. EAT and subcutaneous adipose tissue (SAT) produce a wide range of adipokines. Some of them, including adiponectin and leptin, can influence the risk of development of diabetes and other associated metabolic and cardiovascular conditions. We sought to assess whether EAT and SAT adiponectin and leptin expression levels are different in diabetic patients with respect to nondiabetic subjects.. We collected samples of EAT from 120 patients and samples of SAT from 88 of the same group of patients undergoing elective cardiac surgery for coronary artery bypass grafting (n=69) or other procedures (n=51). After RNA isolation, adiponectin and leptin expression levels were analyzed by real-time reverse transcriptase PCR. Plasma levels were determined in small subsamples of subjects. Baseline clinical and treatment data were obtained from medical records.. A total of 45 diabetic and 75 nondiabetic subjects were included in the study. Mean (s.d.) age was 70.1 (7.8) years and there were 32% women. EAT and SAT adiponectin and leptin mRNA expression levels were similar in the diabetic and the nondiabetic groups (EAT adiponectin 14.4 (4.3) vs 14.6 (3.4) arbitrary units (a.u.), P=0.79; SAT adiponectin 15.6 (4.7) vs 15.1 (3.9), P=0.54; EAT leptin 9.3 (interquartile range 2.5) vs 9.5 (1.9) a.u., P=0.72; SAT leptin 9.9 (3.6) vs 10.0 (2.5) a.u., P=0.96). These findings persisted after stratification for sex and coronary artery disease. Logistic regression models including possible confounders and a combination of diabetes and impaired fasting glucose as a dependent variable led to similar results. Plasma adiponectin levels were lower in diabetic patients, whereas leptin levels showed a nonsignificant trend.. Diabetic and nondiabetic subjects express similar EAT and SAT adiponectin and leptin levels. Counter-regulatory mechanisms of adiponectin and leptin expression in patients with established diabetes might partly account for these findings.

Topics: Adiponectin; Adipose Tissue; Aged; Blotting, Western; Confidence Intervals; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Gene Expression; Humans; Leptin; Male; RNA, Messenger

Previous studies have identified a single-nucleotide polymorphism in the gene encoding peroxisome proliferator-activated receptor-delta (PPARD), rs2016520, that is associated with changes in metabolic disease in some but not all studies, which suggests that PPARD agonists may have therapeutic benefits for the treatment of metabolic disorders, including dyslipidemia, type 2 diabetes, and obesity.. The objective of the study was to determine whether rs2016520 or other single-nucleotide polymorphism in the PPARD locus influenced the risk of developing various characteristics of metabolic disease.. Haplotype tagging analysis across PPARD was performed in 11,074 individuals from the Welcome Trust U.K. Type 2 Diabetes Case Control Collection.. In subjects with and without type 2 diabetes, rs2016520 was associated with body mass index, high-density lipoprotein cholesterol, leptin, and TNFalpha and was dependent on gender.. The current results suggest differential effects of PPARdelta in males and females.

Topics: Adiponectin; Adolescent; Adult; Aged; Aged, 80 and over; Body Mass Index; Cholesterol; Cohort Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Haplotypes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Leptin; Lipids; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; PPAR delta; Reverse Transcriptase Polymerase Chain Reaction; Sex Characteristics; Tumor Necrosis Factor-alpha; Young Adult

Microalbuminuria portends an increased risk for renal and cardiovascular diseases in diabetes. In this pilot study, we determined the effect of weight loss induced by different types of bariatric surgery on albuminuria in severely obese type 2 diabetic (T2DM) subjects.. Fifteen consecutive T2DM patients (9M/6F, 51+/-14 years, body mass index (BMI) 49+/-9 kg/m2, HbA1c 7.2+/-1.1 percent) undergoing either Roux-en-Y gastric bypass (RYGB; N=9) or other types of bariatric surgery (N=6) underwent determination of urine albumin/creatinine ratio (UACR) and adipokine and insulin sensitivity during a mixed meal tolerance test performed 2 weeks prior to and 6 months following surgery.. Following RYGB, there was a significant decrease in BMI ((-4.74)+/-(-5.05) kg/m2), fasting glucose, cholesterol, and leptin levels. Insulin sensitivity (Matsuda index [12.05+/-3.81, p=0.003]) and high molecular weight (HMW) adiponectin increased significantly along with a significant reduction in UACR (median, 36 mg/g [7-94] vs. 27 mg/g [5.5-42.5], p=0.01). The reduction in UACR following RYGB was inversely correlated with the Matsuda index (r=-0.74), p=0.02) and HMW adiponectin (r=(-0.67), p=0.04). In contrast, despite reduction in BMI ((-4.11)+/-(-4.10) kg/m2) following other types of bariatric surgery (n=6), there was no significant improvement in insulin sensitivity (0.88+/-2.40, p=0.63), UACR, or HMW adiponectin levels.. RYGB in severely obese DM subjects is associated with a reduction in albuminuria that correlates to the improvement in insulin sensitivity and HMW adiponectin. The data point to a need for larger studies to confirm these findings and evaluate the micro-macrovascular benefits including renal parenchymal benefits of different types of bariatric surgery in T2DM.

Topics: Adiponectin; Albuminuria; Bariatric Surgery; Blood Glucose; Body Mass Index; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Molecular Weight; Obesity, Morbid; Pilot Projects; Risk Factors; Weight Loss

Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/db mice. APJ expression was decreased in both HF-fed and db/db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.

Topics: Adipokines; Adipose Tissue; Adult; Animals; Apelin; Apelin Receptors; Carrier Proteins; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Muscle, Skeletal; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

We investigated whether hypothalamic leptin alters beta-cell function and mass directly via the sympathetic nervous system (SNS) or indirectly as the result of altered insulin resistant states.. The 90% pancreatectomized male Sprague Dawley rats had sympathectomy into the pancreas by applying phenol into the descending aorta (SNSX) or its sham operation (Sham). Each group was divided into two sections, receiving either leptin at 300ng/kgbw/h or artificial cerebrospinal fluid (aCSF) via intracerebroventricular (ICV) infusion for 3h as a short-term study. After finishing the infusion study, ICV leptin (3mug/kg bw/day) or ICV aCSF (control) was infused in rats fed 30 energy % fat diets by osmotic pump for 4weeks. At the end of the long-term study, glucose-stimulated insulin secretion and islet morphometry were analyzed.. Acute ICV leptin administration in Sham rats, but not in SNSX rats, suppressed the first- and second-phase insulin secretion at hyperglycemic clamp by about 48% compared to the control. Regardless of SNSX, the 4-week administration of ICV leptin improved glucose tolerance during oral glucose tolerance tests and insulin sensitivity at hyperglycemic clamp, compared to the control, while it suppressed second-phase insulin secretion in Sham rats but not in SNSX rats. However, the pancreatic beta-cell area and mass were not affected by leptin and SNSX, though ICV leptin decreased individual beta-cell size and concomitantly increased beta-cell apoptosis in Sham rats.. Leptin directly decreases insulin secretion capacity mainly through the activation of SNS without modulating pancreatic beta-cell mass.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Clamp Technique; Glucose Tolerance Test; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Rats; Rats, Sprague-Dawley; Sympathectomy, Chemical; Sympathetic Nervous System

To investigate ethnic differences in adiponectin and leptin concentration and to determine whether these adipokines and a high-glycemic index diet account for ethnic variation in insulin resistance.. In 1,176 South Asian, Chinese, Aboriginal, and European Canadians, fasting blood samples were drawn, and clinical history and dietary habits including glycemic index/glycemic load were recorded using standardized questionnaires. Insulin resistance was defined using homeostasis model assessment-insulin resistance (HOMA-IR).. Adiponectin concentrations were significantly higher in Europeans (adjusted mean 12.94 [95% CI 2.27-13.64]) and Aboriginal people (11.87 [11.19-12.59]) than in South Asians (9.35 [8.82-9.92]) and Chinese (8.52 [8.03-9.03]) (overall P < 0.001). Serum leptin was significantly higher in South Asians (11.82 [10.72-13.04]) and Aboriginal people (11.13 [10.13-12.23]) than in Europeans (9.21 [8.38-10.12]) and Chinese (8.25 [7.48-9.10]). BMI and waist circumference were inversely associated with adiponectin in every group except the South Asians (P < 0.001 for interaction). Adiponectin was inversely and leptin was positively associated with HOMA-IR (P < 0.001). The increase in HOMA-IR for each given decrease in adiponectin was larger among South Asians (P = 0.01) and Aboriginal people (P < 0.001) than among Europeans. A high glycemic index was associated with a larger decrease in adiponectin among South Asians (P = 0.03) and Aboriginal people (P < 0.001) and a larger increase in HOMA-IR among South Asians (P < 0.05) relative to that in other groups.. South Asians have the least favorable adipokine profile and, like the Aboriginal people, display a greater increase in insulin resistance with decreasing levels of adiponectin. Differences in adipokines and responses to glycemic foods parallel the ethnic differences in insulin resistance.

Topics: Adiponectin; Adiposity; Adult; Aged; Asian People; Canada; Diabetes Mellitus, Type 2; Feeding Behavior; Female; Glycemic Index; Homeostasis; Humans; Indians, North American; Insulin Resistance; Leptin; Male; Middle Aged; Racial Groups; Risk Factors; Surveys and Questionnaires; White People

Major depressive disorder (MDD) is associated with immune system dysfunction and disruption of multiple circadian systems. Adiponectin is an adipocytokine with anti-inflammatory and antiatherogenic effects. Circulating concentrations are inversely related to adiposity and risks of metabolic syndrome and diabetes mellitus. Our goals were (1) to establish whether premenopausal women with MDD exhibit decreased plasma adiponectin concentrations and/or disruption of circadian adiponectin rhythmicity; (2) to assess whether there is a relationship between adiponectin and MDD; and (3) to explore the temporal relationships among adiponectin, leptin, corticotropin, and cortisol secretion.. We conducted a case-control study of community-dwelling premenopausal women with DSM-IV MDD (n = 23) and age- and body mass index (BMI)-matched control subjects (n = 23). Main outcome measures were circulating concentrations of adiponectin, leptin, corticotropin, and cortisol measured hourly for 24 hours. Subjects were recruited from July 1, 2001, to February 28, 2003.. Women with MDD had approximately 30% lower mean 24-hour concentration of adiponectin than did control subjects. Adiponectin concentration was inversely related to depression severity and total duration of disease, suggesting a causal link. In contrast, mean nocturnal leptin concentration was higher in the MDD versus control groups. Mean leptin concentration was inversely related to cortisol and adiponectin concentrations, both in subjects with depression and in control subjects. In cross-correlation analyses, the relationship between corticotropin and cortisol concentrations was stronger in women with MDD than in control subjects, a finding consistent with hypothalamic-pituitary-adrenal (HPA) axis activation in MDD.. In premenopausal women with MDD, reduced daily adiponectin production may increase the risk of diabetes mellitus, and elevated leptin may contribute to osteoporosis.

Topics: Adiponectin; Adrenocorticotropic Hormone; Adult; Alendronate; Body Mass Index; Case-Control Studies; Circadian Rhythm; Depressive Disorder, Major; Diabetes Mellitus, Type 2; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Hydrocortisone; Leptin; Middle Aged; Osteoporosis; Premenopause; Psychiatric Status Rating Scales; Risk Factors; Women's Health

Elevated lipopolysaccharide-binding protein (LBP), a marker of subclinical endotoxemia, may be involved in the pathogenesis of obesity and metabolic risk. We aimed to investigate the association between plasma LBP and metabolic disorders in apparently healthy Chinese.. A population-based study including 559 overweight/obese (BMI >or=24.0 kg/m(2)) and 500 normal-weight (18.0

Topics: Acute-Phase Proteins; Adiponectin; Adult; Asian People; C-Reactive Protein; Carrier Proteins; Diabetes Mellitus, Type 2; Endotoxemia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Leptin; Male; Membrane Glycoproteins; Metabolic Syndrome; Middle Aged; Obesity

Adipokines play an important role in metabolic regulations. Obesity, diabetes, and renal disturbances affect adipokine profile by influencing their complex effects on metabolism. Our objective was to assess the effect of low-energy diet intervention on serum adiponectin, leptin, and resistin levels in diabetic nephropathy.. Seventeen subjects with diabetes type 2 and nephropathy participated in the study. After estimation of individual resting metabolic rates by indirect calorimetry, diets introducing 20% energy deficit were applied. At baseline and after 2 months of dieting, the following parameters were measured: body composition by dual x-ray spectrometry and serum adiponectin (Adp), leptin (Lep), resistin (Res), insulin, urea, creatinine, glucose, glycosylated hemoglobin, C-reactive protein, and tumor necrosis factor-alpha concentrations. Homeostatic model assessment (HOMA) was used to quantify insulin resistance.. Total energy, protein, and fat intakes diminished significantly with intentional dieting. Significant decreases in total body fat mass (FM) and its percentage in body mass (FM%) and trunk and gynoid fat mass, as well as in serum resistin and tumor necrosis factor-alpha levels, were also observed. Responses of adipokines to dietary treatment varied individually. Generally, they were affected by FM. Alterations in Lep concentrations correlated negatively with baseline FM, FM%, and android and gynoid fat mass and positively with changes in intake of protein, carbohydrates, and total energy of the consumed diet. Changes in Adp were inversely related to FM after therapy. Alterations in Res concentrations correlated positively with android fat mass before therapy and initial Lep levels. Adiponectin was inversely related to HOMA index before and after treatment.. Low-energy diet applied in diabetic nephropathy may decrease serum resistin levels and inflammation. In addition, responses of all adipokines to dieting appear to be affected by body fat mass, especially android fat mass.

Topics: Adiponectin; Adipose Tissue; Aged; Blood Glucose; Body Composition; C-Reactive Protein; Calorimetry, Indirect; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, Reducing; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Humans; Inflammation; Leptin; Male; Resistin

Berardinelli-Seip syndrome (BSS), also termed congenital generalized lipodystrophy or congenital generalized lipoatropic diabetes, is a rare autosomal recessive disease characterized by the nearly complete absence of metabolically active adipose tissue from birth, extreme insulin resistance, diabetes mellitus, and hepatomegaly. The aim of this study was to evaluate the effect of diet intervention and oral zinc supplementation on the metabolic control of BSS patients.. During a 3-month period, 10 BSS patients received individualized diets and oral zinc supplementation. Food intake, clinical laboratory parameters, serum zinc and leptin, and plasma C-peptide concentrations were evaluated at the beginning of the study and after 3 months.. At the beginning of the study, all patients had elevated energy, protein, total fat, carbohydrate, calcium, iron, and zinc intakes. After 3 months, all of these parameters had decreased. Total fiber intakes remained low before and after diet intervention and oral zinc supplementation, and plasma levels of fasting glucose remained high. In contrast, glycated hemoglobin decreased significantly. Plasma leptin, C-peptide, and serum zinc levels increased during venous zinc tolerance testing, but there were no significant differences between the 2 curves obtained before and after diet intervention and oral zinc supplementation.. Diet intervention and oral zinc supplementation were effective at controlling energy consumption, macronutrients, and glycated hemoglobin. Zinc likely acts as an adjunct therapy, thereby improving the effectiveness of leptin.

Topics: Adipose Tissue; Adolescent; Adult; Diabetes Mellitus, Type 2; Dietary Supplements; Energy Intake; Fasting; Feeding Behavior; Female; Glycated Hemoglobin; Hepatomegaly; Humans; Insulin; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Male; Young Adult; Zinc

To explore the mechanism of laparoscopic adjustable gastric banding (LAGB) in the treatment of obese patients with type 2 diabetes mellitus (T2DM).. A total of 20 patients with obesity and T2DM were treated with LAGB. During the postoperative 1, 3, 6, 9, 12 months, the body weight changes were monitored and body mass indices (BMI) were calculated. The serum levels of leptin, GLP-1, and ghrelin were examined preoperatively and 1, 3, 6, 9, 12 months after LAGB using enzyme-linked-immunosorbent assay (ELISA). At the same time, the fasting serum insulin (FINS), C-peptide, glycated hemoglobin (HbA1c) levels were examined by electrochemiluminescence and the level of fasting blood glucose (FBG) was tested with oxidase test.. At postoperatively 12 months, all the 20 patients lost weight. The mean body weight decreased from (108 + or - 18) kg to (71 + or - 16) kg (P<0.05) and BMI decreased from 38 + or - 5 to 29 + or - 6 (P<0.05). The HOMA-IR decreased from (12.8 + or - 7.4) to (3.4 + or - 2.0) (P<0.01). The serum ghrelin level increased from (7.8 + or - 1.9) microg/L to (11.6 + or - 2.6) microg/L (P<0.01). The serum leptin level declined from (24.9 + or - 13.7) microg/L to(12.9 + or - 5.1) microg/L (P<0.01). The serum GLP-1 level increased from (0.58 + or - 0.12) microg/L to(0.80 + or - 0.06) microg/L (P<0.01). After LAGB, there were positive correlations between serum leptin level and FBG, FINS, HbA1c,and C-peptide level. Serum ghrelin and GLP-1 were negatively correlated with FBG, FINS, HbA1c,C-peptide.. LAGB is effective in treatment of obesity patients with T2DM. The mechanism may be associated with the increase of serum GLP-1 and ghrelin and the decrease of serum leptin and insulin resistance.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gastroplasty; Ghrelin; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Laparoscopy; Leptin; Male; Middle Aged; Obesity; Young Adult

In order to examine the influence of obesity on metabolic disorder and liver pathogenesis of the Fatty Liver Shionogi (FLS) mouse, which develops hereditary fatty liver and spontaneous liver tumors, we established a new congenic strain named FLS-Lep(ob). The Lep(ob) gene of the C57BL/6JWakShi (B6)-Lep(ob)/Lep(ob) mouse was transferred into the genome of the FLS mouse, by backcross mating. FLS-Lep(ob)/Lep(ob) mice were maintained by intercrossing between Lep(ob)-heterozygous littermates. The FLS-Lep(ob)/Lep(ob) mice of both sexes developed remarkable hyperphagia, obesity and type 2 diabetes mellitus. At 12 weeks of age, glucosuria was detected in all male and female FLS-Lep(ob)/Lep(ob) mice. Biochemical examination demonstrated that the FLS-Lep(ob)/Lep(ob) mice have severe hyperlipidemia and hyperinsulinemia. The livers of FLS-Lep(ob)/Lep(ob) mice showed microvesicular steatosis and deposition of large lipid droplets in hepatocytes throughout the lobules. The steatohepatitis-like lesions including the multifocal mononuclear cell infiltration and clusters of foamy cells were observed earlier in FLS-Lep(ob)/ Lep(ob) mice than in FLS mice. B6-Lep(ob)/Lep(ob) mice did not show hepatic inflammatory change. Furthermore, FLS-Lep(ob)/Lep(ob) mice developed multiple hepatic tumors including hepatocellular adenomas and carcinomas following steatohepatitis. In conclusion, the FLS-Lep(ob)/Lep(ob) mice developed steatohepatitis and hepatic tumors following hepatic steatosis. The FLS-Lep(ob)/Lep(ob) mouse with obesity and type 2 diabetes mellitus might be a useful animal model for human non-alcoholic steatohepatitis (NASH).

Topics: Adenoma, Liver Cell; Animals; Carcinoma, Hepatocellular; Diabetes Mellitus, Type 2; Fatty Liver; Female; Gene Expression; Glucose Tolerance Test; Glycosuria; Hepatocytes; Hyperlipidemias; Insulin Resistance; Leptin; Lipids; Liver; Liver Neoplasms; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Obesity; RNA, Messenger

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.

Topics: Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Heart Rate; Hyperglycemia; Hyperlipidemias; Hypertension; Leptin; Male; Obesity; Proteinuria; Rats; Rats, Sprague-Dawley

The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short- and long-term changes in hormonal determinants of blood glucose.. Eleven morbidly obese women with diabetes were studied before and 1, 6, and 12 months after GBP; eight non-diabetic morbidly obese women were used as controls. The incretin effect was measured as the difference in insulin levels in response to oral glucose and to an isoglycemic intravenous challenge. Outcome measures were glucose, insulin, C-peptide, proinsulin, amylin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) levels and the incretin effect on insulin secretion.. The decrease in fasting glucose (r = 0.724) and insulin (r = 0.576) was associated with weight loss up to 12 months after GBP. In contrast, the blunted incretin effect (calculated at 22%) that improved at 1 month remained unchanged with further weight loss at 6 (52%) and 12 (52%) months. The blunted incretin (GLP-1 and GIP) levels, early phase insulin secretion, and other parameters of β-cell function (amylin, proinsulin/insulin) followed the same pattern, with rapid improvement at 1 month that remained unchanged at 1 year.. The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.

Topics: Adiponectin; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Leptin; Middle Aged; Obesity, Morbid; Postoperative Period; Stomach; Weight Loss

To investigate the association between high level serum leptin in male youths in relation to parental history of type 2 diabetes mellitus (T2DM) and body mass index (BMI).. This cross-sectional study was carried out at the Department of Medical Technology, Applied Science University, Amman, Jordan during the period from January to April 2009. One hundred and sixteen Jordanian male nursing students aged 18-24 years were divided into 4 groups according to parental history of T2DM and BMI. Fasting blood samples were measured for blood glucose, lipid profile, and serum leptin.. Serum leptin levels in overweight and obese male youth diabetic patients with parental history of T2DM were significantly higher than in those overweight and obese without parental history (p<0.001). Of the 116 subjects, 83 (71.6%) had a positive parental history of T2DM. Compared with other groups, significant (p<0.001) elevation was observed in the mean cholesterol and triglyceride levels of obese T2DM. No significant differences were detected in high-density lipoprotein, low-density lipoprotein, and blood glucose levels among all study groups.. High levels of leptin in overweight and obese Jordanian male youths were more likely associated with a positive parental family history of T2DM than BMI factor.

Topics: Adolescent; Adult; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Humans; Jordan; Leptin; Male; Parents; Young Adult

Adipocyte-derived hormones seem to be involved in the development of Type 2 diabetes. Therefore, we assessed the association between the proinflammatory adipokine leptin and incident Type 2 diabetes, taking into account interactions between leptin and the anti-inflammatory adipokine adiponectin.. Using a case-cohort design, serum levels of adipokines were measured in 460 cases with incident Type 2 diabetes and 1474 non-cases selected from a source population of 7936 middle-aged subjects participating in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) Augsburg cohort study between 1984 and 1995 and followed up until 2002 (mean follow-up 10.9+/-4.7 years).. High leptin and low adiponectin levels were associated with an increased Type 2 diabetes risk. The multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing tertile extremes were 1.71 (1.12-2.63) for leptin (top vs. bottom tertile) and 2.65 (1.88-3.76) for adiponectin (bottom vs. top tertile), respectively. There was a significant interaction between leptin and adiponectin, with highest diabetes risk being observed in individuals with high leptin and low adiponectin levels (P = 0.029 for interaction).While the addition of adiponectin to a basic risk factor model improved model prediction (Delta area under the curve 0.011), the change in model prediction was only marginal after the addition of leptin (Delta area under the curve 0.002).. Our findings indicate that the two adipokines leptin and adiponectin interact in modulating Type 2 diabetes risk, but adiponectin is more strongly associated with Type 2 diabetes risk than leptin.

Topics: Adiponectin; Adult; Aged; Area Under Curve; Biomarkers; Case-Control Studies; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Leptin; Male; Middle Aged; Prospective Studies; Risk Factors

To study of the contribution of obesity to renal lesion in patients with type 2 diabetes mellitus (T2DM).. One hundred and fifty-four patients (62 males and 92 females) with T2DM (mean age 58 +/- 8 years) were examined. The study excluded patients with significant stages of diabetic nephropathy (glomerular filtration rate (GFR) < 60 ml/min; proteinuria more than 2 g/day). Anthropometric indicators, such as body mass index (BMI), were estimated. The serum levels of creatinine, uric acid (UA), lipid composition, and the adipose tissue hormones leptin and adiponectin were measured. Renal lesion was evaluated from GFR and urine albumin excretion level. Groups of patients with a less and more than 5-year history and subgroups of a MBI of less and more than 30 kg/mi were identified.. In patients with a more than 5-year history of T2DM, the detection rate of microalbuminuria and proteinuria increased as obesity progressed. This regularity was not found in those with a less than 5-year history of T2DM. Diabetic patients with a BMI of > 30 kg/m2 were more frequently found to have intrarenal hemodynamic disorders (hyperfiltration) elevated blood pressure, increased UA, and decreased high-density lipoproteins, as compared with those with a BMI of < 30 kg/m2. With a higher BMI, leptin levels increased; its highest values were found in a group of patients with proteinuria. Hypoadiponectinemia was detected in most patients with T2DM. Adiponectin was decreased in early-stage nephropathy; its increase was further increased.. There was a greater prevalence of renal lesion in obese (BMI > 30 kg/m2) patients with a more than 5-year history of T2DM than in non-obese patients. Obesity has an impact on renal function due to its hemodynamic, metabolic, and hormonal effects.

Topics: Adiponectin; Adult; Aged; Anthropometry; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Hemodynamics; Humans; Hypertension; Kidney Function Tests; Leptin; Male; Middle Aged; Obesity; Risk Factors; Severity of Illness Index

Leptin is a protein produced in adipose tissue and takes part in angiogenesis and atherogenesis. Leptin is associated with development of type 2 diabetes and cardiovascular disease.. To evaluate leptin concentrations in acute myocardial infarction and in the period of convalescence in patients with type 2 diabetes mellitus.. Coronary angiography was performed in 58 patients with acute myocardial infarction. The study group comprised 35 patients with type 2 diabetes mellitus (DM) (25 men, 10 women, mean age 63.8 + or - 11.5 years) and 23 non-diabetic subjects (17 men, 6 women, mean age 58.6 + or - 9.9 years) - the control group. All patients underwent medical examination and body mass indices (BMI) as well as waist/hip ratios (WHR) were calculated. Venous blood was collected after 24 hours of admission (second day), on day 5 and three weeks after admission.. Leptin level was significantly associated with BMI (DM: r = 0.46, p = 0.005; control group: r = 0.67, p < 0.01), and hip circumference (DM: r = 0.28, p = 0.09; control group: r = 0.41, p = 0.04). Plasma leptin levels in women with type 2 diabetes were higher than in men (32.1 + or - 11.7 microg/mL vs 12.7 + or - 11.2 microg/mL, p < 0.01). Plasma leptin levels were significantly lower in non-diabetics compared to diabetic patients. Plasma leptin levels in diabetic patients were significantly higher in the acute phase of myocardial infarction than in the period of convalescence (18.3 + or - 14.3 microg/mL, 16.1 + or - 12.8 microg/mL, 14.8 + or - + or - 11.2 microg/mL, p = 0.02) but not in the control group (10.6 + or - 8.2 microg/mL, 10.0 + or - 7.3 microg/mL, 9.6 + or - 7.0 microg/mL, NS).. Plasma leptin levels in diabetic patients were significantly higher in the acute myocardial infarction than in the period of convalescence. These findings suggests that leptin may play an important role in the metabolic changes taking place during the first days of myocardial infarction.

Topics: Body Mass Index; Convalescence; Coronary Angiography; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Myocardial Infarction; Sex Characteristics

Topics: Body Mass Index; Convalescence; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Myocardial Infarction

Hyperinsulinemic euglycemic clamp is the gold standard to evaluate the insulin sensitivity, but it is too complicated and expensive to use in clinic. We tried to find an alternative indicator to reflect insulin sensitivity. To evaluate the association between the four adipokines, adiponectin, leptin, resistin and tumor necrosis factor-alpha (TNF-alpha) with insulin sensitivity, we used a hyperinsulinemic euglycemic clamp to test insulin sensitivity in Chinese patients with obesity and type 1 or type 2 diabetes mellitus versus controls.. In this parallel control study, we tested insulin sensitivity using a hyperinsulinemic euglycemic clamp in different groups, then examined levels of adiponectin, leptin, resistin and TNF-alpha in serum, and the relationship between the different adipokines and glucose disposal rate (M value), as well as insulin sensitivity index (M value/insulin, M/I), which are the "gold standard" indices of insulin sensitivity.. There were significant differences in mean leptin values in the four adipokines from the four different groups (P < 0.001; comparison of the variation between different groups was analyzed by variance analysis). Compared to controls (using multiple comparison two-way Dunnett t test), only the leptin level showed significant differences in the four adipokines from the four different groups at the same time (P < 0.001). The association analysis between the different adipokines and M or M/I values also showed that only leptin negatively correlated with M (r = -0.64, P < 0.001) or M/I values (r = -0.56, P < 0.001); there was no relationship between the other three adipokines and M or M/I values.. Only leptin was associated with M or M/I values. Therefore, leptin might be one of the predictive factors of the degree of insulin resistance and risk of the accompanying disease.

Topics: Adipokines; Adiponectin; Asian People; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Obesity; Resistin; Tumor Necrosis Factor-alpha

The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.. To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals.. The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver.. These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.

Topics: Aging; Animals; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Liver; Male; Mice; Mice, Transgenic; Obesity; Polymerase Chain Reaction; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Altered adipokine serum concentrations early reflect impaired adipose tissue function in obese patients with type 2 diabetes (T2D). It is not entirely clear whether these adipokine alterations are already present in prediabetic states and so far there is no comprehensive adipokine panel available. Therefore, the aim of this study was to assess distinct adipokine profiles in patients with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or T2D.. Based on 75 g oral glucose tolerance tests, 124 individuals were divided into groups of IFG (n = 35), IGT (n = 45), or NGT (n = 43). Furthermore, 56 subjects with T2D were included. Serum concentrations of adiponectin, chemerin, fetuin-A, leptin, interleukin (IL)-6, retinol-binding protein 4 (RBP4), monocyte chemoattractant protein (MCP)-1, vaspin, progranulin, and soluble leptin receptor (sOBR) were measured by ELISAs.. Chemerin, progranulin, fetuin-A, and RBP4, IL-6, adiponectin and leptin serum concentrations were differentially regulated among the four investigated groups but only circulating chemerin was significantly different in patients with IGT compared to those with IFG. Compared to T2D the IFG subjects had higher serum chemerin, progranulin, fetuin-A and RBP4 levels which was not detectable in the comparison of the T2D and IGT group.. Alterations in adipokine serum concentrations are already detectable in prediabetic states, mainly for chemerin, and may reflect adipose tissue dysfunction as an early pathogenetic event in T2D development. In addition, distinct adipokine serum patterns in individuals with IFG and IGT suggest a specific role of adipose tissue in the pathogenesis of these prediabetic states.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Blood Glucose; Blood Proteins; Body Mass Index; Chemokine CCL2; Chemokines; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Middle Aged; Progranulins; Receptors, Leptin; Retinol-Binding Proteins, Plasma; Serpins; Young Adult

The aim of this study was to investigate the relationship between plasma leptin levels and the chronic complications in type 2 diabetic (T2DM) patients.. There were 157 T2DM patients (age, 56.7 ± 11.4 years; mean diabetes duration, 8.9 ± 3.6 years; mean body mass index, 28.1 ± 4.3 kg/m(2)) included to the study. Microvascular and macrovascular complications of diabetes were evaluated in all patients. There were 46 healthy subjects as control group. Plasma leptin levels were measured in both diabetic and healthy subjects.. Plasma leptin levels of the diabetic patients were not significantly different from the healthy subjects (26.4 ± 18.2 vs. 29.1 ± 13.1 ng/mL, P > 0.05). Plasma leptin levels in obese diabetic patients were higher than in nonobese (37.6 ± 20.9 vs. 20.0 ± 17.2 ng/mL, P = 0.001); in hypertensive diabetic patients than normotensive (35.2 ± 19.3 vs. 19.4 ± 13.9 ng/mL, P < 0.001); dyslipidemic diabetic patients than normolipidemic diabetic subjects (38.5 ± 18.3 vs. 31.3 ± 19.5 ng/mL, P = 0.038); diabetic patients with metabolic syndrome than diabetic patients without metabolic syndrome (37.9 ± 20.1 vs. 23.2 ± 15.3 ng/mL, P = 0.001). Plasma leptin levels were lower in diabetic patients who were smokers than nonsmokers (20.0 ± 15.5 vs. 24.7 ± 17.4 ng/mL, P = 0.023). There was no significant difference between patients with and without diabetic nephropathy, retinopathy, neuropathy, coronary artery disease or peripheral vascular disease (P > 0.05).. Our data suggest that obesity, hypertension, dyslipidemia, and metabolic syndrome in T2DM were associated with increased plasma leptin levels. We conclude that plasma leptin levels may not be strongly associated with microangiopathy and macroangiopathy in T2DM individuals.

Topics: Adult; Aged; Body Mass Index; Case-Control Studies; Chronic Disease; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Leptin; Male; Middle Aged; Obesity

Glycosylated haemoglobin (HbA1c), leptin, leptin soluble receptors (sOB-R) and free leptin index (FLI) may all be influenced by diabetes, but their associations remain unclear. Therefore, we put forward a hypothesis that serum leptin, sOBR and FLI might be parallel to Hb1c, as they all reflect the metabolic status.. We measured leptin and sOB-R concentrations in 97 obese non-diabetic (47 women and 50 men), and 65 obese diabetic (32 women and 33 men) humans, and examined whether they were related to HbA1c. Under the condition, the presence of diabetes was the only differentiating factor between two groups of frankly obese humans.. Non-diabetic vs. diabetic, median and interquartile range, respectively: Leptin (ng/ml), 30.83, 37.27 vs. 28.24, 23.34; p>0.05; sOB-R (ng/ml), 17.62, 17.05 vs. 21.81, 16.61, p<0.05; FLI, 231.23, 310.00 vs. 131.76, 157.68, p<0.05. To investigate the influence of HbA1c on leptin and sOB-R, both groups were divided into tertiles based on HbA1c. In diabetics, leptin did not differ between the high, intermediate, and low HbA1c levels subgroups, p>0.05, and leptin was not influenced by HbA1c levels: r=0.086; p>0.05. For sOB-R, respectively: p>0.05; r=0.080; p>0.05. In non-diabetics, respectively: p<0.05; r=0.2923; p<0.05 for leptin; and p<0.0001, r=0.5103; p<0.0001, for s-OB-R.. Not leptin alone but serum sOB-R and FLI are the markers of leptin action impairment in type 2 diabetes. Further, HbA1c is not associated with metabolic status of leptin in obese diabetic patients, whereas this association is found in obese non-diabetic humans.

Topics: Adult; Biomarkers; Blood Glucose; Body Mass Index; Case-Control Studies; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Poland; Predictive Value of Tests; Receptors, Leptin

To estimate the incidence and clinical value of metabolic syndrome, insulin resistance, and steatosis in patients with chronic hepatitis C (CHC) caused by its virus genotype 1.. One hundred and fourteen patients (67 men and 47 women; mean age 44.9 +/- 13.3 years) were examined.. There were high incidence rates of metabolic syndrome (47.2%) and insulin resistance (50%), in the genesis of which the host-virus interaction is discussed. There was an independent correlation of the insulin resistance and elevated leptin levels with abdominal obesity and hepatic steatosis; however, these indicators did not correlate with the stage of fibrosis. At the same time hepatic steatosis (found in 38% of the patients) and its degree correlated with the stage of fibrosis. Thirty-four of 66 (54.5%) patients receiving antiviral therapy achieved a stable virological response.. Obesity, hyperglycemia, and significant insulin resistance along with the stage of hepatic cirrhosis are independent cofactors that determine no treatment response.

Topics: Adult; Antiviral Agents; Diabetes Mellitus, Type 2; Fatty Liver; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Incidence; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Prospective Studies; Treatment Outcome

This investigation was made in regard to the changes of plasma Leptin, Tumor Necrosis Factor-alpha (TNF-alpha) and Neuropeptide Y (NPY) levels and their association with insulin resistance and beta-cell secretion function in normal glucose tolerant first-degree relatives of familial type 2 diabetic pedigrees in Chengdu area. Levels of Leptin, TNF-alpha, NPY and lipids (TG, TC, HDL-C) were determined in 86 type 2 diabetic mellitus (DM) patients, 73 normal glucose tolerant (NGT) first-degree relatives in familial type 2 diabetic pedigrees and 65 normal controls (NC) from non-diabetic families. All of the subjects underwent 75 g oral glucose tolerance test (OGTT). Plasma glucose, immunoreactive insulin (IRI) and true insulin (TI) levels were also determined. Fasting glucose and TI levels were used to calculate homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA-beta cell indexes. After being adjusted for age and body mass index (BMI), the levels of Leptin in DM and NGT first-degree relatives were all significantly higher than that in normal controls (P < 0.05). Type 2 diabetic patients showed significantly elevated TNF-alpha levels than did the normal controls (P < 0.05). Furthermore, diabetic subjects showed significantly higher HOMA-IR and lower HOMA-B levels, compared with those in NGT and NC groups (P < 0.05). No statistically significant difference was found in regard to NPY among three groups. NGT first-degree relatives showed significantly higher levels of TG, fasting IRI, OGTT-2h IRI and HOMA-IR than did the normal controls (P < 0.05). Leptin was positively correlated with age, BMI, waist, A1c, fasting and OGTT-2h glucose, OGTT-2h TI and TNF-alpha in all subjects, and was negatively correlated with HOMA-B in females. Leptin levels were significantly elevated in NGT first-degree relatives, which implied that genetic defects of Leptin may play a role in the development of familial type 2 diabetic pedigrees.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Middle Aged; Neuropeptide Y; Pedigree; Tumor Necrosis Factor-alpha

Pigment epithelium-derived factor (PEDF) inhibits endothelial cell injury. Further, serum levels of PEDF are elevated in the metabolic syndrome. These observations suggest that PEDF may be elevated as a counter-system against vascular cell damage in the metabolic syndrome. However, little is known about the regulation of PEDF in patients with diabetes. In order to clarify the determinants of serum PEDF, here, we examined the relationship between the 1-year changes in PEDF levels and those in anthropometric and metabolic variables in type 2 diabetic patients.. Eighty-six consecutive outpatients with type 2 diabetes underwent a complete history and physical examination, determination of blood chemistries, and serum levels of PEDF at baseline and 1 year after. PEDF gene expression in cultured subcutaneous or omental adipocytes were analysed by quantitative real-time reverse transcription-polymerase chain reactions.. Multiple regression analyses revealed that waist circumference, triglycerides, creatinine, and TNF-alpha were independently associated with PEDF. Further, the percent changes in serum levels of PEDF during 1-year observational periods were positively correlated with those of BMI. In addition, PEDF mRNA levels in cultured adipocytes were increased in parallel to the BMI values of subjects from whom adipocytes were derived, especially in omental adipocytes.. These results demonstrated that serum levels of PEDF were positively associated with metabolic components and TNF-alpha in Japanese patients with type 2 diabetes. Our present study suggests that PEDF may be generated from adipose tissues and play some role in visceral obesity in type 2 diabetic patients.

Topics: Adipocytes; Adipose Tissue; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Eye Proteins; Female; Follow-Up Studies; Humans; Japan; Leptin; Male; Metabolic Syndrome; Middle Aged; Nerve Growth Factors; Obesity; Regression Analysis; RNA, Messenger; Serpins; Serum Amyloid A Protein; Time Factors; Viscera

To investigate the relationship between human leptin receptor (LEPR) gene G3057A polymorphism and type 2 diabetes mellitus (T2DM) patients complicated with or without non-alcoholic fatty liver disease (NAFLD).. Two hundred and sixteen cases of newly diagnosed T2DM patients (104 cases complicated with NAFLD) and 108 cases of normal glucose tolerances (NGT) were recruited. Hemi-nested polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and PCR-direct sequence analysis were conducted to detect the polymorphism of LEPR G3057A variation. Plasma leptin levels were measured by enzyme-linked immunosorbent assay kit. Plasma lipid and glucose metabolic parameters were measured routinely. Liver ultrasound was carried out for all subjects.. T2DM patients complicated with NAFLD had higher plasma insulin, leptin, triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels than those without NAFLD and NGT subjects. The variant frequency at nucleotide 3057 G-->A transversion was 76.0% in type 2 diabetic patients complicated with NAFLD, which was also significantly higher than those without NAFLD (62.1%) and NGT cases (53.2%). There was also significant difference in genotype distribution between the three groups (chi(2) = 14.63, P < 0.01).. The polymorphism of LEPR gene 3057 probably contributes to the onset of NAFLD by regulating lipid metabolism and affecting insulin sensitivity.

Topics: Aged; Asian People; Blood Glucose; Case-Control Studies; China; Cholesterol, LDL; Diabetes Complications; Diabetes Mellitus, Type 2; DNA Mutational Analysis; Fatty Liver; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Insulin; Leptin; Liver; Logistic Models; Male; Middle Aged; Phenotype; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Leptin; Risk Assessment; Risk Factors; Triglycerides; Ultrasonography

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise of MC4R knockout mice that were allowed access to a running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Gene Expression Regulation; Insulin; Leptin; Liver; Magnetic Resonance Imaging; Mice; Mice, Knockout; Obesity; Organ Size; Pancreas; Phenotype; Physical Conditioning, Animal; Receptor, Melanocortin, Type 4; RNA, Messenger; Signal Transduction

In the present study, we investigated the effects of a treadmill exercise on serum glucose levels and Ki67 and doublecortin (DCX) immunoreactivity, which is a marker of cell proliferation expressed during cell cycles except G0 and early G1 and a marker of progenitors differentiating into neurons, respectively, in the subgranular zone of the dentate gyrus (SZDG) using a type II diabetic model. At 6 weeks of age, Zucker lean control (ZLC) and Zucker diabetic fatty (ZDF) rats were put on a treadmill with or without running for 1 h/day/5 consecutive days at 22 m/min for 5 weeks. Body weight was significantly increased in the control (without running)-ZDF rats compared to that in the other groups. In the control groups blood glucose levels were increased by 392.7 mg/dl in the control-ZDF rats and by 143.3 mg/dl in the control-ZLC rats. However, in the exercise groups, blood glucose levels were similar between the exercise-ZLC and ZDF rats: The blood glucose levels were 110.0 and 118.2 mg/dl, respectively. Ki67 positive nuclei were detected in the SZDG in control and exercise groups. The number of Ki67 positive nuclei was significantly high in exercise groups compared to that in the control groups. In addition, Ki67 positive cells were abundant in ZLC groups compared to those in ZDF groups. DCX-immunoreactive structures in the control-ZDF rats were lower than that in the control-ZLC rats. In the exercise groups, DCX-immunoreactive structures (somata and processes with tertiary dendrites) and DCX protein levels were markedly increased in both the exercise-ZLC and ZDF rats compared to that in the control groups. These results suggest that a treadmill exercise reduces blood glucose levels in ZDF rats and increases cell proliferation and differentiation in the SZDG in ZLC and ZDF rats compared to those in control groups.

Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Cell Differentiation; Cell Division; Cell Proliferation; Dentate Gyrus; Diabetes Mellitus, Type 2; Doublecortin Domain Proteins; Doublecortin Protein; Eating; Exercise Test; Female; Interphase; Ki-67 Antigen; Leptin; Male; Microtubule-Associated Proteins; Neurogenesis; Neurons; Neuropeptides; Physical Conditioning, Animal; Rats; Rats, Zucker; Stem Cells

Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown.. For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1-based cell migration assays.. Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Galpha. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels.. Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes.

Topics: Adiponectin; Adipose Tissue; Adult; Cohort Studies; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Macrophages; Male; Middle Aged; Obesity; Omentum; Progranulins; Reference Values; RNA, Messenger

The health benefits of pomegranate consumption have recently received considerable scientific focus, with most studies examining fruit and/or juice consumption. Pomegranate seed oil (POMo) is a rich source of 9-cis, 11-trans conjugate linolenic acid (CLA), which may offset the side-effects associated with weight gain. Male, wild-type CD-1 mice were divided into one of three groups (twenty per group): high-fat (HF), HF+seed oil (HF + POMo) or lean control (LN). In HF and HF + POMo, mice were provided access ad libitum to a high-fat chow (60 % of energy from fat). HF + POMo was supplemented with 61.79 mg POMo/d. LN consumed a restricted low-fat (10 % of energy from fat) chow to maintain body weight within 5 % of initial weight. Plasma was analysed for biomarkers associated with cholesterol profile (total cholesterol, HDL and TAG), glucose sensitivity (glucose and insulin), adipose tissue accumulation (leptin and adiponectin) and systemic low-grade inflammation (C-reactive protein and haptoglobin). The key findings of this study were that weight gain was associated with an increase in biomarkers of cholesterol profile, glucose sensitivity, adipose tissue accumulation and systemic low-grade inflammation (P < 0.05). POMo only altered body weight accumulation, final body weight, leptin, adiponectin and insulin (P < 0.05). We found that despite a similar level of energy intake, HF mice had a greater concentration of leptin and a lower concentration of adiponectin compared to HF + POMo mice. POMo intake was associated with an improvement in insulin sensitivity, suggesting that risk of developing type 2 diabetes may have been reduced; however, CVD risk did not change.

Topics: Adiponectin; Animals; Biomarkers; Body Composition; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Type 2; Dietary Fats; Dietary Fats, Unsaturated; Dietary Supplements; Energy Intake; Haptoglobins; Insulin; Leptin; Lythraceae; Male; Mice; Mice, Inbred Strains; Plant Oils; Random Allocation; Risk; Seeds; Weight Gain

Hyperleptinemia, hypoadiponectinemia, and hyperresistinemia were found to be significantly higher with odds ratios (CI 95%) of 2.15, 2.05 and 3.05, respectively, among cigarette smokers with type 2 diabetes in Saudi Arabian population. Smoking cessation restored the adiponectin and leptin levels while having a modest effect on resistin levels.

Topics: Adipokines; Adiponectin; Adult; Blood Pressure; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Leptin; Male; Middle Aged; Prevalence; Resistin; Smoking; Smoking Cessation

We have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity.. To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 microg/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight](-1) h(-1)) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined.. Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of alpha2 AMPK activity in skeletal muscle. Pair-feeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction.. This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Energy Intake; Leptin; Male; Mice; Mice, Inbred C57BL; Streptozocin; Weight Loss

For experimental research on type 2 diabetes mellitus, a diet-induced obesity-dependent diabetes model developed using genetically normal animals is essential. However, attempts at feeding a high-fat diet (HFD) to major inbred strains of mice have not resulted in the establishment of an ideal model. Here, we show that BDF1 mice, the F(1) hybrids of C57BL/6 and DBA/2 normal strains, develop HFD-induced obesity-dependent diabetes. BDF1 mice fed a HFD gained weight rapidly and developed severe diabetes characterized by hyperglycemia, glucosuria, and elevation of hemoglobin A(1C) levels in 3 to 4 months. The glucose tolerance of the diabetic mice was significantly impaired, and the elevation of plasma insulin after a glucose load was significantly reduced. Isolated pancreatic islets of HFD-fed BDF1 mice showed decreased insulin content and a reduced insulin secretory response to higher concentrations of glucose. Immunohistochemical analysis of the pancreas showed reduced staining intensity to insulin and aberrant distribution of glucagon-positive cells in diabetic BDF1 mice. These observations suggest the cause of the diabetes in HFD-fed BDF1 mice to be dysfunction of the pancreatic beta-cells, which do not produce or secrete enough insulin to compensate for insulin resistance. BDF1 mice fed a HFD showing obesity-dependent diabetes are suggested to be an appropriate animal model of type 2 diabetes mellitus. This model would be useful for exploring the mechanism of obesity-dependent type 2 diabetes mellitus and evaluating antiobesity and antidiabetic drugs.

Topics: Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Dietary Fats; Fatty Acids, Nonesterified; Glucose Tolerance Test; Glycosuria; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Models, Biological; Obesity; Triglycerides; Weight Gain

Obesity and type 2 diabetes increase the risk of atherosclerosis. It is unknown to what extent this reflects direct effects on the arterial wall or secondary effects of hyperlipidaemia.. The effect of obesity and type 2 diabetes on the development of atherosclerosis and inflammation, in the absence or presence of hyperlipidaemia, was assed in wild-type (n = 36) and human apolipoprotein B (apoB) transgenic mice (n = 27) that were fed normal chow or 60% fat for 12 months.. Fat-feeding caused obesity, glucose intolerance and elevated plasma leptin and soluble vascular cell adhesion molecule-1 (sVCAM-1) in both wild-type and apoB transgenic mice. In wild-type mice, plasma very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) were unaffected by fat-feeding. ApoB transgenic mice had mildly elevated plasma LDL-C (approximately 1 mmol L(-1)), which was slightly increased by fat-feeding. Sixty-four per cent of fat-fed wild-type mice vs. 7% of chow-fed wild-type mice had lipid-staining intimal lesions in the aortic root (P = 0.002). Eighty-six per cent of fat-fed apoB transgenic mice had lipid-staining lesions and the median lesion area was 8.0 times higher than in fat-fed wild-type mice (P = 0.001). Intracellular adhesion molecule-1 staining of the aortic endothelium was most pronounced in the fat-fed apoB transgenic mice.. Our findings suggest that diet-induced type 2 diabetes causes early atherosclerosis in the absence of dyslipidaemia, and that even a moderate level of LDL-C markedly augments this effect.

Topics: Animals; Arteritis; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dietary Fats; Disease Models, Animal; Female; Humans; Hyperlipidemias; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Random Allocation; Risk Factors; Statistics as Topic; Time Factors; Vascular Cell Adhesion Molecule-1

To determine how the levels of leptin and monocyte chemotactic protein-1 (MCP-1) are associated with insulin resistance (IR) in obese, non-obese, diabetic and non-diabetic subjects.. 112 type 2 diabetics and 43 non-diabetics were studied fasting. Anthropometric indices were measured and glucose, insulin, leptin and MCP-1 were measured in blood. IR was calculated.. MCP-1 level was significantly higher in diabetics than non-diabetics irrespective of gender (p < 0.05). Irrespective of diabetes status, the serum leptin concentration was significantly higher (p < 0.05) in obese and females subjects than in non-obese and male subjects respectively. There were no significant correlations between IR and MCP-1 or leptin in all subgroups of subjects studied. General linear modelling analysis showed that only diabetes state significantly predicted MCP-1 levels (p < 0.05) whereas non of the factors predicted leptin levels (p > 0.05).. Routine measurement of leptin and MCP-1 would be potentially useful in assessment of patients for the metabolic syndrome or coronary heart disease especially in black population.

Topics: Africa; Aged; Animals; Chemokine CCL2; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Racial Groups; Trinidad and Tobago

Phenotypic analyses of mice null for the individual Akt isoforms suggested that they are functionally distinct and that only Akt2 plays a role in diabetes. We show here that Akt isoforms play compensatory and complementary roles in glucose homeostasis and diabetes. Insulin resistance in Akt2(-/-) mice was inhibited by haplodeficiency of Pten, suggesting that other Akt isoforms can compensate for Akt2 function. Haplodeficiency of Akt1 in Akt2(-/-) mice, however, converts prediabetes to overt type 2 diabetes, which is also reversed by haplodeficiency of Pten. Akt3 does not appear to contribute significantly to diabetes. Overt type 2 diabetes in Akt1(+/-) Akt2(-/-) mice is manifested by hyperglycemia due to beta-cell dysfunction combined with impaired glucose homeostasis due to markedly decreased leptin levels. Restoring leptin levels was sufficient to restore normal blood glucose and insulin levels in Akt1(+/-) Akt2(-/-) and Akt2(-/-) mice, suggesting that leptin-deficiency is the predominant cause of diabetes in these mice. These results uncover a new mechanism linking Akt to diabetes, provide a therapeutic strategy, and show that diabetes induced as a consequence of cancer therapy, via Akt inhibition, could be reversed by leptin therapy.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Feeding Behavior; Homeostasis; In Vitro Techniques; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoenzymes; Leptin; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt

We explored the interrelationships of coagulation FVII activity levels with obesity, leptin and insulin resistance in diabetes mellitus (DM Type 2) and in non-diabetic control subjects. We found FVII hypercoagulant activity levels in DM not associated with obesity, leptin levels or insulin resistance. It was found independently associated with hypertriglyceridemia.

Topics: Adult; Diabetes Mellitus, Type 2; Factor VII; Fasting; Female; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Leukocyte Count; Male; Middle Aged; Obesity; Reference Values; Regression Analysis; Sex Characteristics

Pneumologists frequently see obese and diabetic patients because of the high prevalence of these pathologies associated with sleep apneas. Nevertheless, the search for a sleep apnea syndrome is sometimes negative and the pneumologist is faced with unexplained complaints of sleepiness and sleep disorders. Pneumologists have to be familiar with and explore other nonrespiratory disorders in order to improve patient care. Inflammatory mechanisms have been suspected in several recent studies on daytime sleepiness. Sleep duration, obesity and diabetes are supposed to be linked because of hormonal modifications induced by sleep deprivation. Moreover, a relationship between diabetes and restless legs syndrome is not excluded.

Topics: Cytokines; Diabetes Mellitus, Type 2; Ghrelin; Humans; Inflammation; Leptin; Obesity; Restless Legs Syndrome; Sleep Wake Disorders

Adipocytes express all components of the renin-angiotensin system, and the renin-angiotensin system is involved in obesity and insulin resistance. Circulating angiotensin II (Ang II) is detectable in blood, but its significance in human obesity remains unknown. The aim of this study was to investigate plasma Ang II in obese patients with type 2 diabetes mellitus (T2D) and the change during weight loss. Fifty Japanese obese subjects with T2D (body weight, 75.0 +/- 14.1 kg; body mass index, 29.1 +/- 3.7 kg/m(2); visceral fat area [VFA], 169.3 +/- 54.3 cm(2); hemoglobin A(1c), 7.6% +/- 1.5%) were enrolled. The subjects were prescribed a diet of daily caloric intake of 20 kcal/kg for 24 weeks. Plasma Ang II was measured by radioimmunoassay. Leptin, adiponectin, and lipoprotein lipase mass in preheparin serum were also measured as adipocyte-derived factors. After 24 weeks of weight reduction diet, the mean body weight, VFA, and hemoglobin A(1c) decreased significantly by 2.3%, 7.0%, and 8.3%, respectively. The mean plasma Ang II decreased by 24% (P < .0001) and correlated with body weight both at baseline (r = 0.425, P = .0018) and at 24 weeks (r = 0.332, P = .0181). The change in Ang II correlated with changes in body weight (r = 0.335, P = .0167) and VFA (r = 0.329, P = .0191). The change in Ang II also correlated positively with change in leptin (r = 0.348, P = .0127) and tended to correlate negatively with change in lipoprotein lipase mass in preheparin serum (r = -0.260, P = .0683), which is a marker of insulin sensitivity. Plasma Ang II is associated with body weight, decreases during weight loss, and is associated with markers of insulin resistance in obese subjects with T2D.

Topics: Adiponectin; Adipose Tissue; Angiotensin II; Blood Pressure; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Lipoprotein Lipase; Male; Middle Aged; Obesity; Tomography, X-Ray Computed; Weight Loss

We have previously shown that treatment with zinc plus cyclo-(His-Pro) (CHP) significantly stimulated synthesis of the insulin degrading enzyme and lowered plasma insulin and blood glucose levels, alongside improving oral glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) rats and in aged obese Sprague-Dawley (S-D) rats. Thus, we postulated that zinc plus CHP (ZC) treatment might also improve body weight control in these rats. We therefore determined the effects of ZC treatment on body weights in both genetically diabetic, mature G-K rats and non-diabetic, obese S-D rats.. G-K rats aged 1.5-10 months and non-diabetic overweight or obese S-D rats aged 6-18 months were treated with 0-6 mg CHP plus 0-10 mg zinc L(-1) drinking water for 2-4 weeks, and changes in weight, serum leptin and adiponectin levels, food and water intakes were measured.. The optimal dose of CHP (in combination with zinc) to reduce weight and plasma leptin levels and to increase plasma adiponectin levels was close to 0.1 mg kg(-1) day(-1), in either mature G-K rats and aged overweight or obese S-D rats. Food and water intake significantly decreased in ZC treated rats in both aged S-D rats and mature G-K rats, but not in young S-D and G-K rats.. ZC treatment improved weight control and may be a possible treatment for overweight and obesity.

Topics: Adiponectin; Administration, Oral; Age Factors; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Leptin; Male; Obesity; Peptides, Cyclic; Piperazines; Rats; Rats, Sprague-Dawley; Zinc

Type 2 diabetes is characterized by hyperglycaemia, delayed gastric emptying and a blunted response of gut hormones during feeding that may modulate satiety. We hypothesized that it is associated with more hunger when treated by medication.. We studied nine type 2 diabetic men (A1C: 6.7+/-0.3%, waist circumference: 104+/-4 cm) after an overnight fast, during 5 h in response to a 2.88 MJ breakfast, twice, in a crossover design, with or without antihyperglycaemic agents. Satiety ratings, thermic effect of meal, gastric emptying, plasma concentrations of gut peptides, leptin, insulin and substrates and intake from a subsequent buffet were determined.. With medication, fasting and postprandial plasma glucose levels were lower but area under the curve (AUC) did not vary vs. without medication. Gastric emptying was shortened, branched chain amino acids (BCAA) AUC and thermic effect were lower, and postprandial glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY3-36) were maintained at higher levels beyond 4 h. Correlations were significant between duration of diabetes and fasting ghrelin (r=0.779, p=0.013) and peak insulin (r=-0.769, p=0.016), 5-h postmeal ghrelin and peak glucose (r=0.822, p=0.007), 5-h glucose and GLP-1 (r=-0.788, p=0.012), and 5-h hunger scores and energy intake at buffet (r=0.828, p=0.006). Without medication, fullness scores correlated with BCAA levels. Visual analogue scale scores, ghrelin and leptin levels did not differ between studies.. The decrease in factors associated with postprandial satiety with treatment is counterbalanced by higher GLP-1 and PYY3-36. Medication may normalize the link between perception of hunger and subsequent food intake.

Topics: Aged; Amino Acids; Area Under Curve; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptides; Fasting; Gastric Emptying; Glucagon-Like Peptide 1; Glyburide; Humans; Hunger; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Middle Aged; Postprandial Period; Satiation; Thiazolidinediones

Infusion of insulin acutely stimulates leptin production and chronic insulin treatment is associated with elevated serum leptin levels and body weight in subjects with type 2 diabetes.. The objective of the study was to investigate the relationship between insulin administration, leptin levels, and weight gain in subjects with type 2 diabetes.. This was a post hoc analysis of two randomized, controlled trials.. The study was conducted at an outpatient clinic.. Subjects included 35 (study 1) and 32 (study 2) poorly controlled oral hypoglycemic agent (OHA)-treated type 2 diabetic subjects.. Study 1: subjects were investigated during a hyperinsulinemic, euglycemic glucose clamp and 12 months after being randomly allocated to start insulin or continue on OHAs. Study 2: 1 yr treatment with either OHAs and lifestyle intervention or insulin with or without concomitant lifestyle intervention.. Changes in serum leptin levels during clamp and during 1 yr of treatment in relationship to changes in body weight.. Study 1: during acute insulin infusion leptin levels increased by 10% (P < 0.001). During 1 yr of insulin therapy, mean body weight increased by 6%, whereas the fasting leptin levels increased by 108% (both P < 0.001). The weight gain observed at 1 yr correlated with the increase in leptin levels observed during the clamp (r = 0.62, P = 0.003). Study 2: mean body weight increased by 4% (P < 0.01), whereas leptin levels increased by 56% (P < 0.001) during 1 yr of insulin treatment and the increase in leptin preceded the increase in body weight.. Significant correlations were observed between insulin's effect on serum leptin levels and the increase in weight that accompanied insulin therapy.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Signal Transduction; Weight Gain

Feeding behavior control and dietetics with consequent weight reduction can be the most efficacious and fundamental methods to normalize fasting blood glucose. However, pioglitazone treatment has been found to incrementally increase body weight. In this study, we investigated whether the combined application of a 5-HT(2A) receptor antagonist, sarpogrelate, with pioglitazone can provide a clinical benefit.. Diabetic male KK-A(y) mice were randomly assigned to four groups: those receiving 10 mg/kg/day pioglitazone treatment for 30 days (pioglitazone group, n = 7), those receiving 30 mg/kg/day sarpogrelate treatment for 30 days (sarpogrelate group, n = 7), those receiving both agents for 30 days (pioglitazone + sarpogrelate group, n = 7) and those receiving no treatment (control group, n = 7).. Feed intake was lower in the pioglitazone + sarpogrelate group than in the pioglitazone group. Water intake was also significantly lower in the pioglitazone, sarpogrelate and pioglitazone + sarpogrelate groups than in the control group. Combined application (pioglitazone + sarpogrelate) resulted in a 176% increase in leptin concentration compared with vehicle control. Body weight was significantly higher in the pioglitazone group, and there was a trend toward a smaller increment in body weight in the pioglitazone + sarpogrelate group. Mean values, calculated by multiplying insulin concentration and nonfasting glucose concentration, were significantly lower in the pioglitazone + sarpogrelate group than in the control group.. These results suggest that the combined application of sarpogrelate with pioglitazone provides therapeutic benefits not only in preventing adverse effects but also in the treatment of diabetes.

Topics: Abdominal Fat; Adipocytes; Animals; Blood Glucose; Cell Count; Diabetes Mellitus, Type 2; Disease Models, Animal; Drinking; Drug Therapy, Combination; Eating; Hypoglycemic Agents; Insulin; Leptin; Lipids; Male; Mice; Pioglitazone; Serotonin 5-HT2 Receptor Antagonists; Succinates; Thiazolidinediones

We tested the association of adiponectin/leptin ratio with diabetes type after adjusting for multiple factors in 1156 youths with newly diagnosed diabetes in the SEARCH study. Although adiponectin/leptin ratio is associated with diabetes type in youth, it is due to differences in adiponectin, but not leptin levels.

Topics: Adiponectin; Adolescent; Body Mass Index; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Leptin; Male; Population Surveillance; United States; Waist Circumference; Young Adult

Topics: Bone Density; Bone Diseases; Collagen; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fractures, Bone; Homeostasis; Humans; Hypoglycemic Agents; Leptin; Metformin; Osteoporosis; Pregnancy; Thiazolidinediones

Present researchers studied the relation between insulin with free and total leptin in type 2 diabetic patients. Thirty non insulin dependent diabetic obese patients (age: 50 +/- 12 year and BMI>30 kg m(-2)) and thirty non insulin dependent diabetic non obese patients (age: 49 +/- 25 year and BMI<25 kg m(-2)) were studied. Free leptin was purified by Gel filtration Chromatography and the fractions were collected and then their free leptin was measured by a high sensitive ELISA Kit. Circulation total leptin and insulin were measured by ELISA. Circulation free and total leptin were significantly correlated to insulin (p < 0.005). Free leptin concentrations were higher in women than in men (p < 0.001). Ratio of free leptin to total in obese subjects is more than non-obese subjects (0.27 +/- 0.1 vs. 0.03 +/- 0.04, p < 0.001). Ratio of free to total leptin showed a positive correlations with insulin (r = 0.58, p < 0.001) insulin resistance (r = 31, p < 0.015) and BMI (r = 0.86, p < 0.001). The majority of leptin which circulates in obese individuals was free form. Presumably it is bioactive portion of hormone and thus obese subjects are resistant to free leptin. These observations are consistent with the view that free leptin levels in diabetes patients attributed to changes in serum insulin level and insulin resistant.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Young Adult

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes.. MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2), 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files.. At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality.. In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target.

Topics: Atherosclerosis; Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Chemokine CCL2; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glucose Tolerance Test; Humans; Insulin; Italy; Leptin; Life Style; Middle Aged; Prognosis; Risk Factors; Stroke

Fibroblast growth factor-21 (FGF21) is a novel endocrine and paracrine regulator of metabolic homeostasis. The aim of our study was to measure its serum concentrations in patients with obesity, obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C), and to assess the changes of its circulating levels and mRNA expression after dietary and pharmacological interventions.. We measured biochemical parameters, serum FGF21, adiponectin, leptin and insulin levels by commercial ELISA and RIA kits, and mRNA expression in the liver, subcutaneous and visceral fat by RT PCR in 26 obese patients, 11 T2DM patients and 32 control subjects. The interventions were acute hyperinsulinaemia during isoglycaemic-hyperinsulinaemic clamp, very low calorie diet (VLCD) and 3 months treatment with PPAR-alpha agonist fenofibrate.. Baseline serum FGF21 levels were significantly higher in both obese and T2DM patients relative to healthy controls. FGF21 levels in obesity did not significantly differ from T2DM group. Both 3 weeks of VLCD and 3 months of fenofibrate treatment significantly increased FGF21 levels. FGF21 mRNA expression in visceral fat was twofold higher in obesity relative to C group, while it did not differ in subcutaneous fat. VLCD significantly increased FGF21 mRNA expression in subcutaneous fat of obesity. 3-h hyperinsulinaemia during the clamp increased FGF21 levels in T2DM but not in C group.. An increase in FGF21 levels after VLCD and fenofibrate treatment may contribute to positive metabolic effect of these interventions and suggests the possibility of direct positive metabolic effects of FGF21 in humans.

Topics: Adiponectin; Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Fenofibrate; Fibroblast Growth Factors; Gene Expression; Humans; Leptin; Liver; Middle Aged; Obesity

1. Assessment of cell surface expression of adhesion molecule CD11b on peripheral blood neutrophils in patients with type 2 diabetes without vascular complications. 2. Analysis of serum levels of soluble adhesion molecules: E-selectin (sE-selectin), soluble Intercellular Adhesion Molecule-1 (sICAM-1), soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and von Willebrand Factor (vWF). 3. Evaluation of systemic inflammatory markers: Interleukin-6 (IL-6), soluble Interleukin-6 Receptor (IL-6Rs), high sensitivity C-Reactive Protein (hsCRP), fibrinogen and leptin.. 22 patients with type 2 diabetes were enrolled in the study (10-female, 12-male), aged from 40 to 65 yrs, diabetes duration mean 5.32 +/- 1.70 yrs. The control group included 20 healthy volunteers. Flow cytometry was used to analyse neutrophil expression of CD11b. Both inflammatory markers and soluble adhesion molecules were determined by immunoenzymatic assay.. Neutrophil surface CD11b expression did not vary between groups. Significantly higher concentrations of sE-selectin, hsCRP, leptin and IL-6 were found in diabetic patients in comparison with the control group, sICAM-1, sVCAM-1, fibrinogen, vWF and IL-6Rs concentrations did not significantly vary between groups. In the diabetic group--a positive correlation was established between neutrophil CD11b expression and hsCRP, HOMA IR, BMI, leptin and fibrinogen.. Type 2 diabetes without vascular complications is not accompanied by increase in CD11b expression on peripheral blood neutrophils. The degree of neutrophil activation is correlated with an increase in leptin serum levels. Obtained results confirm mutual connections between obesity, type 2 diabetes and chronic inflammatory process.

Topics: Adult; Aged; C-Reactive Protein; CD11b Antigen; Diabetes Mellitus, Type 2; E-Selectin; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Neutrophils

Accumulating evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D- and obesity-related traits in a bi-racial sample of 2985 subjects at baseline and after 7 years of follow-up.. We examined six T2D-related traits (T2D status, HbA(1c), fasting glucose, insulin, adiponectin and HOMA-IR) as well as six obesity-related traits (obesity status, BMI, leptin, % body fat, visceral and subcutaneous fat mass) using logistic and linear regression models.. In all subjects at baseline, oxLDL was positively associated with T2D (OR = 1.3, 95% CI:1.1-1.5), fasting glucose (ss = 0.03 +/- 0.006), HbA(1c) (ss = 0.02 +/- 0.004), fasting insulin (ss = 0.12 +/- 0.02), HOMA-IR (ss = 0.13 +/- 0.02) and negatively with adiponectin (ss = -0.16 +/- 0.03), (all p < 0.001). The strength and magnitude of these associations did not differ much between blacks and whites. In both blacks and whites, oxLDL was also associated with obesity (OR = 1.3, 95% CI:1.1-1.4) and three of its related traits (ss = 0.60 +/- 0.14 for BMI, ss = 0.74 +/- 0.17 for % body fat, ss = 0.29 +/- 0.06 for visceral fat; all p < 0.001). Furthermore, of four traits measured after 7 years of follow-up (fasting glucose, HbA1c, BMI and % fat), their relationship with oxLDL was similar to baseline observations. No significant association was found between oxLDL and incident T2D. Interestingly, oxLDL was significantly associated with % change in T2D- and obesity-related traits in whites but not in blacks.. Our data suggest that systemic oxidative stress may be a novel risk factor for T2D and obesity.

Topics: Adiponectin; Aged; Black or African American; Blood Glucose; Body Composition; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Leptin; Lipoproteins, LDL; Male; Obesity; Oxidation-Reduction; Predictive Value of Tests; Prospective Studies; Statistics as Topic; Surveys and Questionnaires; United States; White People

Yellow KK mice carrying the 'yellow obese' gene Ay are a well established polygenic model for human non-insulin dependent diabetes mellitus. These animals develop marked adiposity and decreased glucose tolerance relative to their control littermates, KK mice. The authors monitored glucose tolerance in KK-Ay mice over time and observed a significant (P

Topics: Age Factors; Amyloid; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glucose; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Inbred ICR

Certain human subpopulations are metabolically healthy but obese, or metabolically obese but normal weight; such mutations uncouple obesity from glucose intolerance, revealing pathways implicated in Type 2 diabetes. Current searches for relevant genes consume significant effort. We have reported previously a novel double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin. In the present study, we show that wholebody disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated pro-inflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic beta-cells, where it normally inhibits beta-cell mitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-alpha (tumour necrosis factor-alpha)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Blood Glucose; Cell Differentiation; Cell Line; Cell Line, Tumor; Chromosomal Proteins, Non-Histone; Cytokines; Diabetes Mellitus, Type 2; Fasting; Gene Expression; Humans; Insulin; Insulin Resistance; Leptin; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; PPAR gamma; Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Severity of Illness Index; Transcription Factors

At the obese ones, there is an imbalance between the free defenses antioxydants and radicals from where the installation of an oxydative stress, responsible for the development of non-insulin-dependent diabetes.. Our objectives was to evaluate the levels of vitamins A, E and of leptin, to search the link witch could exist between vitamins and leptin.. We proportioned the rates in vitamins A, E and in leptine at 30 obese subjects diabetic of type 2 including 12 men and 18 women of average age (50.93 +/- 6.13) years not carrying pathologies other than the diabetes and obesity compared to 30 witnesses who theirs are paired according to the age and the sex... Our results chows that levels of antioxidants did not differ between the two groups but we find a non significant decrease in vitamin E/(TC +TG) ratio (1.86 +/- 0.38 vs. 2.11 +/- 0.74 ; p = 0.08) and significant increase of vitamin A level in women obese with non-insulin-diabetes mellitus compared with control group of women (0.69 +/- 0.16 vs. 0.55 +/- 0.15 ; p = 0.01). Moreover a negative and significative correlation between vitamin E and leptin (r = 0.452 ; p = 0.01), and a negative and no significative correlation between vitamin A and leptin (2 = - 0.221; p > 0.05) were observed.. The rate of vitamin A, is different for each sex with share. The vitamin E could have a negative control on the secretion of the leptin.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity; Vitamin A; Vitamin E

In type 2 diabetes mellitus, circulating C-reactive protein (CRP) is increased, whereas the high density lipoprotein (HDL)-associated, anti-oxidative and anti-inflammatory enzyme, paraoxonase-I, is decreased. Both high CRP and low paraoxonase-I activity may predict cardiovascular disease. It is unknown whether lower paraoxonase-I activity contributes to higher CRP levels in diabetes. In type 2 diabetic and control subjects, we determined the relationship of CRP with paraoxonase-I when taking account of plasma levels of pro- and anti-inflammatory adipokines.. In 81 type 2 diabetic patients and 89 control subjects, plasma high-sensitive CRP, serum paraoxonase-I activity (arylesterase activity, assayed as the rate of hydrolysis of phenyl acetate into phenol), plasma leptin, adiponectin, resistin and lipids were determined.. Body mass index (BMI), waist, insulin resistance, triglycerides, CRP, leptin and resistin levels were higher (P < 0.05 to P < 0.001), whereas HDL cholesterol, paraoxonase-I activity and adiponectin levels were lower (P = 0.02 to P < 0.001) in diabetic compared to control subjects. Multiple linear regression analysis demonstrated that, after controlling for age and gender, CRP was inversely related to paraoxonase-I activity (beta = -0.15, P = 0.028) and adiponectin (beta = -0.18, P = 0.009), and positively to leptin (beta = 0.33, P < 0.001) and BMI (beta = 0.22, P = 0.007), independently of the diabetic state (or of fasting glucose or HbA1c), insulin resistance and lipids (P > 0.20 for all).. Low paraoxonase-I activity is related to higher CRP, independently of adipokines, as well as of obesity and lipids. Low paraoxonase-I activity in type 2 diabetes mellitus may contribute to increased cardiovascular risk via an effect on enhanced systemic low-grade inflammation.

Topics: Adiponectin; Aged; Aryldialkylphosphatase; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Resistin; Risk Factors

To determine the association of leptin with insulin resistance, body composition, and lipid parameters in postmenopausal women and men with type 2 diabetes mellitus (T2DM).. This study was conducted in 158 patients (87 postmenopausal women and 71 men) with T2DM, and 99 healthy controls (52 postmenopausal women and 47 men). Type 2 diabetes mellitus patients were selected consecutively from the outpatient Endocrinology Service of Cumhuriyet University Hospital, Sivas, Turkey from April 2002 to March 2005. We collected demographic, leptin, insulin resistance, and lipid and body composition parameters.. Serum leptin levels of females were significantly higher than those of men in both T2DM, and healthy participants. The basal metabolic rate, fat free mass, and total body water of males, were lower than those of females. In both T2DM and healthy participants, leptin was positively correlated with insulin resistance and body composition parameters in both gender. Serum leptin levels of females were higher compared with males in the same BMI, independent of T2DM.. Leptin was associated with insulin, insulin resistance, and body composition parameters (body mass index, basal metabolic rate, body weight, %fat, and fat mass) in participants, with or without T2DM in both genders. Type 2 diabetes mellitus seemed more effective on insulin resistance than obesity. We suggest that the female gender, and fat mass, and not T2DM might have significant influence on leptin levels in age.

Topics: Adipose Tissue; Adult; Aged; Body Composition; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Postmenopause

The objectives of this study were to identify potential alterations in gene expression of melanocortin-4 receptor (MC4-R), proopiomelanocortin (POMC), and Agouti-related protein (AgRP) in mouse hypothalamus under a chronic peripheral infusion of leptin or at early (8 weeks) and advanced (16 weeks) phases of diet-induced obesity. Control or diet-induced obesity mice (8 or 16 weeks of high-fat diet) were either treated or not treated with leptin. Metabolic features were analyzed and expression of the genes of interest was measured by quantitative reverse transcriptase-PCR (RT-qPCR) and western blot. We reported that in control mice, but not in obese mice, leptin infusion induced an increase in POMC mRNA level as well as in MC4-R mRNA level suggesting that leptin could act directly and/or through alpha-melanocyte-stimulating hormone (alpha-MSH). This hypothesis was reinforced after in vitro studies, using the mouse hypothalamic GT1-7 cell line, since both leptin and Norleucine(4), D-Phenylalanine(7)-alpha-MSH (NDP-alpha-MSH) treatments increased MC4-R expression. After 8 weeks of high-fat diet, nondiabetic obese mice became resistant to the central action of leptin and their hypothalamic content of POMC and AgRP mRNA were decreased without modification of MC4-R mRNA level. After 16 weeks of high-fat diet, mice exhibited more severe metabolic disorders with type 2 diabetes. Moreover, hypothalamic expression of MC4-R was highly increased. In conclusion, several alterations of the melanocortin system were found in obese mice that are probably consecutive to their central resistance to leptin. Moreover, when the metabolic status is highly degraded (with all characteristics of a type 2 diabetes), other regulatory mechanisms (independent of leptin) can also take place.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Cell Line; Diabetes Mellitus, Type 2; Disease Models, Animal; Hypothalamus; Infusions, Parenteral; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Norleucine; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; RNA, Messenger

Both type 1 and 2 diabetes are associated with differential regulation of leptin, adiponectin and ASP. Our aim was to examine whether or not acute hyperinsulinaemia and/or hyperglycaemia per se have differential regulation of these hormones in healthy subjects.. We examined changes in leptin, adiponectin and ASP concentrations and subcutaneous white adipose tissue mRNA expression with 3-hour hyperinsulinaemic (HI, n=10), hyperglycaemic (HG, n=7) and hyperinsulinaemic-hyperglycaemic (HGHI, n=8) clamps in healthy lean young men. As somatostatin was used for the HG and HGHI clamps, a control somatostatin clamp was carried out (n=4). Changes in the expression of HKII and p85alpha Pi3K were examined as positive controls for the induction of gene expression by the insulin pathway.. HI, HG and HGHI clamps increased expression of HKII and p85alpha Pi3K while somatostatin did not. The HI clamp decreased serum adiponectin (-15%, P<0.001) and increased serum leptin (+11%, P=0.031), while the HG clamp reduced serum leptin (-20%, P=0.003). The HGHI clamp increased serum ASP (+21%, P=0.047) and expression of C3 (+26%, P=0.018) and leptin (+50%, P=0.024). Interestingly, the control somatostatin clamp suppressed both serum leptin (-17%, P=0.043) and adiponectin (-7%, P=0.020).. HG and/or HI per se regulated the concentrations and expression of leptin, adiponectin and ASP in healthy lean young men, suggesting a contribution to dysregulation of these hormones in diabetes.

Topics: Adiponectin; Adipose Tissue, White; Adult; Blood Glucose; Complement C3; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Somatostatin

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. Leptin inhibits the glucose-stimulated insulin secretion, and leptin receptors are present on beta cells as well as on fat cells, thus enabling leptin to modulate both insulin secretion and action. Therefore, leptin (LEP) and leptin receptor (LEPR) genes could play a role in the regulation of glucose and insulin after an oral glucose load. For the association study of LEP and LEPR with T2DM and metabolic traits, 752 women from Seoul National University Hospital (SNUH data) and 532 women from the Korean Health and Genome Study (KHGS data) were selected. Using the SNUH data, we identified that LEP-632G>A and +4998A>C polymorphisms were marginally associated with T2DM, LEP+4950G>A was significantly associated with several metabolic traits, and LEPR+5193G>A, +7187A>C, +27265G>A, +35861T>C, and +52289A>G showed strongly significant association with body mass index (BMI). We observed reproducibility of these results using the KHGS data; LEP+4950G>A and +4998A>C were significantly associated with systolic blood pressure and low-density lipoprotein cholesterol level, respectively. In conclusion, we observed that several polymorphisms in LEPR that had previous reports of association with BMI were significantly replicated in our samples and newly found that some variations of LEP were associated with T2DM and metabolic traits.

Topics: Aged; Asian People; Blood Pressure; Body Mass Index; Case-Control Studies; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Humans; Korea; Leptin; Metabolism; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Leptin

Studies indicate that an association exists between periodontitis and type 2 diabetes mellitus (T2DM) and/or obesity, with chronic inflammation hypothesized as the common denominator. The purpose of this study was to determine the causal effect of periodontitis and the concomitant impact of diet on the onset of insulin resistance (IR) and T2DM using a rat model system that simulates human obesity and T2DM.. Twenty-eight, 5-week-old female Zucker diabetic fatty (ZDF, fa/fa) rats were divided into four groups of seven animals: high-fat fed-periodontitis (HF/P), high-fat fed-no periodontitis (HF/C), low-fat fed-periodontitis (LF/P), and low-fat fed-no periodontitis (LF/C). Periodontitis was induced by ligature placement. Fasting plasma insulin and glucose levels were measured, and glucose tolerance tests were performed to assess glucose homeostasis, IR, and the onset of T2DM. The level of tumor necrosis factor-alpha (TNF-alpha), leptin, triglycerides, and free fatty acids were determined in week 13 at sacrifice.. HF/P rats developed more severe IR compared to HF/C rats (P <0.01) and LF/P or LF/C rats (P <0.001) as measured by fasting insulin levels and homeostasis model assessment analysis. The onset of severe IR occurred approximately 3 weeks earlier in HF/P rats compared to HF/C rats. HF/P rats developed impaired (110 to 125 mg/dl) and frank fasting hyperglycemia (>125 mg/dl) 2 weeks earlier than HF/C rats. There was no difference in the severity and onset of IR and T2DM between LF/P and LF/C rats. The level of TNF-alpha was significantly higher in HF/P rats compared to HF/C rats (P <0.01).. Periodontitis accelerated the onset of severe IR and impaired glucose homeostasis in high-fat fed ZDF rats.

Topics: Alveolar Bone Loss; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Dietary Fats; Disease Models, Animal; Fasting; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Periodontitis; Rats; Rats, Zucker; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha

The current study investigated the antidiabetic effect of chungkukjang, a widely used traditional Korean soybean fermentation food, in a type 2 diabetic animal model, C57BL/KsJ-db/db mice. After a 2-week acclimation period, the db/db mice (male, 5 weeks old) were divided into three groups: diabetic control (AIN-76 diet), chungkukjang (5 g/100 g of diet), and rosiglitazone (0.005 g/100 g of diet). The supplementation of chungkukjang induced a significant reduction of blood glucose and glycosylated hemoglobin level, and it improved insulin tolerance compared to the diabetic control group. Plasma and pancreatic insulin levels of the chungkukjang-supplemented group were significantly higher than those of the diabetic control mice, and the plasma glucagon level was also significantly different. The supplementation of chungkukjang and rosiglitazone significantly elevated hepatic glucokinase activity with a simultaneous reduction of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activity in the db/db mice compared to the diabetic control mice. In addition, the chungkukjang-supplemented group had an increased hepatic glycogen content compared to the diabetic control and rosiglitazone-supplemented groups. Consequently, these results suggest that chungkukjang may be beneficial in improving insulin resistance and hyperglycemia in type 2 diabetic animals that are partly medicated by the regulation of hepatic glucose enzymes and insulin sensitivity in peripheral tissues.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Fermentation; Glucagon; Glucokinase; Glycated Hemoglobin; Glycine max; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Isoflavones; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Pancreas; Rosiglitazone; Soybean Proteins; Thiazolidinediones

We previously reported that in mesenteric arteries from aged Otsuka Long-Evans Tokushima fatty (OLETF) rats (a type 2 diabetes model) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired while endothelium-derived contracting factor (EDCF)-mediated contraction is enhanced (Matsumoto T, Kakami M, Noguchi E, Kobayashi T, Kamata K. Am J Physiol Heart Circ Physiol 293: H1480-H1490, 2007). Here we investigated whether acute and/or chronic treatment with metformin might improve this imbalance between the effects of the above endothelium-derived factors in mesenteric arteries isolated from OLETF rats. In acute studies on OLETF mesenteric arteries, ACh-induced relaxation was impaired and the relaxation became weaker at high ACh concentrations. Both metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside [AICAR, an AMP-activated protein kinase (AMPK) activator that is also activated by metformin] 1) diminished the tendency for the relaxation to reverse at high ACh concentrations and 2) suppressed both ACh-induced EDCF-mediated contraction and ACh-stimulated production of prostanoids (thromboxane A2 and PGE2). In studies on OLETF arteries from chronically treated animals, metformin treatment (300 mg.kg(-1).day(-1) for 4 wk) 1) improved ACh-induced nitric oxide- or EDHF-mediated relaxation and cyclooxygenase (COX)-mediated contraction, 2) reduced EDCF-mediated contraction, 3) suppressed production of prostanoids, and 4) reduced superoxide generation. Metformin did not alter the protein expressions of endothelial nitric oxide synthase (eNOS), phospho-eNOS (Ser1177), or COX-1, but it increased COX-2 protein. These results suggest that metformin improves endothelial functions in OLETF mesenteric arteries by suppressing vasoconstrictor prostanoids and by reducing oxidative stress. Our data suggest that within the timescale studied here, metformin improves endothelial function through this direct mechanism, rather than by improving metabolic abnormalities.

Topics: Animals; Blood Glucose; Blood Pressure; Cholesterol; Cyclooxygenase 1; Cyclooxygenase 2; Diabetes Mellitus, Type 2; Endothelium, Vascular; Fatty Acids, Nonesterified; Hypoglycemic Agents; Insulin; Isometric Contraction; Leptin; Mesenteric Arteries; Metformin; Muscle, Smooth, Vascular; Nitric Oxide; Prostaglandins; Rats; Rats, Inbred OLETF; Superoxides; Triglycerides; Vasoconstrictor Agents

Macrophages (MPhis) utilize macropinocytosis to integrate immune and metabolic signals in order to initiate an effective immune response. Diabetes is characterized by metabolic abnormalities and altered immune function. Here we examine the influence of diabetes on macropinocytosis in primary mouse macrophages and in an in vitro diabetes model.. The data demonstrate that peritoneal MPhis from diabetic (db/db) mice had reduced macropinocytosis when compared to MPhis from non-diabetic (db/+) mice. Additionally, MPhis cultured in hyperglycemic conditions were less adept at macropinocytosis than those cultured in low glucose. Notably, AMP-activated protein kinase (AMPK) activity was decreased in MPhis cultured in hyperglycemic conditions. Activation of AMPK with leptin or 5-aminoimidazole-4-carboxamide-1-beta-riboside (AICAR) increased macropinocytosis and inhibition of AMPK with compound C decreased macropinocytosis.. Taken together, these findings indicate that MPhis from diabetic mice have decreased macropinocytosis. This decrease appears dependent on reduced AMPK activity. These results demonstrate a previously unrealized role for AMPK in MPhis and suggest that increasing AMPK activity in diabetic MPhis could improve innate immunity and decrease susceptibility to infection.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Cell Culture Techniques; Cell Line, Tumor; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Glucose; Hyperglycemia; Immunity; Leptin; Macrophage Activation; Macrophages, Peritoneal; Mice; Pinocytosis; Pyrazoles; Pyrimidines; Ribonucleosides

Genetic mutations resulting in obesity and type 2 diabetes mellitus (T2D) are described for both inbred and outbred mice. However, no known mouse model completely recapitulates human T2D and its comorbidities. We identified a cohort of obese, male, outbred Swiss-Webster (SW) mice as polyuric, polydipsic, glucosuric, and hyperglycemic. Prevalence of glucosuria in the SW colony reached 60% (n=70) in males 8 weeks to 6 months of age. Despite severe obesity in some females, no females were diabetic. Pathologic findings in affected males included cachexia, dilated gastrointestinal tracts with poor muscular tone, pancreatic islet degeneration and atrophy with compensatory metaplasia and/or neogenesis, bacterial pyelonephritis, membranous glomerulopathy, and late-onset hepatic tumors with macrosteatosis, microsteatosis, and hydropic change in aged males. Serum insulin correlated with blood glucose in a nonlinear pattern, suggestive of islet exhaustion. Circulating leptin levels showed a weak inverse correlation with glucose. Diabetic males were bred with obese colony females to produce 20 male and 20 female offspring. Prevalence of diabetes in male offspring was 80% (16/20) with a median age of onset of 18 weeks. By contrast, no diabetic females were identified, despite being significantly more obese than males. Male predominance is likewise a feature of T2D in humans. To our knowledge, this is the first documentation of hepatocellular carcinoma and islet metaplasia and/or neogenesis in a spontaneous outbred mouse model of T2D. The SW availability and histopathologic features represent a promising new model for the study of T2D.

Topics: Animals; Blood Glucose; Body Weight; Carcinoma, Hepatocellular; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Glucose Tolerance Test; Glycosuria; Immunohistochemistry; Insulin; Kaplan-Meier Estimate; Leptin; Male; Mice; Obesity

Adipocytes regulate blood vessel formation, and in turn endothelial cells promote preadipocyte differentiation through the expression of proangiogenic factors, such as vascular endothelial growth factor (VEGF)-A. Some adipocytokines and hormones also have an effect on vascular development.. Our objectives were to analyze the relationship between weight and circulating VEGF-A in morbidly obese subjects before and after bariatric surgery, and investigate the relationship between circulating VEGF-A and certain adipocytokines and hormones regulating adipocytes.. A total of 45 morbidly obese women and nine lean females were included in the study. Patients underwent bariatric surgery: vertical banded gastroplasty (n=17), gastric bypass (n=17), and biliopancreatic diversion (n=11). Serum samples for VEGF-A, adiponectin, leptin, ghrelin, and insulin were obtained preoperatively and 9-12 months after surgery.. Obese patients showed significantly higher VEGF-A levels than controls (306.3+/-170.3 vs. 187.6+/-91.9 pg/ml; P=0.04), decreasing to 246.1+/-160.4 after surgery (P<0.001), with no differences among surgical procedures. In controls there was an inverse correlation between VEGF-A and ghrelin (r=-0.85; P<.01), but not in obese patients. Leptin and insulin concentrations were increased in obese patients, with a significant decrease shown after weight loss with surgery. Conversely, adiponectin concentrations were lower in obese patients, with a significant increase shown after weight loss with surgery. Ghrelin was higher in controls than obese patients, decreasing after gastric bypass and biliopancreatic diversion, but not after vertical banded gastroplasty.. Serum VEGF-A levels are significantly higher in obese patients than in lean controls, decreasing after weight loss with bariatric surgery, behaving similarly to other hormones related to adipose mass like leptin and insulin.

Topics: Adipokines; Adult; Aged; Bariatric Surgery; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Hypertension; Insulin; Leptin; Middle Aged; Obesity, Morbid; Sleep Apnea, Obstructive; Vascular Endothelial Growth Factor A; Weight Loss; Young Adult

Despite the well-known inverse association between smoking and body weight, there have been conflicting reports on the association between smoking and adipokines such as leptin and adiponectin.. To determine and compare whether tobacco smoking (cigarettes or sheesha) affects circulating levels of adiponectin and/or influences leptin and leptin receptor (sOb-R) concentrations and free leptin in diabetic and non-diabetic subjects.. Fasting plasma adiponectin, leptin, sOb-R, glucose, insulin, and lipid profile were determined in 236 subjects grouped as control subjects (n = 53); non-diabetic cigarette smokers (n = 34), non-diabetic sheesha smokers (n = 38), diabetic nonsmokers (n = 75) and diabetic smokers (n = 36). Uni- and multivariate regression analyses were used to determine the associations of these variables with body mass index (BMI) and smoking.. When compared to control subjects, smoking cigarettes or sheesha was associated with significantly higher glucose, insulin resistance, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and lower serum leptin, sOb-R and free leptin. The effects of smoking on BMI, leptin and sOb-R were dose-dependent. Binary logistic regression analysis showed that smoking is a significant determinant of BMI; leptin, sOb-R, free leptin index, adiponectin and LDL-C.. We conclude that smoking sheesha does not reduce the metabolic effects of smoking. Smoking may modify leptin receptors and modulate leptin synthesis but the weight-lowering effect may not be related to leptin-induced anorectic signals.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; Body Mass Index; Case-Control Studies; Cholesterol; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Receptors, Leptin; Smoking

Leptin has been linked to adiposity, insulin resistance, and coronary artery disease (CAD). We examined whether the leptin concentrations are associated with the risk of CAD and metabolic syndrome (MS). The plasma leptin concentrations were measured in 556 diabetic patients (341 men and 215 women). The odds ratio (OR) of CAD and MS were increased on moving from the lowest quartile (Q1) of leptin concentration to the highest quartile (Q4) and remained significant after adjusting for age, sex, BMI, concentrations of total cholesterol, triglyceride, or high-sensitivity C-reactive protein (hsCRP), and treatment modalities for hyperglycemia. The frequency of CAD was highest in the insulin resistant group (Q4 of homeostasis model assessment-insulin resistance index [HOMA-IR]) at Q4 of leptin concentration (34.5%), compared with that of Q4 of leptin (26.4%) or HOMA-IR (21.9%). In multivariate analysis, plasma leptin concentration was identified as the most significantly independent predictor for CAD (OR 10.24, 95% CI 3.01 to 45.05). Other variables with associated with CAD were age, sex, hypertension, low-HDL cholesterolemia, and hsCRP. In conclusion, hyperleptinemia might be an independent risk factor for CAD and MS in diabetic subjects. And the simultaneous measurement of insulin resistance and leptin concentration might be helpful for screening subjects with a high-risk of CAD.

Topics: Adult; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Odds Ratio; Prevalence; Risk Factors

To determine the relationships between androgen receptor CAG repeat polymorphism length (AR CAG), sex hormones and clinical variables in men with type 2 diabetes (DM2). Men with DM2 are known to have a high prevalence of low testosterone levels. Studies suggest that testosterone replacement therapy may improve insulin sensitivity and glycaemic control in men with DM2 and reduces central obesity and serum leptin. AR CAG is known to correlate negatively with AR sensitivity and positively with body fat, insulin levels, and leptin in healthy men.. Cross-sectional study set in a district general hospital diabetes centre.. Sex hormones, AR CAG and symptoms of hypogonadism were assessed in 233 men with DM2. Associations were sought between these variables and others such as obesity, leptin, glycaemic control, and blood pressure.. Testosterone was negatively associated and AR CAG positively associated with obesity and leptin. The associations of AR CAG with leptin and obesity were independent of testosterone, estradiol, gonadotropins, and age. AR CAG was also independently associated with total, bioavailable and free testosterone, LH, waist circumference, body mass index, leptin, and systolic blood pressure. There was no association of AR CAG with sex hormone binding globulin, estradiol, HbA(1C) or the symptoms of hypogonadism.. The association of longer AR CAG with obesity and leptin suggests that shorter AR CAG may have an influence in maintaining healthy anthropomorphics and metabolism in men with DM2. Testosterone and LH levels are higher in men with longer AR CAG, probably reflecting reduced negative feedback through a less sensitive receptor.

Topics: Adult; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Leptin; Male; Obesity; Polymorphism, Genetic; Receptors, Androgen; Testosterone; Trinucleotide Repeats

The aim of this study was to investigate serum leptin, adiponectin and paraoxonase1 levels in adult females receiving pharmacotherapy for various psychiatric disorders.. The study group consisted of 32 obese females (mean age 40.53 +/- 11.00 years, mean body mass index 35.44 +/- 5.33 kg/m(2)) who were receiving treatment for psychiatric disorders, and the control group included 22 obese females (mean age 35.95 +/- 9.16 years, mean body mass index 30.78 +/- 3.33 kg/m(2)) who were free of psychiatric disorders. Analyses were performed using a bioelectrical impedance device. Fasting blood samples were obtained for complete blood count and various biochemical tests, including determination of leptin, adiponectin and paraoxonase1 activity.. Body mass index, waist and hip circumference, body fat percentage, fasting blood glucose, insulin, glycosylated hemoglobin, homeostasis model assesement of insulin resistance, alanine transaminase, aspartate tarnsaminase, and leptin levels were significantly higher in the study group than in controls. Although body weight was positively correlated with leptin levels in both groups, body weight was negatively correlated with adiponectin levels in the control group and positively correlated with adiponectin levels in the study group. In the study group, body mass index and hip circumference correlated positively with leptin levels, hip circumference correlated positively with adiponectin levels, and waist to hip ratio correlated positively with paraoxonase levels. In the control group, body mass index as well as waist and hip circumferences were positively correlated with leptin levels. Weight, body mass index, and hip circumference were also negatively correlated with the adiponectin/leptin ratio in the control group.. This study indicates a higher risk for obesity-related disorders, particularly metabolic syndrome, diabetes and cardiovascular disease, in patients treated with psychiatric drugs.

Topics: Adiponectin; Adult; Antidepressive Agents; Aryldialkylphosphatase; Biomarkers; Body Mass Index; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Mental Disorders; Metabolic Syndrome; Obesity; Waist-Hip Ratio

Diabetes mellitus impairs endothelial function, an effect that can be considered a hallmark of the development of cardiovascular diseases in diabetics. Cilostazol, a selective phosphodiesterase 3 inhibitor, is currently used to treat patients with diabetic vascular complications. However, the effects of cilostazol on responses mediated by endothelium-derived relaxing [in particular, nitric oxide (NO) and hyperpolarizing factors (EDHF)] and contracting factors remain unclear. Here, we hypothesized that cilostazol could improve endothelial dysfunctions in mesenteric arteries isolated from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Using cilostazol-treated (100 mg/kg/day for 4 weeks) or -untreated OLETF and control (Long Evans Tokushima Otsuka) rats, we examined the acetylcholine-induced endothelium-dependent responses and the cell-permeant cyclic adenosine monophosphate (cAMP) analog-induced relaxations in the superior mesenteric artery. We also determined blood parameters in these animals. In OLETF rats, chronic treatment with cilostazol reduced the blood levels of triglyceride, non-esterified fatty acids, and leptin, and increased antioxidant capacity, but did not alter the blood glucose or insulin levels. In studies on mesenteric arteries from cilostazol-treated OLETF animals, the cilostazol treatment improved: (a) the acetylcholine-induced EDHF-mediated relaxation and (b) the cAMP-mediated relaxation. However, cilostazol did not alter the NO-mediated relaxation or the endothelium-derived contracting factor-mediated contraction. These results suggest that cilostazol improves endothelial functions in OLETF mesenteric arteries by increasing EDHF signaling, and that it normalizes some metabolic abnormalities in OLETF rats. On that basis, cilostazol may prove to be a potent drug for the clinical treatment of diabetic vasculopathy.

Topics: Acetylcholine; Animals; Biological Factors; Cilostazol; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelium, Vascular; Fatty Acids, Nonesterified; Leptin; Male; Mesenteric Arteries; Nitric Oxide; Phosphodiesterase Inhibitors; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Signal Transduction; Tetrazoles; Triglycerides

High levels of leptin and low adiponectin are associated with Type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease. We studied the prognostic implications of leptin and adiponectin in patients with acute myocardial infarction (AMI) without previously known Type 2 DM.. One hundred and eighty-one patients were included. Based on an oral glucose tolerance test at hospital discharge (day 4-5), 168 (67% men) had normal or abnormal glucose tolerance (AGT), defined as impaired glucose tolerance or T2DM. Sex- and age-matched healthy persons served as control subjects (n = 185). The associations between fasting serum leptin and adiponectin (day 2) and newly discovered AGT and CV events (CV mortality, non-fatal stroke, reinfarction or severe heart failure) during a median follow-up of 34 months were investigated.. Compared with control subjects, patients of both genders had significantly higher levels of leptin 2 days after an AMI. These levels were higher than those obtained at hospital discharge and 3 months later. Circulating levels of (ln) leptin 2 days after the AMI predicted AGT at discharge (odds ratio 2.03, P = 0.042). Ln leptin at day 2 was the only biochemical variable that significantly predicted CV events both on univariate [hazard ratio (HR) 1.60, P = 0.018] and on multivariate analysis (HR 1.75, P = 0.045). Adiponectin levels did not differ between patients and control subjects and did not relate to AGT or CV events.. Elevated circulating levels of leptin on the first morning after an AMI are associated with the presence of AGT at discharge and with a poorer long-term prognosis.

Topics: Adiponectin; Aged; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Prognosis; Reference Values; Risk Factors

Obesity is a common and rapidly growing health problem today. Obesity is characterized by the increase of body fat and an excess of total body fat and, in particular, visceral fat accumulation, is considered to be a risk factor for type 2 diabetes mellitus. To determine whether the malfunction of the mesenteric adipose tissue plays an important role in the diabetic related metabolic syndrome, in this study, lipolysis and gene expression in the subcutaneous, omental and mesenteric adipose tissue of the diabetic subjects were evaluated.. Lipolysis and real time PCR were utilized to determine adipocyte function.. Basal adipose tissue glycerol release is higher in diabetics than that of the non diabetics in all three fat depots. Isoproterenol (ISO) significantly increases glycerol release in subcutaneous, omental and mesenteric adipose tissues of non diabetic subjects but it stimulated glycerol release was significantly impaired in all three fat depots of the diabetic subjects. Gene expression studies indicate that leptin, Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), Fatty acid translocase (FAT/CD36) and 11beta-hydroysteroid dehydrogenase (HSD) gene expression were significantly up regulated in the mesenteric adipose tissue of the diabetic patients.. Human mesenteric adipose tissue in obese diabetic subjects has high basal glycerol release and impaired isoproterenol stimulated glycerol release. The obesity-related gene expressions in the mesenteric adipose tissue are up regulated, suggesting that the alterations of these genes in mesentery adipose depot may play a critical role in insulin resistance of type 2 diabetes and metabolic syndrome.

Topics: Adiponectin; CD36 Antigens; Diabetes Mellitus, Type 2; Fatty Acids; Gene Expression Regulation; Glycerol; Humans; Isoproterenol; Leptin; Mesentery; Middle Aged; Obesity; Omentum; PPAR gamma; RNA, Messenger; Subcutaneous Fat

To study effects of avandia and its combination with metformine (avandamet) on secretion of fat tissue hormones.. The examination protocol for 42 patients with type 2 diabetes mellitus (DM) aged 62.4 +/- 7.7 years comprised tests for blood levels of leptin, soluble receptor to leptin, insulin, grelin, resistin and adiponectine.. The treatment resulted in reduction of fasting glycemia from 10.69 +/- 2.54 to 8.42 +/- 1.73 mmol/l, of glycosilated hemoglobin--from 8.1 + 1.6 to 7.75%, immunoreactive insulin--from 19.1 +/- 8.3 to 12.0 +/- 6.5 mg/ml, grelin--from 21.7 +/- 14.6 to 17.3 +/- 13.7 mg/ml, leptin--from 40.3 +/- 24.2 to 26.9 +/- 15.4 mg/ml, soluble receptor to leptin--from 17.9 +/- 4.5 to 13.1 +/- 3.5 mg/ml. LDLP and HDLP cholesterol was high.. Avandia and avandamet are effective antidiabetic drugs with a beneficial effect on secretion of fat tissue hormones.

Topics: Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Drug Combinations; Female; Fibrinolytic Agents; Ghrelin; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Middle Aged; Resistin; Rosiglitazone; Thiazoles; Thiazolidinediones

High leptin and low ghrelin are associated with the metabolic syndrome (MS).. Ghrelin, leptin (RIA kits), and insulin-like growth factor I (IGF-I) (ELISA kit) concentrations of the population-based cohort of 1045 subjects and their interactions with metabolic parameters were analysed. Intima-media thickness (IMT) was measured with carotid ultrasound.. The interaction between leptin and ghrelin on the MS was significant (P = 0.011). An additive effect of high leptin and low ghrelin on metabolic disturbances was observed: low ghrelin concentration (adjusted for age and sex) (P < 0.001) was associated with the MS and type 2 diabetes in the highest but not in the lower leptin quartiles. In the highest leptin quartile, ghrelin concentrations decreased linearly when the number of International Diabetes Federation MS criteria met (P < 0.01) increased. Ghrelin-leptin relation was independently associated with carotid IMT (P < 0.005). The independent positive association (P < 0.01) between the plasma ghrelin quartile and the carotid IMT was evident in the lowest IGF-I quartile.. Low ghrelin is associated with MS and type 2 diabetes in the presence of insulin and leptin resistance. Ghrelin-leptin relation is associated with early atherosclerosis. The interaction between IGF-I and ghrelin modifies the association of ghrelin with early atherosclerosis.

Topics: Adult; Carotid Artery Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Insulin-Like Growth Factor I; Leptin; Male; Metabolic Syndrome; Middle Aged; Tunica Intima; Tunica Media

To investigate the importance of a maternal and paternal family history of Type 2 diabetes and their combined association with plasma leptin and adiponectin levels in overweight Latino children with a family history of Type 2 diabetes (T2DM).. This cross-sectional study investigated the combined association of a maternal and paternal family history of T2DM with leptin and adiponectin in 175 overweight Latino children (age 11.1 +/- 1.7 years). All subjects had a family history of T2DM. Plasma adiponectin and leptin levels, body fat measured by dual-energy X-ray absorptiometry, Tanner stage, age and insulin sensitivity were assessed.. After adjustment for age, gestational diabetes, insulin sensitivity and body fat, a combined maternal and paternal family history of T2DM was associated with higher leptin concentrations (P = 0.004) compared with a maternal or paternal family history alone. This association was most pronounced at Tanner stage 1 (P for interaction family history x tanner stage = 0.022). The presence of a combined maternal and paternal family history of T2DM accounted for 4% (P = 0.003) of the variation in leptin concentrations. No such combined association was observed for adiponectin levels.. Maternal and paternal family history of T2DM may have an additive impact on leptin, but not on adiponectin levels independent of adiposity and insulin sensitivity in overweight Latino children. This may contribute to a further clinically relevant deterioration of metabolic health in this population.

Topics: Adiponectin; Child; Diabetes Mellitus, Type 2; Family Health; Female; Genetic Predisposition to Disease; Hispanic or Latino; Humans; Leptin; Lipid Metabolism; Male; Overweight; Pedigree; Risk Factors; Sex Factors

Using bioinformatics techniques and sequence analyses algorithms, a comparative study between human and rodents revealed similarity in the behavior of genes involved in the control of energy homeostasis. Brain-derived neurotrophic factor (BDNF) modulates the secretion and actions of insulin, leptin, ghrelin, various neurotransmitters and peptides, and pro-inflammatory cytokines involved in energy homeostasis suggesting that it (BDNF) has a significant role in the pathobiology of obesity and type 2 diabetes mellitus. Based on these evidences, we propose that obesity and type 2 diabetes could be disorders of the brain and BDNF could serve as a biomarker in predicting their development. Hence, methods developed to selectively deliver BDNF to appropriate hypothalamic neurons may form a novel approach in their treatment.

Topics: Animals; Biomarkers; Brain; Brain-Derived Neurotrophic Factor; Computational Biology; Diabetes Mellitus, Type 2; Energy Metabolism; Ghrelin; Homeostasis; Humans; Insulin; Leptin; Melanocortins; Mice; Models, Biological; Obesity; Phylogeny; Sequence Alignment; Species Specificity

The aim of this study was to determinate both the oxidative stress/anti-oxidative defense status and the concentration of leptin in obese, overweight and normal weight type 2 diabetes mellitus patients to seek possible association between oxidative stress and hyperleptinemia. Oxidative stress status parameters [thiobarbituric acid-reacting substances (TBARS), superoxide anion (O(2)(-)), superoxide dismutase (SOD) activity and total sulphydryl groups] and the concentration of leptin were measured in 312 subjects (178 patients and in 134 control subjects). Obese patients had a significantly higher concentration of leptin compared to obese subjects in the control population (P<0.001). They also had significantly higher plasma concentrations of TBARS, O(2)(-) and SOD activity in combination with a lower sulphydryl group concentration when compared to control subjects. Obese patients had significantly higher concentrations of both TBARS and O(2)(-) and increased SOD activity compared to normal weight patients. The odds ratio for the degree of association between oxidative stress status parameters and hyperleptinemia was strongest for TBARS [odds ratio 2.66, 95% CI (1.02-6.94), P=0.045]. The observed positive correlation between TBARS and leptin (rho=0.29, P<0.01) in obese patients suggests that increased oxidative stress and hyperleptinemia, both consequences of obesity, may play a role in type 2 diabetes mellitus development.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Diet, Diabetic; Female; Humans; Hypoglycemic Agents; Leptin; Male; Middle Aged; Obesity; Oxidative Stress; Risk Factors; Thiobarbituric Acid Reactive Substances

Type II diabetes, often associated with abdominal obesity, frequently leads to heart failure. Clinical and epidemiological evidence suggests that supplemental dyslipidaemia and hypertension, as clustered in the metabolic syndrome, aggravate the cardiovascular outcome. The differential impact of type II diabetes and the metabolic syndrome on left ventricular function, however, remains incompletely defined.. We studied left ventricular function in vivo using pressure-volume analysis in obese diabetic mice with leptin deficiency (ob/ob) and obese diabetic dyslipidemic mice with combined leptin and low-density lipoprotein-receptor deficiency (DKO). ob/ob and DKO mice developed a diabetic cardiomyopathy, characterized by impaired contractility and relaxation, from the age of 24 weeks onwards. This was-at least partially-explained by increased apoptosis and disturbed Ca(2+) reuptake in the sarcoplasmic reticulum (SR) in both mouse models. DKO, but not ob/ob, developed increased end-diastolic ventricular stiffness, paralleled by increased left ventricular myocardial fibrosis. Cardiac output was preserved in ob/ob mice by favourable loading conditions, whereas it decreased in DKO mice.. Type II diabetes in mice leads to impaired contractility and relaxation due to disturbed Ca(2+) reuptake in the SR, but only when dyslipidaemia and hypertension are superimposed does vascular-ventricular stiffening increase and left ventricular myocardial fibrosis develop.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocardium; Receptors, LDL; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Function, Left

The WBN/Kob-Lepr(fa) rat is a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr(fa) rats provide a model of non-insulin-dependent diabetes with obesity. Here, we describe the characteristics of this new animal model in detail. At 7 weeks of age, both male and female obese WBN/Kob rats showed inflammatory cell infiltration of the pancreas that suggested pan-pancreatitis and an abnormal OGTT. At 3 months of age, both male and female obese WBN/Kob rats developed overt diabetes mellitus associated with severe chronic pancreatitis. In contrast, lean female WBN/Kob rats do not develop pancreatitis or diabetes. In WBN/Kob rats, this mutation might promote the onset of severe pancreatitis, leading to the rapid development of diabetes mellitus.

Topics: Animals; Animals, Congenic; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Obesity; Pancreatitis; Rats; Receptors, Leptin

The level of leptin increases with obesity, whereas that of adiponectin decreases with obesity. It is reported that the ratio of leptin to adiponectin (L/A) is associated with insulin resistance. It is difficult to evaluate insulin resistance in diabetic patients who have a dysfunction of insulin secretion. The aim of this study was to examine whether the L/A ratio is a useful marker for insulin resistance in diabetic patients. We examined L/A in the serum of a total of 139 Japanese patients with type 2 diabetes mellitus (66 women and 73 men) and 7 healthy individuals recruited in our hospital. Changes in the levels of leptin and adiponectin were observed using the oral glucose tolerance test and a hyper- and euglycemic clamp test. Twenty-one patients with type 2 diabetes mellitus were observed for more than 6 months after treatment with pioglitazone, and 31 patients with type 2 diabetes mellitus were observed for more than 6 months after the treatment with metformin. The mean value of L/A in 139 Japanese patients with type 2 diabetes mellitus was 1.22 +/- 1.41 (1.68 +/- 1.76 in women, 0.81 +/- 0.80 in men; P = .0002). In the clamp tests, L/A correlated with glucose infusion rate (GIR) (r(2) = 0.26, P = .0034). The correlation of L/A and GIR indicated a stronger correlation than either leptin (r(2) = 0.144, P = .03) or adiponectin alone (r(2) = 0.023, P = .41), or the homeostasis model assessment of insulin resistance (r(2) = 0.103, P = .08). The average hemoglobin A(1c) (HbA(1c)) improved from 10.2% +/- 1.2% to 9.2% +/- 1.6% (P = .0037) in 6 months after treatment with pioglitazone. Our results indicate pioglitazone to be effective for HbA(1c) improvement in subjects with high L/A and low L/A. The average HbA(1c) improved from 9.2% +/- 0.9% to 8.0% +/- 1.2% (P = .0002) in 6 months after treatment with metformin. Our results indicate metformin to be effective for HbA(1c) improvement in subjects with a low L/A. In conclusion, we demonstrate that L/A is different between male and female subjects. The correlation of L/A and GIR by the euglycemic hyperinsulinemic clamp test suggests that L/A is a useful indicator for the choice of drug to treat diabetes mellitus.

Topics: Adiponectin; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Pioglitazone; Thiazolidinediones

Keishibukuryogan, one of the traditional herbal formulations, is used clinically to improve blood circulation. In this study, we examined the effects of keishibukuryogan on glucose and lipids metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. Forty-five-week-old male OLETF rats were divided into three groups: diabetic control rats given a standard chow; diabetic rats given keishibukuryogan (3%, w/w in chow); diabetic rats given pioglitazone (0.01%, w/w in chow). Oral administration of keishibukuryogan produced significant improvement against impaired glucose tolerance. On the other hand, fasting serum glucose and insulin levels, and the homeostasis index of insulin resistance did not change by keishibukuryogan treatment. Against lipid parameters, keishibukuryogan significantly lowered serum total cholesterol and triglyceride levels, and the hepatic total cholesterol level. Keishibukuryogan treatment also significantly reduced the serum leptin level, but it had no effect on the serum adiponectin level. Additionally, keishibukuryogan showed significant effects on epididymal adipose tissue by decreasing the size of fat cells and on skeletal muscle by reducing TNF-alpha protein content. From these results, it was suggested that keishibukuryogan exerts beneficial effects on the features associated with type 2 diabetes.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Hyperlipidemias; Hypoglycemic Agents; Insulin; Leptin; Lipid Metabolism; Male; Organ Size; Phytotherapy; Pioglitazone; Rats; Rats, Inbred OLETF; Thiazolidinediones; Tumor Necrosis Factor-alpha

Adipose tissue secretes a variety of cytokines, some of which are increased in the serum of obese patients. The anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) is the most highly elevated known cytokine in human obesity, and its serum levels are strongly associated with the degree of insulin resistance in non-diabetic patients.. The present study examined serum levels of IL-1Ra in type 2 diabetic patients (T2DM) and their relationships with three other adipokines (leptin, interleukin-6 [IL-6], adiponectin). Their correlation with anthropometric and biochemical variables was examined, as well as their intraindividual fluctuations.. Fifty T2DM patients, aged 58+/-13 years, were consecutively recruited among those electively hospitalized for a one-week intensive training course with our Diabetes Education Service. Anthropometric measurements and blood samples were taken after an overnight fast on admission (baseline) and after four days.. Mean serum levels of IL-1Ra and leptin, but not of IL-6 and adiponectin, were significantly higher in women than in men (P<0.0006), and this difference persisted after correction for body mass index (BMI) (P<0.0004). In addition, IL-1Ra and leptin were strongly correlated with the BMI (P<0.0004). By contrast, no significant correlations were observed between IL-1Ra and glucose-control parameters. Finally, all four adipokines exhibited wide interindividual variability, but with limited intraindividual fluctuations over the short time period.. IL-1Ra, leptin and adiponectin serum levels exhibit marked interindividual variation with high intraindividual consistency. A gender-based dimorphic pattern for IL-1Ra, independent of the degree of adiposity and glucose control, was also found.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Interleukin 1 Receptor Antagonist Protein; Leptin; Male; Middle Aged; Patient Selection; Sex Characteristics

c-Jun N-terminal kinases (SAPK/JNKs) are activated by inflammatory cytokines, and JNK signaling is involved in insulin resistance and beta-cell secretory function and survival. Chronic high glucose concentrations and leptin induce interleukin-1beta (IL-1beta) secretion from pancreatic islets, an event that is possibly causal in promoting beta-cell dysfunction and death. The present study provides evidence that chronically elevated concentrations of leptin and glucose induce beta-cell apoptosis through activation of the JNK pathway in human islets and in insulinoma (INS 832/13) cells. JNK inhibition by the dominant inhibitor JNK-binding domain of IB1/JIP-1 (JNKi) reduced JNK activity and apoptosis induced by leptin and glucose. Exposure of human islets to leptin and high glucose concentrations leads to a decrease of glucose-induced insulin secretion, which was partly restored by JNKi. We detected an interplay between the JNK cascade and the caspase 1/IL-1beta-converting enzyme in human islets. The caspase 1 gene, which contains a potential activating protein-1 binding site, was up-regulated in pancreatic sections and in isolated islets from type 2 diabetic patients. Similarly, cultured human islets exposed to high glucose- and leptin-induced caspase 1 and JNK inhibition prevented this up-regulation. Therefore, JNK inhibition may protect beta-cells from the deleterious effects of high glucose and leptin in diabetes.

Topics: Apoptosis; Caspase 1; Cells, Cultured; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; JNK Mitogen-Activated Protein Kinases; Leptin; Up-Regulation

Serum retinol-binding protein (RBP4) is secreted by liver and adipocytes and is implicated in systemic insulin resistance in rodents and humans. RBP4 normally binds to the larger transthyretin (TTR) homotetramer, forming a protein complex that reduces renal clearance of RBP4. To determine whether alterations in RBP4-TTR binding contribute to elevated plasma RBP4 levels in insulin-resistant states, we investigated RBP4-TTR interactions in leptin-deficient ob/ob mice and high-fat-fed obese mice (HFD). Gel filtration chromatography of plasma showed that 88-94% of RBP4 is contained within the RBP4-TTR complex in ob/ob and lean mice. Coimmunoprecipitation with an RBP4 antibody brought down stoichiometrically equal amounts of TTR and RBP4, indicating that TTR was not more saturated with RBP4 in ob/ob mice than in controls. However, plasma TTR levels were elevated approximately fourfold in ob/ob mice vs. controls. RBP4 injected intravenously in lean mice cleared rapidly, whereas the t(1/2) for disappearance was approximately twofold longer in ob/ob plasma. Urinary fractional excretion of RBP4 was reduced in ob/ob mice, consistent with increased retention. In HFD mice, plasma TTR levels and clearance of injected RBP4 were similar to chow-fed controls. Hepatic TTR mRNA levels were elevated approximately twofold in ob/ob but not in HFD mice. Since elevated circulating RBP4 causes insulin resistance and glucose intolerance in mice, these findings suggest that increased TTR or alterations in RBP4-TTR binding may contribute to insulin resistance by stabilizing RBP4 at higher steady-state concentrations in circulation. Lowering TTR levels or interfering with RBP4-TTR binding may enhance insulin sensitivity in obesity and type 2 diabetes.

Topics: Animals; Blotting, Western; Body Weight; Diabetes Mellitus, Type 2; Dietary Fats; Female; Injections, Intravenous; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Obese; Obesity; Prealbumin; Retinol-Binding Proteins, Plasma

A genome-wide association study conducted by the Wellcome Trust Case Control Consortium recently associated single nucleotide polymorphisms (SNPs) in the FTO (fatso/fat mass and obesity associated) gene with type 2 diabetes. These associations were shown to be mediated by obesity. Other research groups found similar results in Europeans and Hispanics but not African Americans. The mechanism by which FTO influences obesity and type 2 diabetes is currently unknown. The present study investigated the role of two FTO SNPs (rs17817449 and rs1421085) in adiposity, insulin sensitivity, and body weight regulation, including energy intake and expenditure.. We genotyped 908 individuals from the Quebec City metropolitan area that participated in the Quebec Family Study, a long-term study of extensively phenotyped individuals designed to investigate factors involved in adiposity.. We found significant associations for both SNPs with several obesity-related phenotypes. In particular, rs17817449 was associated with BMI (P = 0.0014), weight (P = 0.0059), and waist circumference (P = 0.0021) under an additive model. In addition, this FTO SNP influenced fasting insulin (P = 0.011), homeostasis model assessment of insulin resistance (P = 0.038), and an insulin sensitivity index derived from an oral glucose tolerance test (P = 0.0091). Associations were also found with resting metabolic rate (RMR) (P = 0.042) and plasma leptin levels (P = 0.036). Adjustment for BMI abolished the associations with insulin sensitivity, RMR, and plasma leptin levels.. These results confirm that genetic variation at the FTO locus contributes to the etiology of obesity, insulin resistance, and increased plasma leptin levels.

Topics: Adult; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Mass Index; Bone Density; Diabetes Mellitus, Type 2; Family; Female; Genetic Variation; Humans; Leptin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Proteins; Quebec

To compare the phenotypic appearance of the skull bones and teeth of wild type C57BL/6J mice with that of diabetic leptin-deficient (ob/ob) and diabetic leptin receptordeficient (db/db) mice used as models for diabetes.. Skulls were extracted from the carcasses of mice belonging to wild-type C57B/6J mice, db/db mice on a C57BLKS/J background, and ob/ob mice on a C57B/6J background. After removal of overlying tissue, the skulls and mandibles were then left to dehydrate and examined for phenotypic variations in structure and wear.. Bone surfaces of the skulls of wild type mice had a whiter and smoother surface compared with a yellowish colour with a grainy texture in the two mutant strains. The frontal, parietal and occipital bones were translucent in the two mutant strains. Breakages of the zygomatic arches and mandibles were more common in the ob/ob and db/db mice than in the wild type mice. Half of the teeth of the db/db mice and 90% teeth of the ob/ob mice showed considerable wear compared with marginal wear in the wild type mice.. These observations suggested that the teeth of the two diabetic mutant strains are exhibiting considerable signs of hypomineralization with increased fragility and decreased bone thickness.

Topics: Animals; Diabetes Mellitus, Type 2; Facial Bones; Frontal Bone; Leptin; Mandible; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Molar; Obesity; Occipital Bone; Parietal Bone; Phenotype; Receptors, Leptin; Skull; Tooth; Tooth Attrition; Tooth Crown; Zygoma

The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in a Aboriginal Canadian [corrected] population.. Of the 606 Sandy Lake Health and Diabetes Project cohort subjects who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Concentrations of fasting adiponectin, leptin, CRP, IL-6, SAA, and covariates were measured at baseline. Fasting glucose and a 75-g oral glucose tolerance test were obtained at baseline and follow-up to determine incident type 2 diabetes, defined as clinically diagnosed type 2 diabetes or as fasting plasma glucose > or =7.0 mmol/l or 2-h postload plasma glucose > or =11.1 mmol/l at follow-up.. Low adiponectin, high leptin, and low adiponectin-to-leptin ratio at baseline were associated with increased risk of incident type 2 diabetes after adjustment for age, sex, triglycerides, HDL cholesterol, hypertension, and impaired glucose tolerance (odds ratio 0.63 [95% CI 0.48-0.83], 1.50 [1.02-2.21], and 0.54 [0.37-0.77], respectively). When the models were additionally adjusted for waist circumference or BMI, however, only low adiponectin remained significantly associated with increased incident diabetes (0.68 [0.51-0.90]). Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction.. Low baseline adiponectin is associated with increased risk of incident type 2 diabetes independent of leptin, CRP, IL-6, SAA, and metabolic syndrome variables including obesity.

Topics: Adipokines; Adult; C-Reactive Protein; Canada; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Incidence; Insulin Resistance; Inuit; Leptin; Male; Obesity

Chromium has gained popularity as a nutritional supplement for diabetic patients. This study evaluated the effect of chronic administration of a chromium complex of D-phenylalanine (Cr(D-phe)(3)) on glucose and insulin tolerance in obese mice. The study tested the hypothesis that Cr(D-phe)(3) suppresses endoplasmic reticulum (ER) stress and insulin resistance in these animals.. C57BL lean and ob/ob obese mice were randomly divided to orally receive vehicle or Cr(D-phe)(3) (3.8 mug of elemental chromium/kg/day) for 6 months. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Protein levels of phosphorylated pancreatic ER kinase (PERK), alpha subunit of translation initiation factor 2 (eIF2alpha) and inositol-requiring enzyme-1 (IRE-1), p-c-Jun, and insulin receptor substrate-1 (IRS-1) phosphoserine-307 were assessed by western blotting. In vitro ER stress was induced by treating cultured muscle cells with thapsigargin in the presence or absence of Cr(D-phe)(3).. ob/ob mice showed poor glucose and insulin tolerance compared to the lean controls, which was attenuated by Cr(D-phe)(3). Markers of insulin resistance (phospho-c-Jun and IRS-1 phosphoserine) and ER stress (p-PERK, p-IRE-1, p-eIF2alpha), which were elevated in ob/ob mice, were attenuated following Cr(D-phe)(3) treatment. Chromium treatment was also associated with a reduction in liver triglyceride levels and lipid accumulation. In cultured myotubes, Cr(D-phe)(3) attenuated ER stress induced by thapsigargin.. Oral Cr(D-phe)(3) treatment reduces glucose intolerance, insulin resistance, and hepatic ER stress in obese, insulin-resistant mice.

Topics: Animals; Blood Glucose; Chromium; Diabetes Mellitus, Type 2; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Protein Serine-Threonine Kinases; Thapsigargin; Trace Elements

Rosiglitazone (RSG) is known to be an agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma) and promotes differentiation of pre-adipocytes into adipocytes. Leptin is highly correlated with adiposity, while the activation of PPARgamma is known to inhibit Lep gene expression and leptin release. This study was performed to evaluate the relationship between changes in circulating leptin levels, insulin sensitivity and regional adiposity after RSG treatment. Two hundred fifty-one type 2 diabetic patients (176 men and 75 women) who had been treated with sulfonylurea and/or metformin received 4 mg of RSG daily, in addition to the previous medications. Before and after RSG treatment (average duration 5.6+/-0.9 months), indices of insulin resistance, metabolic parameters, and serum leptin and adiponectin levels were measured. Abdominal subcutaneous fat thickness (SFT(max)) and visceral fat thickness were measured by sonography. After RSG treatment, HOMA-IR index decreased significantly (2.82+/-1.94 vs. 2.01+/-1.58), while BMI and SFT(max) increased, and leptin (4.72+/-3.77 vs. 5.69+/-4.30 ng/ml) and adiponectin levels (7.54+/-10.20 vs. 12.89+/-10.13 microg/ml) increased. The increase in serum leptin correlated with an increase in SFT(max) (r=0.511, p<0.001) and with a reduction in HOMA-IR (r=-0.368, p<0.001). The correlation of Delta leptin with Delta HOMA-IR and with Delta SFT(max) was higher in females and among insulin-resistant subjects. In conclusion, RSG improves the insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus, which is related to an increase in subcutaneous adiposity.

Topics: Adult; Blood Glucose; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Rosiglitazone; Thiazolidinediones; Waist-Hip Ratio

The aims of this study were to measure serum levels of brain-derived neurotrophic factor (BDNF) in patients with type 2 diabetes mellitus (T2DM) and to investigate the association of these BDNF levels with biomarkers of glucose metabolism and insulin resistance.. We studied 112 patients with T2DM and 80 age- and gender-matched control subjects.. Serum BDNF levels were significantly lower in patients with T2DM compared to control subjects (15.5+/-5.2 ng/mL vs. 20.0+/-7.3 ng/mL, P<0.01). In patients with T2DM, BDNF levels were significantly higher in females than in males (P<0.01). In the female patients, BDNF was positively related to immunoreactive insulin (IRI) (rho=0.458, P<0.05) and HOMA-R (rho=0.444, P<0.05). Stepwise multiple regression analysis showed a significant relationship between BDNF and IRI (F=5.294, P<0.05) in female patients with diabetes.. These findings suggest that BDNF may contribute to glucose metabolism.

Topics: Adiponectin; Aged; Albuminuria; Blood Glucose; Blood Pressure; Brain-Derived Neurotrophic Factor; Creatinine; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Patient Selection; Reference Values

Leptin and tumor necrosis factor-alpha (TNF-alpha) play important role in homeostasis and insulin resistance in the treatment of Type 2 diabetes (T2DM). The aims of the present study were to investigate the association between leptin G-2548A and TNF-alpha G-308A polymorphisms and rosiglitazone response in T2DM patients.. 245 patients with T2D and 122 health volunteers were enrolled to identify leptin G-2548A and TNF-alpha G-308A genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Forty-two T2D patients with different leptin G-2548A and TNF-alpha G-308A genotypes received orally rosiglitazone as a single-agent therapy (4 mg day(-1) p.o.) for 12 weeks. Serum triglyceride (TG), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting serum insulin (FINs), glycated hemoglobin (HbAlc), postprandial serum insulin (PINS), homeostasis model assessment for insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol (HDL-c) were determined before and after rosiglitazone treatment.. A significant association between the variation of G-2548A allele with body mass index (BMI), serum leptin levels and FPG was observed in T2DM patients. Moreover, patients with G allele of leptin G-2548A had lower BMI and serum leptin concertration as well as bigger FPG than that in AA genotypes (P < 0.05). Moreover, we found an enhanced rosiglitazone effect in patients with AA genotype of leptin G-2548A on FINS and PINS compared with GG+GA genotype (P < 0.05). Finally, our results showed an attenuated rosiglitazone effect in patients with GA+AA genotype of TNF-alpha G-308A on FINS compared with GG genotype (P < 0.05).. These data suggest there were not significantly differences in the frequencies of leptin G-2548A and TNF-alpha G-308A between patients with T2DM and health control. TNF-alpha G-308A polymorphism might be associated with the therapeutic efficacy of rosiglitazone in T2DM patients.

Topics: Adult; Aged; Blood Glucose; China; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Polymorphism, Genetic; Rosiglitazone; Thiazolidinediones; Triglycerides; Tumor Necrosis Factor-alpha

To compare leptin content in morphologically heterogenic group of patients with type 2 diabetes mellitus and obese patients without family history of diabetes.. Leptin concentration was estimated with enzyme immunoassay (Leptin kit Sandwish ELISA, DRG diagnostics GmdH) in 21 patients with type 2 diabetes mellitus (2DM) and 12 obese patients without family history of diabetes. Distribution of patients with a documented diagnosis type 2 diabetes mellitus was conducted with application of instruments for antropometric examination (G.P. Gneupel, Switzerland). Statistic processing was made with the program Statistica 6 using Student's t-criterion.. Patients with diabetes mellitus and phenotypical marker of 2DM had the lowest level of leptin (mean leptin level 1.99 ng/ml in males, 11.01 ng/ml in females versus 2DM patients without the marker (mean leptin level 9.16 n/mg in males, 23.56 n/mg in females) and control group (13.86 ng/ ml in males, 22.55 ng/ml in females).. There is a correlation between leptin concentration and anthropological features of the patients.

Topics: Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Obesity; Risk Factors; Severity of Illness Index

Obesity is characterized by systemic low-grade inflammation in which adipose tissue, especially the omental depot, is thought to play a key role. We have previously shown that inflammation impairs 3T3-L1 preadipocyte cell line differentiation. To explore whether this interaction also takes place in vivo, the expression of several genes related to inflammation and adipocyte differentiation was assessed in human samples. Paired adipose tissue biopsies (from omental and subcutaneous depots) were obtained from 24 women: 6 lean normoglycemic and 18 obese volunteers with different glycemic states (normoglycemic, glucose-intolerant, or type 2 diabetic). The expression levels of CD14, IL-18, leptin, adiponectin, sterol regulatory element binding transcription factor 1 (SREBP1), peroxisome proliferator-activated receptor gamma (PPARgamma), pre-B-cell colony enhancing factor 1 (PBEF1) (or visfatin), glycerol-3-phosphate dehydrogenase 1 (soluble) (GPD1), lipoprotein lipase (LPL), fatty acid binding protein 4, adipocyte (FABP4), and hypoxia-inducible factor 1alpha were determined by quantitative real-time PCR. CD14 and IL-18 were overexpressed in omental adipose tissue compared with the subcutaneous depot, irrespective of the subject's obesity or diabetes status. A significant decrease of LPL, GPD1, and leptin expression was observed in omental tissue, and an inverse correlation between expression of CD14 and IL-18 and that of PPARgamma, LPL, and FABP4 was observed. The underexpression of omental lipogenic markers was more accentuated in the presence of glucose intolerance. Furthermore, adiponectin and SREBP1 expression was also significantly decreased in omental tissue of type 2 diabetic patients. PBEF1 and HIF1alpha expression remained comparable in all samples. Therefore, in humans, inflammation is increased in the omental depot, as evidenced by CD14 and IL-18 expression. In this localization, the inflammatory state is associated with a decreased expression of lipogenic markers, which is more pronounced in diabetic subjects.

Topics: Adiponectin; Adipose Tissue; Adult; Body Composition; Cytokines; Diabetes Mellitus, Type 2; Fatty Acid-Binding Proteins; Female; Gene Expression Regulation; Glucose Intolerance; Glycerolphosphate Dehydrogenase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-18; Leptin; Lipogenesis; Lipopolysaccharide Receptors; Lipoprotein Lipase; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Omentum; PPAR gamma; RNA, Messenger; Sterol Regulatory Element Binding Protein 1

Advanced glycation endproducts (AGEs) and oxidative stress (OS) contribute to the development and progression of diabetic complications. We have reported that dietary AGEs and OS induce acute endothelial dysfunction in vivo, but little is known about their effects on adipokines. Twenty inpatients with type 2 diabetes mellitus (mean age: 55.9; range: 32-71 years), received a standard diabetes diet for 6 days. On days 4 and 6, the acute effects of a high-AGE (HAGE) or a low-AGE (LAGE) meal (15.100 vs. 2.750 kU AGE) were studied in a randomized, cross-over, investigator-blinded design. Measurements were performed after an overnight fast, at baseline (B) and at 2, 4, and 6 h after the HAGE or LAGE meals. Both meals had the same ingredients and differed only by the cooking method. Two h following HAGE, a significant decrease from baseline occurred in adiponectin (-10%*double dagger vs. +0%) and leptin (-22%*double dagger vs. -13%*), and a significant increase occurred in vascular cell adhesion molecule 1 (+19%*double dagger vs. -5%) and thiobarbituric acid reactive substances (+23%*double dagger vs. +6%). These changes did not occur, or occurred to a lesser extent, following LAGE. At 4 h following HAGE, an increase in methylglyoxal (+20%double dagger vs. -5%) and E-selectin (+54%*double dagger vs. -3%) occurred. Urinary AGEs increased only after HAGE (+51%*double dagger vs. -2%; values presented as HAGE vs. LAGE; *P < 0.05 vs. baseline, double daggerP < 0.05 vs. LAGE). The postprandial excursions in glucose, insulin, and triglycerides were similar between both meals. A meal rich in AGEs induces acute endothelial and adipocyte dysfunction. These effects were prevented by changing the cooking method.

Topics: Adipokines; Adiponectin; Adult; Age of Onset; Aged; Diabetes Mellitus, Type 2; Diet; E-Selectin; Endothelium, Vascular; Female; Glycation End Products, Advanced; Humans; Inpatients; Leptin; Male; Middle Aged; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Tyrosine

Ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) is a positional candidate gene at chromosome 6q23 where we previously detected strong linkage with fasting-specific plasma insulin and obesity in Mexican Americans from the San Antonio Family Diabetes Study (SAFDS). We genotyped 106 single-nucleotide polymorphisms (SNPs) within ENPP1 in all 439 subjects from the linkage study, and measured association with obesity and metabolic syndrome (MS)-related traits. Of 72 polymorphic SNPs, 24 were associated, using an additive model, with at least one of eight key metabolic traits. Three traits were associated with at least four SNPs. They were high-density lipoprotein cholesterol (HDL-C), leptin, and fasting plasma glucose (FPG). HDL-C was associated with seven SNPs, of which the two most significant P values were 0.0068 and 0.0096. All SNPs and SNP combinations were analyzed for functional contribution to the traits using the Bayesian quantitative-trait nucleotide (BQTN) approach. With this SNP-prioritization analysis, HDL-C was the most strongly associated trait in a four-SNP model (P=0.00008). After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to our previous linkage peak with MS-related traits in Mexican Americans. However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations.

Topics: Adult; Aged; Aged, 80 and over; Bayes Theorem; Blood Glucose; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Female; Gene Expression Regulation, Enzymologic; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; Humans; Leptin; Male; Metabolic Syndrome; Mexican Americans; Middle Aged; Models, Genetic; Obesity; Phenotype; Phosphoric Diester Hydrolases; Polymorphism, Single Nucleotide; Pyrophosphatases; Risk Factors; Texas

Topics: Adipose Tissue; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Obesity; Sex Factors

Children born small for gestational age are at increased risk of developing type 2 diabetes in adulthood. The satiety signal leptin that regulates food intake and energy expenditure might be a possible molecular link, as umbilical cord leptin levels are positively correlated with birth weight. In the present study, we examined whether common single nucleotide polymorphisms (SNPs) in the leptin (LEP; 19G>A) gene and its receptor (LEPR; Q223R and K109R) are associated with birth weight and adult metabolic risk factors for type 2 diabetes in twins.. SNPs were genotyped in 396 monozygotic and 232 dizygotic twins (286 men and 342 women, mean age 25 years) recruited from the East Flanders Prospective Twin Survey. Data were analysed using linear mixed models.. The LEPR K109R SNP was associated with birth weight (KK, KR and RR (95% confidence interval, CI): 2511 (2465-2557), 2575 (2516-2635) and 2726 (2606-2845) gram; P(additive)=0.001). Also the LEPR Q223R SNP showed a significant association with weight at birth (QQ, QR and RR (95% CI): 2492 (2431-2554), 2545 (2495-2595) and 2655 (2571-2740) gram; P(additive)=0.003). Furthermore, an interaction between the LEPR K109R and the Q223R SNP on birth weight was observed (P=0.014). G allele carriers of the LEP 19G>A SNP had higher high-density lipoprotein (HDL) cholesterol levels compared to 19A homozygotes (GX vs AA (95% CI): 1.62 (1.58-1.66) vs 1.49 (1.40-1.58) mmol l(-1); P(recessive)=0.013).. This study indicates that leptin may act as a growth-promoting signal during fetal development, and suggests a possible role for the LEPR in explaining the inverse relationship between birth weight and the development of metabolic diseases in adulthood. Additionally, these results suggest that the LEP 19G>A SNP affect HDL cholesterol levels.

Topics: Adult; Birth Weight; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diseases in Twins; Female; Genetic Predisposition to Disease; Genotype; Humans; Infant, Newborn; Leptin; Male; Phenotype; Polymorphism, Single Nucleotide; Prospective Studies; Receptors, Leptin; Risk Factors; Twins, Dizygotic; Twins, Monozygotic; Young Adult

Obesity and the metabolic syndrome have emerged as clinical and public health crises in many populations, but not all obese patients have the syndrome. As adipocytes produce several adipokines that modulate insulin action as well as glucose and lipid metabolism, we postulate that estimation of adipokines may be useful addition to the criteria used to identify obese individuals with the metabolic syndrome.. To evaluate the determinants and associations of plasma adiponectin in relation to the metabolic syndrome in patients with Type 2 diabetes.. Cross-sectional study.. General Teaching Hospital.. One hundred and thirty five (57 M, 78 F) patients with Type 2 diabetes mellitus.. Adiponectin, leptin, high-sensitivity C-reactive protein (hs-CRP), fasting plasma insulin, glucose, glycated hemoglobin and full lipid profile. Patients were classified on the basis of the degree of adiposity, insulin resistance (IR) (homeostasis model assessment of insulin resistance (HOMA-IR)) and the number of the American Heart Association and the National Heart, Lung and Blood Institute criteria of the metabolic syndrome.. Adiponectin levels were inversely correlated with age, indices of obesity, IR and hs-CRP. Overweight/obese and non-obese insulin-sensitive patients had significantly higher (P<0.05) adiponectin levels than those with IR despite similar body mass index and waist circumference. Therefore, within each category of obesity stratification, lower adiponectin levels were associated with IR. Adiponectin showed stepwise decrease with increasing number of the criteria for diagnosis of the metabolic syndrome. Using multiple logistic regression, the odds ratio of the metabolic syndrome as predicted by adiponectin was 0.73 (95% confidence interval 0.53-0.96; P=0.04). At cutoff point of 18 ng/ml, the diagnostic sensitivity and specificity of adiponectin for the metabolic syndrome were 83 and 65%, respectively, in male patients and 92 and 41%, respectively, in female patients. Receiver operating characteristic analysis showed that adiponectin had significantly higher area under the curve compared with leptin, leptin:adiponectin ratio and triglycerides for the detection of the metabolic syndrome.. In patients with Type 2 diabetes, adiponectin concentrations are closely related to IR and the components of the metabolic syndrome. Adiponectin concentration may be a useful addition to the criteria used for identifying obese subjects with the metabolic syndrome.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Sensitivity and Specificity

The aim of the present study was to investigate the factors contributing to the concentration of serum C-reactive protein in type 2 diabetic patients. One hundred and 48 Japanese type 2 diabetic patients were studied. In conjunction with C-reactive protein (CRP), BMI, systolic and diastolic blood pressure, glycosylated hemoglobin (HbA1c), fasting concentrations of plasma glucose, and serum lipids (triglycerides, HDL cholesterol, and total cholesterol), interleukin 6 (IL-6), and leptin were measured. Insulin resistance was also estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). With univariate analysis, serum CRP was positively correlated with BMI (r=0.281, P<0.001), diastolic blood pressure (r=0.176, P=0.048), triglycerides (r=0.293, P<0.001), HOMA-IR (r=0.294, P<0.001), IL-6 (r=0.323, P<0.001), and leptin (r=0.330, P<0.001), and negatively correlated with HDL cholesterol (r=-0.181, P=0.028). Multiple regression analyses showed that serum CRP was independently predicted by the level of IL-6 (P<0.001, F=4.04), leptin (P<0.001, F=7.09), and triglycerides (P<0.001, F=15.13), which explained 17.6% of the variability of serum CRP concentration in these patients. From these results, it can be concluded that along with IL-6 and triglycerides, leptin is another important independent factor that is associated with CRP in Japanese type 2 diabetic patients.

Topics: Adult; Aged; Aged, 80 and over; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Interleukin-6; Japan; Leptin; Male; Middle Aged; Regression Analysis; Triglycerides

The potential benefits of hyperbaric oxygen therapy (HBOT) have been reported in diabetic patients with foot ulcers. However, the roles of HBOT on wound healing-associated growth factors and inflammatory mediators are not completely understood in diabetes mellitus (DM).. The aim of this study was to investigate the effects of HBOT on circulating cytokines, NO, and insulin-like growth factors (IGF) in patients with type 2 DM.. Serum samples were collected from patients with type 2 DM (n=31) and healthy subjects (n=29) before (baseline) and after the first and third exposure.. Before HBOT, body mass index (BMI) and serum HbA1c were significantly greater, whereas serum IGF-I was significantly lower in diabetic patients compared to healthy subjects (one-way ANOVA, p<0.05). After adjusting for age, gender, and BMI, serum insulin, growth hormone (GH), IGF-II, IGF-binding protein (IGFBP)-1, IGFBP-3, leptin, interleukin (IL)-8, and NO were not significantly altered by HBOT in diabetic patients and healthy subjects (repeated-measures ANOVA). Change in serum insulin (baseline to the third exposure) was a positive predictor of changes in leptin and NO in healthy subjects and diabetic patients, respectively.. Our results suggest that short-term HBOT may not alter the circulating insulin, IGF, leptin, IL-8, and NO levels. In addition, healthy subjects and diabetic patients showed differential responses to HBOT in the relationships of leptin, insulin, and NO. Further studies are needed to clarify the mechanism of HBOT-improved wound healing in diabetic patients with foot ulcers.

Topics: Adult; Aged; Aged, 80 and over; Aging; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Growth Hormone; Humans; Hyperbaric Oxygenation; Insulin; Insulin-Like Growth Factor Binding Proteins; Interleukin-8; Leptin; Male; Middle Aged; Nitric Oxide; Regression Analysis; Somatomedins

Topics: Aged; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Risk Factors; Sex Characteristics

In order to find orally active Zn(II) complexes that can treat diabetes mellitus (DM) at low doses, four new Zn(II)-dithiocarbamate complexes with Zn(II)-sulfur coordination bonds were prepared and their in vitro insulinomimetic activity and in vivo anti-diabetic ability were evaluated. Among the Zn(II)-dithiocarbamate complexes, the bis(pyrrolidine-N-dithiocarbamate)zinc(II) (Zn(pdc)(2)) complex was found to be the most effective in terms of inhibiting free fatty acid-release and enhancing glucose-uptake in adipocytes. After oral administration of the Zn(pdc)(2) complex to KK-A(y) mice with obesity and type 2 DM, we observed that the high blood glucose levels in the mice were lowered from approximately 500 mg/dL to 350 mg/dL within 6 days, and the effect was maintained during the administration period. Also, indicators of insulin resistance such as serum insulin, leptin, and triglyceride levels were also reduced compared with those in untreated mice. Moreover, the Zn(pdc)(2) complex improved not only the hypertension in the mice, but also the adiponectin level in the serum. On the basis of the results, the Zn(pdc)(2) complex is proposed to improve hyperglycemia and insulin resistance in type 2 DM animals on daily oral administrations.

Topics: Adipocytes; Adiponectin; Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Organometallic Compounds; Thiocarbamates; Triglycerides; Zinc Sulfate

Human data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown.. To determine whether leptin resistance, which is seen in humans with diabetes, protects mice from hyperoxic lung injury.. Wild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O(2)) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo.. Lung leptin levels were increased both in wild-type and leptin receptor-defective db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared with wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared with wild-type control animals, db/db mice were resistant to hyperoxia-induced mortality (lethal dose for 50% of mice, 152 vs. 108 h). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of proinflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na,K-ATPase function compared with wild-type mice.. These results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Count; Cytokines; Diabetes Mellitus, Type 2; Hyperoxia; Leptin; Lung; Lung Injury; Male; Mice; Mice, Inbred C57BL; Neutrophils; Pulmonary Alveoli; Pulmonary Edema; Receptors, Cell Surface; Receptors, Leptin; Survival Analysis

Controversy exists regarding the effects of statin therapy on progressive insulin resistance (IR) and its consequences, in the present study a rat model of spontaneously developing type II diabetes mellitus (DM) was used to examine the impact of atorvastatin (AS) vs pravastatin (PS).. The Otsuka Long-Evans Tokushima Fatty rats were either untreated or treated with 100 mg/kg per day of AS or PS from 6 weeks of age for 24 weeks. AS achieved much greater lipid lowering than PS. Serial oral glucose tolerance tests revealed new-onset diabetes was delayed by PS only. The untreated rats exhibited a progressive decrease in plasma adiponectin, increases in plasma leptin and tumor necrosis factor-alpha, and reduction of plasma nitric oxide (NO), which were limited more by PS than AS. PS, but not AS, enhanced adiponectin mRNA expression in white adipose tissue at 30 weeks. Cardiac endothelial NO synthase expression was upregulated, and overexpression of both transforming growth factor-beta1 and monocyte chemoattractant protein-1 mRNA was limited more by PS than AS. Coronary perivascular fibrosis at 30 weeks was suppressed only by PS, which was accompanied by preserved left ventricular diastolic function assessed with Doppler echocardiography.. The moderate lipid lowering by PS, but not the intensive lipid lowering by AS, prevented new-onset DM and diastolic dysfunction in a rat model of IR, and this was associated with preferable adipocytokine profiles and cardiac redox states.

Topics: Adiponectin; Adipose Tissue; Animals; Anticholesteremic Agents; Atorvastatin; Chemokine CCL2; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Glucose; Heptanoic Acids; Hypertriglyceridemia; Insulin Resistance; Leptin; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Pravastatin; Pyrroles; Rats; Rats, Long-Evans; Rats, Mutant Strains; RNA, Messenger; Transforming Growth Factor beta1; Ventricular Dysfunction, Left

The aim of this study was to explore whether fat cell size in human subcutaneous and omental adipose tissue is independently related to insulin action and adipokine levels.. Fat cells were prepared from abdominal subcutaneous biopsies obtained from 49 type 2 diabetic and 83 non-diabetic subjects and from omental biopsies obtained from 37 non-diabetic subjects. Cell size and insulin action on glucose uptake capacity in vitro were assessed in isolated fat cells. Insulin sensitivity in vivo was assessed with euglycaemic-hyperinsulinaemic clamps. Fasting blood samples were collected and adipokines and NEFA were measured.. Negative correlations were found between subcutaneous fat cell size and insulin sensitivity assessed as M-value during clamp and as insulin action on glucose uptake in fat cells in vitro. This was seen in non-diabetic subjects after including age, sex and BMI in the analyses. No such relationship was found in type 2 diabetic subjects. In both groups, subcutaneous fat cell size correlated positively and independently with plasma levels of leptin but not to any of the other assessed adipokines. In non-diabetic subjects, omental fat cell size was independently and negatively correlated with insulin action in subcutaneous, but not omental, fat cells in vitro.. Fat cell enlargement is associated with insulin resistance in non-diabetic individuals independently of BMI. This was not seen in type 2 diabetic subjects, suggesting that after development of type 2 diabetes other factors, not related to fat cell size, become more important for the modulation of insulin resistance.

Topics: Adipose Tissue; Blood Pressure; Cell Size; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Omentum; Reference Values

Leptin regulates a constellation of neuroendocrine processes that control energy homeostasis. The infusion of leptin in rodents lacking endogenous leptin promotes physical activity energy expenditure (PAEE) and improves insulin signaling, whereas hyperleptinemia is associated with physical inactivity and insulin resistance (IR). We tested whether baseline leptin levels predict changes in PAEE and IR over time, independent of obesity. We also assessed whether the relationship between leptin and change in IR is mediated by PAEE. The population consisted of 288 nondiabetic UK Caucasian adults (mean age: 49.4 yr; SD: 0.7 yr), in whom leptin, insulin, glucose, PAEE (via heart rate monitoring with individual calibration by indirect calorimetry), and anthropometric characteristics had been measured at baseline and 5 yr later. In linear regression models, baseline leptin levels inversely predicted follow-up PAEE (P = 0.033). On average, individuals with low leptin levels (below sex-specific median) increased their daily activity 35% more during the 5-yr follow-up period than those with above-median leptin levels. Baseline leptin level also predicted worsening IR (fasting, 30-min, and 2-h insulins, and homeostasis model assessment-IR; all P < 0.01). Associations were independent of potential confounders, such as adiposity, age, and sex. Including baseline PAEE as a cofactor in the leptin-insulin models reduced the strength (1-4% reduction) and significance of the associations, suggesting that PAEE mediates the leptin-insulin relationships. Hyperleptinemia predicts a relative decline in PAEE and worsening insulin resistance, possibly via shared molecular pathways.

Topics: Adiposity; Cohort Studies; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Follow-Up Studies; Heart Rate; Humans; Insulin; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Models, Biological; Motor Activity; Prospective Studies; Time Factors

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Mice; Obesity; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Tumor Necrosis Factor-alpha

The aim was to assess the relationship between adipokines, including interleukin (IL)-6, leptin, and adiponectin, with development of type 2 diabetes and assess the role of obesity and insulin resistance in these relationships.. We conducted a prospective study of 3,599 nondiabetic men aged 60-79 years and followed up for a mean period of 5 years, during which time there were 108 incident cases of type 2 diabetes.. Elevated IL-6, leptin, and low adiponectin were associated with increased risk of type 2 diabetes even after adjustment for BMI, lifestyle factors, preexisting cardiovascular disease, and systolic blood pressure. The relative risks (RRs) (top vs. bottom third) were 2.02 (95% CI 1.14-3.58) for IL-6, 1.91 (0.97-3.76) for leptin, and 0.40 (0.23-0.70) for adiponectin. Further adjustment for insulin resistance made minor differences to the IL-6 diabetes relationship (adjusted RR 2.12 [1.18-3.81]), weakened the associations with adiponectin (0.59 [0.33-1.04]), and abolished the association between leptin and diabetes (1.12 [0.55-2.26]). The inverse relation between low adiponectin and diabetes was significantly stronger in men who were obese (waist circumference > 102 cm or BMI > or = 30 kg/m2) (0.30 [0.11-0.79]) relative to leaner men (0.93 [0.44-1.96]) (test for interaction P = 0.04).. The association between leptin and incident diabetes is mediated by insulin resistance. By contrast, the positive association between IL-6 and diabetes appeared to be independent of obesity and insulin resistance. Finally, the association between low adiponectin and increased risk of diabetes appears to be significantly stronger in obese men than in leaner counterparts.

Topics: Adiponectin; Adult; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Incidence; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Risk

We tested the extent to which altered plasma adipokine levels may contribute to the increased carotid artery intima-media thickness (IMT) associated with type 2 diabetes mellitus and with male gender, independently of conventional cardiovascular risk factors, insulin resistance, and plasma C-reactive protein (CRP).. IMT (mean of three segments of both carotid arteries by ultrasonography), insulin resistance (homeostasis model assessment; HOMA(ir)), plasma CRP, lipids, adiponectin, leptin, resistin, and tumor necrosis factor-alpha (TNF-alpha) were measured in 84 type 2 diabetic patients and 85 control subjects.. In diabetic patients, IMT (P<0.001), mean arterial pressure (P<0.001), HOMA(ir) (P<0.001), plasma CRP (P=0.003), triglycerides (P=0.037), leptin (P=0.023), resistin (P=0.003), and TNF-alpha (P=0.003) levels were higher, whereas high-density lipoproteins (HDL) cholesterol (P<0.001) and adiponectin (P<0.001) levels were lower compared with control subjects. Plasma adiponectin (P<0.001) and leptin (P<0.001) were substantially lower in men than in women. IMT was positively and independently associated with age (P<0.001), diabetes (P=0.049), and male gender (P=0.002) in a multivariate regression model, not including other variables. Further analyses showed that IMT was positively related to age (P<0.001) and plasma triglycerides (P=0.038) and negatively to adiponectin (P<0.001), without independent effects of diabetes, gender, and HOMA(ir).. Increased IMT in type 2 diabetes may in part be explained by lower plasma adiponectin and higher triglycerides, but not by leptin, resistin, and TNF-alpha. The gender effect on IMT is related to lower plasma adiponectin.

Topics: Adiponectin; Aged; C-Reactive Protein; Carotid Arteries; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Leptin; Male; Middle Aged; Resistin; Sex Factors; Triglycerides; Tumor Necrosis Factor-alpha; Tunica Intima; Ultrasonography

To determine if levels of the adipocyte-derived hormone, leptin, predict the development of type 2 diabetes.. Population-based surveys were undertaken in the multiethnic nation of Mauritius in 1987, 1992 and 1998. Questionnaires, anthropometric measurements, and a 2-h 75-g oral glucose tolerance test were included. A cohort of 2330 participants who were free of diabetes, aged 25-79 years in 1987, and who were followed-up in 1992 and 1998 was studied. Serum leptin was measured in baseline samples. Glucose tolerance was classified according to WHO (World Health Organization) 1999 criteria.. In total, 456 subjects developed diabetes over 11 years with similar incidences in all ethnic groups (P=0.2). Baseline leptin correlated positively with anthropometric measurements, fasting and postload insulin and homeostasis model assessment indices (all P<0.001), and inversely with subsequent weight increase. Participants with incident diabetes had higher serum levels of leptin at baseline than those remaining nondiabetic (P<0.001). After adjustment for confounders, high leptin levels and high leptin/body mass index ratio were independently associated with incident diabetes over 11 years in men (odds ratio for top versus bottom quartile of leptin 2.18; 95% CI: 1.09-4.35), but not in women.. We conclude that high leptin levels are associated with the future development of diabetes, and the association is independent of other factors in men, but not in women.

Topics: Adult; Aged; Data Collection; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Leptin; Male; Mauritius; Middle Aged; Predictive Value of Tests; Risk Factors; Sex Distribution; Surveys and Questionnaires

The objective of this study was to compare plasma levels of adiponectin and leptin in lean (LN), obese (OB) and obese diabetic (OD) postmenopausal females (PMF). We recruited 26 PM women (group 1, mean age - 59,7+/-8,1 years, BMI - 36,6+/-1,8 kg/m(2)). All women had their last menstrual flow more than 2 year before the study (mean duration of PM period was 11,9+/-8,3 years). No woman had received hormones within 3 months of this study. All Women were diabetic patients (mean duration of DM2 was 9,5+/-5,5 years). Ten obese (group 2; mean BMI - 35,9+/-2,3 kg/m(2) and age - 58,1+/-4,7 years) and ten lean (group 3; mean BMI - 22,3+/-1,9 kg/m(2) and age - 56,5+/-5,6 years) PM women were recruited as controls for comparing adipocytokine levels. Adiponectin was significantly decreased and leptin is significantly elevated in OD PMF in comparison with group 1 and 2 (p<0,001 and p=0,003, respectively). There was a tendency for adiponectin levels to be lower in OD PMF as compared with OB individuals (p=0,053). OD PMF were more insulin resistant than OB and LN subjects (p<0,001). Hypoadiponectinemia in PMF may be explained by IR and obesity. Leptin levels in OD PMF are not significantly different from leptin levels of OB subjects, although they significantly differ from leptin levels of LN individuals.

Topics: Adiponectin; Aged; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leptin; Middle Aged; Obesity; Postmenopause; Testosterone

Recently, we reported that [meso-tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadium(IV)(4-), VO(tpps), shows in-vitro insulin-mimetic and in-vivo anti-diabetic activity in streptozotocin (STZ)-induced type 1 diabetic mice. This result prompted us to examine its ability in type 2 diabetic model KKA(y) mice with insulin resistance. We studied the in-vivo anti-diabetic activity of VO(tpps), compared with that of vanadium(IV) oxide sulfate, VS, as control. Both compounds were orally administered at doses of 5-10 mg (0.1-0.2 mmol) V/kg body weight to the KKA(y) mice for 28 days. VO(tpps) normalized the hyperglycaemia within 15 days, while VS lowered the blood glucose concentration only by a small degree. In addition, metabolic syndromes characterized by insulin and leptin resistance were significantly improved in VO(tpps)-treated KKA(y) mice compared with those treated with VS. The improvement in diabetes was validated by oral glucose tolerance test and decrease in HbA(1c) concentration. Based on these observations, VO(tpps) is proposed to be an orally active oxovanadium(IV)-porphyrin complex for treating not only type 2 diabetes but also metabolic syndromes in animals.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Glycated Hemoglobin; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metalloporphyrins; Mice

To clarify the relationship between serum leptin concentration and platelet aggregation mechanism, we investigated serum leptin concentration and agonist-induced platelet aggregation in eight obese subjects and eight non-obese and non-diabetic controls. In addition we also measured them in 15 type 2 diabetic subjects and 17 control subjects. Maximum platelets aggregation rate (MPAR) in control and diabetic subjects by adenosine diphosphate (ADP), collagen and thrombin were measured by aggregometer after pretreatment with 100 ng/ml leptin for 60 min. The MPAR by 0.15 U/ml thrombin stimulation in leptin-treated platelet in the controls was significantly increased compared with that in non-treated platelets, but not by ADP and collagen stimulation. Despite a significantly higher concentration of leptin in obese subjects, agonist-induced platelet aggregation in obese subjects was not different from that in controls. There were no significant differences in serum leptin concentration and MPAR by various agonists between diabetic and control subjects. When MPAR by ADP in the diabetic subjects was divided into two groups (high group: >50%, low group: <50%), the serum leptin concentration in the high group was significantly increased, compared with that in the low group. These results suggest that ADP-induced platelet aggregation may be associated with serum leptin concentration in diabetic subjects, and that leptin-associated platelet aggregation may affect the development of cardiovascular complications in obese and diabetic subjects.

Topics: Adenosine Diphosphate; Adult; Aged; Blood Platelets; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity; Platelet Aggregation; Thrombin

The G protein-coupled receptor 39 (GPR39) has recently been identified as the receptor for obestatin, a peptidic hormone involved in energy homeostasis. However, the expression levels of this receptor in human adipose tissue in obesity and obesity-associated type 2 diabetes mellitus (T2DM) remain unknown. Therefore, we evaluated the actual presence of GPR39 mRNA in human adipose tissue and whether GPR39 expression levels are altered in obesity and obesity-associated T2DM.. Omental adipose tissue biopsies obtained from 15 women were used in the study. Patients were classified as lean (body mass index 20.8 +/- 1.0 kg/m(2)), obese normoglycaemic (body mass index 48.4 +/- 2.1 kg/m(2)) and obese T2DM patients (body mass index 52.6 +/- 4.9 kg/m(2)). Anthropometric measurements and biochemical profiles were assessed for each subject. Real-time RT-PCR analyses were performed to quantify transcript levels of GPR39 and adiponectin.. Obese T2DM patients exhibited significantly lower GPR39 expression levels compared to lean (P = 0.016) and obese normoglycaemic subjects (P = 0.008), while no differences between lean and obese normoglycaemic patients were observed. The mRNA expression levels of GPR39 were negatively correlated to fasting glucose concentrations (r = -0.581, P = 0.023), while exhibiting a positive correlation to adiponectin mRNA expression levels (r = 0.674, P = 0.006).. GPR39 is expressed in human adipose tissue. The reduced expression levels of GPR39 in omental adipose tissue observed in obese patients with T2DM suggest an involvement of obestatin signalling in glucose homeostasis and T2DM development.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Case-Control Studies; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Female; Gene Expression; Glucose Tolerance Test; Humans; Insulin; Intra-Abdominal Fat; Leptin; Obesity; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric

Leptin, an adipocyte-secreted hormone, plays an important role in regulating neuroendocrine and immune function as well as insulin resistance and metabolism. Our objective was to examine the relationship between leptin levels and cardiovascular morbidity and overall mortality in women with type 2 diabetes.. This prospective cohort study included 1,194 women with a confirmed diagnosis of type 2 diabetes, who provided a blood sample at baseline in 1989-1990. Participants were followed for 12 years for the development of health outcomes including cardiovascular disease (CVD) events as well as total mortality.. There were 218 new CVD events and 228 deaths from all causes. Cox proportional hazards analysis was used to estimate the relative risks (RRs) for each quintile level of leptin compared with the lowest quintile. Leptin levels were positively associated with several CVD risk factors including BMI and inflammatory markers, but were not independently associated with the incidence of CVD or total mortality in women with diabetes. The multivariate RRs (95% CIs) for CVD across the quintiles of leptin were 0.96 (0.61-1.53), 0.99 (0.61-1.61), 1.04 (0.63-1.71), 1.02 (0.59-1.75) (p for trend = 0.83).. Although circulating leptin levels are associated with obesity and inflammatory markers, they are not significantly related to the risk of CVD or mortality in women with diabetes.

Topics: Adult; Aged; Blood Specimen Collection; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Leptin; Life Style; Middle Aged; Prospective Studies; Risk Factors; Surveys and Questionnaires; Survival Analysis

There have been several reports about associations of serum leptin or adiponectin with bone mineral density and biochemical markers of bone turnover. However, the precise roles of adipocytokines in bone metabolism have not been fully elucidated. We investigated the associations of serum level of leptin or adiponectin with bone mineral density, serum osteocalcin, and urinary N-terminal telopeptide of type I collagen (NTX) in 40 Japanese patients with type 2 diabetes mellitus. Bone mineral density was measured by using dual-energy x-ray absorptiometry at different sites (distal radius, femoral neck, and lumbar spine) and was expressed as z score. Multiple regression analysis revealed that there were significant positive correlations between serum leptin or adiponectin level and z score at the distal radius, but not at the femoral neck or the lumbar spine. Although no correlation was observed between serum leptin and serum osteocalcin, there was a significant negative correlation between serum leptin and urinary NTX, a marker of bone resorption. No correlation was observed between serum adiponectin and serum osteocalcin or urinary NTX. These results indicate that leptin and adiponectin may have a protective effect on bone metabolism in patients with type 2 diabetes mellitus.

Topics: Absorptiometry, Photon; Adiponectin; Body Mass Index; Bone Density; Collagen Type I; Diabetes Mellitus, Type 2; Female; Femur Neck; Glycated Hemoglobin; Humans; Leptin; Lumbar Vertebrae; Male; Middle Aged; Osteocalcin; Peptides; Radius; Regression Analysis

Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiologic features responsible for development of hyperglycemia in type 2 diabetes mellitus. Insulin resistance is often associated with increased adipose tissue mass. To examine which variables influence insulin sensitivity, we compared metabolic parameters, serum resistin, leptin, and adiponectin concentrations to the insulin sensitivity, obtained by frequently sampled intravenous glucose tolerance test using the minimal model analysis, in 113 Japanese patients with type 2 diabetes mellitus. Duration of diabetes, fasting plasma glucose, fasting insulin, homeostasis model assessment of insulin resistance index, and serum resistin concentration were significantly higher in the insulin-resistant subgroup compared with the insulin-sensitive subgroup and correlated with insulin sensitivity. Stepwise regression analysis also identified these parameters as independent regulators of insulin sensitivity. The present study reconfirmed that fasting insulin level or homeostasis model assessment of insulin resistance would be a surrogate measure of insulin resistance and demonstrated that insulin resistance increases progressively after the onset of overt diabetes and that the serum resistin level is associated with insulin sensitivity, suggesting that resistin plays an important role in the development of insulin resistance in Japanese patients with type 2 diabetes mellitus.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Japan; Leptin; Male; Middle Aged; Regression Analysis; Resistin

Pinitol (3-O-methyl-D-chiro-inositol) was identified in putative insulin mediator fractions that have hypoglycemic activity, and appears to mimic the act effects of insulin by acting downstream in the insulin signaling pathway. We evaluated the effect of pinitol therapy in type 2 diabetic patients who were poorly controlled with hypoglycemic drugs, such as sulfonylurea, metformin and/or insulin. Twenty type 2 diabetic patients were enrolled in our study. Fasting glucose, fasting c-peptide, total cholesterol, triglyceride, and HDL- and LDL-cholesterol were checked before and after a 12-week pinitol treatment (20 mg kg(-1)day(-1)). All subjects continued their current medications during the study. Adipocytokines, such as adiponectin, leptin, free fatty acids, and c-reactive protein (CRP) were checked before and after pinitol treatment. After pinitol treatment, fasting glucose, post-prandial glucose levels, and hemoglobin A1c were significantly decreased (P<0.05). Fasting serum adiponectin, leptin, free fatty acid, and CRP levels did not change after pinitol treatment. In the unresponsive group, serum c-peptide levels were higher than in the responsive group. Twelve weeks of pinitol treatment altered glucose metabolism, but not lipid profiles or adipocytokine levels, in type 2 diabetic patients. Additional research is needed to define the physiological and potential therapeutic effects of pinitol administration.

Topics: Adiponectin; Aged; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Leptin; Male; Middle Aged

Endocrinal products of adipocytes (PPARgamma, A-FABP, E-FABP, leptin, adiponectin and others) modulate insulin tissue sensitivity enabling them to participate in the ethiopathogenesis of diabetes mellitus type 2 (DM2T). Persons with DM2T are characterised by typical changes in lipid spectrum (lower HDL-cholesterol and higherTAG) and in the endocrinal function of subcutaneous adipose tissue; adipocytes produce more PPARgamma, A-FABP and E-FABP and less adiponectin.. To measure chosen markers of metabolic syndrome (MS) in serum and in abdominal subcutaneous adipose tissue in healthy persons and patients with DMT2, to determine basic statistical characteristics of investigated parameters and to discus their role in the genesis and progress of the MS.. Samples of blood and abdominal subcutaneous adipose tissue were collected from each participant (healthy: 7 men and 8 women; diabetics: 18 men, 11 women) to investigate the levels of HDL, TAG, insulin, C-peptide, glycaemia and the concentrations of A-FABP, E-FABP, leptin, adiponectin, resistin, PPARgamma and TNFalpha.. In most cases the average concentration of investigated parameters in serum was higher in persons with DM 2 regardless of gender. Lower values were only found for HDL and adiponectin. The same situation prevailed in the subcutaneous adipose tissue. Values of most other parameters (A-FABP, E-FABP, and PPARgamma) were also higher in patients. The values of measured parameters not only differed in healthy and in sick persons but depended on gender. The increase/decrease in concrete parameters was greater in diabetic women than diabetic men.. Higher concentrations of A-FABP, E-FABP in serum and in subcutaneous adipose tissue in diabetic persons also higher concentrations of PPARgamma in subcutaneous adipose tissue suggest that these investigated parameters are closely associated with obesity and MS. We can assume that in the near future these parameters will be used in clinical work for diagnosis of this syndrome.

Topics: Abdominal Fat; Adipocytes; Adiponectin; Adult; Diabetes Mellitus, Type 2; Fatty Acid-Binding Proteins; Female; Humans; Leptin; Male; Middle Aged; PPAR gamma; Resistin; Tumor Necrosis Factor-alpha

Nitrosative stress contributes to nerve conduction slowing, thermal hypoalgesia, and impaired nitrergic innervation in animal models of Type 1 diabetes. The role for reactive nitrogen species in Type 2 diabetes-associated neuropathy remains unexplored. This study evaluated the role for nitrosative stress in functional and structural neuropathic changes in ob/ob mice, a model of Type 2 diabetes with mild hyperglycemia and obesity. Two structurally diverse peroxynitrite decomposition catalysts, Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)-pyridyl porphyrin (FP15) and Fe(III) tetra-mesitylporphyrin octasulfonate (FeTMPS), were administered to control and 8-week-old ob/ob mice for 3 weeks at the doses of 5 mg kg(-1) day(-1) (FP15) and 5 and 10 mg kg(-1) day(-1) (FeTMPS). The 11-week-old ob/ob mice developed motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable ( approximately 78%) loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion neurons. Treatment with two structurally diverse peroxynitrite decomposition catalysts was associated with restoration of normal MNCV and SNCV, and alleviation of thermal hypoalgesia. Tactile response thresholds increased in response to peroxynitrite decomposition catalyst treatment, but still remained approximately 2.7- to 3.2-fold lower compared with non-diabetic controls. Intraepidermal nerve fiber loss was not alleviated by either FP15 or FeTMPS. Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglia of peroxynitrite decomposition catalyst-treated ob/ob mice were essentially normal. In conclusion, nitrosative stress plays an important role in functional abnormalities associated with large motor, large sensory, and small sensory fiber neuropathy, but not in small sensory nerve fiber degeneration, in this animal model. Peroxynitrite decomposition catalysts alleviate Type 2 diabetes-associated sensory nerve dysfunction, likely by mechanism(s) not involving arrest of degenerative changes or enhanced regeneration of small sensory nerve fibers.

Topics: Anesthesia; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Immunohistochemistry; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Motor Neurons; Nerve Fibers; Neural Conduction; Neurons, Afferent; Nitrites; Pain; Pain Measurement; Peroxynitrous Acid; Poly Adenosine Diphosphate Ribose; Touch

Acetate has been found to have an inhibitory effect on the activity of carbohydrate-responsive element-binding protein (ChREBP) in cultured hepatocytes, this being a transcription factor that regulates several genes required for the conversion of glucose to fatty acids in the liver. The aim of this study was to investigate whether an oral administration of acetate would contribute to reducing lypogenic genes and protecting against obesity. We orally injected 5.2 mg/kg BW of acetate to obesity-linked type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The treatment with acetate showed a marked reduction in lipid accumulation in the adipose tissue, protection against accumulation of fat in the liver, and improved glucose tolerance. An analysis by Northern blotting revealed that the transcripts of several lipogenic genes in the liver of OLETF rats were decreased by the acetate treatment. On the basis of those results, it was indicated that acetate was a potential compound to improve obesity and obesity-linked type 2 diabetes.

Topics: Acetates; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Insulin; Leptin; Lipids; Male; Models, Biological; Obesity; Random Allocation; Rats; Rats, Inbred OLETF; RNA, Messenger; Time Factors; Triglycerides

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that plays a role in e.g. circulation, hormone release and angiogenesis. Earlier studies have shown that the Leucine 7 to Proline 7 (Leu7Pro) polymorphism of preproNPY is associated with increased risk for vascular complications in type 2 diabetes. The mechanism for this maybe altered transmitter and hormone levels or altered cardiovascular functions, which have been observed in healthy subjects having the Leu7Pro polymorphism. The current study was undertaken to explore if the Leu7Pro polymorphism has an impact on these functions in subjects with type 2 diabetes. Diurnal measurements were performed for Finnish Caucasian type 2 diabetes patients of two preproNPY genotypes (matched by sex, age, BMI, duration of diabetes and HbA1c) in resting position to prevent sympathetic stimulation. Standard meals were offered during the 24-hour study period. Nine subjects with the Leu7Pro polymorphism and ten subjects without this polymorphism were studied. Plasma concentrations of NPY, glucose, insulin, cortisol, prolactin and leptin were measured by taking blood samples at 20 time points (from 8 a.m. to 8 a.m.). Heart rate and blood pressure were measured at the same time points. The results show that NPY concentrations were similar in both preproNPY genotypes. Glucose, insulin, cortisol and leptin concentrations as well as heart rate and blood pressure were also similar. However, a significant difference between genotypes was found in the association of NPY concentrations with cortisol concentrations (p for difference=0.002). Also a statistically significant negative association of plasma NPY levels with plasma glucose levels was found in both genotypes. Since no impact of preproNPY genotype on mean NPY or hormone levels were detected in subjects with type 2 diabetes, the mechanisms for the increased risk for diabetic complications in the subjects with the Leu7Pro polymorphism need to be further explored.

Topics: Aged; Amino Acid Substitution; Blood Glucose; Blood Pressure; Circadian Rhythm; Diabetes Mellitus, Type 2; Female; Humans; Hydrocortisone; Leptin; Leucine; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Proline; Protein Precursors

Type 2 diabetes is a heterogeneous syndrome characterized by defective insulin secretion and/or insulin resistance. In distinct from Caucasian populations, Japanese type 2 diabetic patients are divided into two categories: one with insulin resistance and the other with normal insulin sensitivity. This unique feature allows us to explore the factors responsible for the evolution of insulin resistance in Japanese type 2 diabetic patients. In this article, we describe the factors responsible for insulin resistance in Japanese type 2 diabetic patients and discuss the relationships between these factors and atherosclerosis. Japanese type 2 diabetic patients with insulin resistance had significantly higher concentrations of triglyceride, remnant-like particle cholesterol, subcutaneous and visceral abdominal fat areas, leptin, high sensitive C-reactive protein (hs-CRP), and soluble E-selectin and lower concentration of adiponectin when compared to those with normal insulin sensitivity. There were, however, no significant difference in tumor necrosis factor (TNF)-alpha and soluble TNF receptors between the two groups. Serum triglyceride was positively correlated to visceral abdominal fat area, while serum leptin was positively correlated with subcutaneous abdominal fat area. In contrast, serum adiponectin was negatively correlated to visceral abdominal fat area. High sensitive CRP was positively correlated to BMI, triglyceride, and leptin, but was negatively correlated to adiponectin. Tumor necrosis factor-alpha and soluble TNF receptors, however, were not associated with any of these factors. Thus, it may be hypothesized that Japanese type 2 diabetic patients are divided into two categories: one with normal insulin sensitivity and the other with insulin resistance. The former group has a low cardiovascular risk factor, whereas the latter one has a markedly increased cardiovascular disease risk factor. Furthermore, abdominal fat related insulin resistance seems to be associated with insulin resistance in Japanese type 2 diabetic patients. In this section, we would like to focus on the factors contributing to insulin resistance and discuss the association of these factors with atherosclerosis in Japanese type 2 diabetic patients.

Topics: Adiponectin; Atherosclerosis; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Insulin Resistance; Japan; Leptin; Triglycerides

To verify whether a diabetes family history might be a risk factor for the development, in adult age, of metabolic disorders, leptin, anthropometric and endocrine parameters were analysed in 95 babies with grandparents affected by type 2 diabetes (DF) and in 95 matched babies without diabetes family history (NDF). A sexual dimorphism for leptin was present in the NDF group (males: 6.7+/-4.1 ng/ml; females: 12.3+/-6.5; p < 0.0001) but not in the DF group (males: 9.0+/-5.5; females: 10.8+/-6.4), due to the significant increase in DF male leptin level, compared to that of NDF males (p < 0.05). In DF males only, leptin was positively correlated with body length, PI, C-peptide, IGF-1 and IGF1BP3. These results suggest that the increase in DF male leptin could be a compensatory mechanism for reduced insulin sensitivity in a pre-clinical alteration of glucose metabolism.

Topics: Birth Weight; Body Height; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Fetal Blood; Genetic Predisposition to Disease; Humans; Infant, Newborn; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Italy; Leptin; Male; Sex Characteristics

A paradox is hidden in the increasing number of patients with insulin resistance, Type 2 diabetes and osteoporosis, as the world wide diabetes epidemic is driven by the same obesity which protects the bones in the obese females. Our aim was to investigate the connection between the early glucose intolerance, insulin resistance and bone density and metabolism. After metabolic status of matched 20 healthy and 51 glucose intolerant women (age: 49 +/- 9 y.) was determined, hyperinsulinemic-euglycemic clamps were done, while adipo- and cytokine levels were measured. Bone mineral density over lumbar spine and the femur neck were measured by DEXA. No differences in bone density were observed between groups at any sites measured. Tight correlations were found between total body glucose utilization and bone density in healthy group (lumbar spine r = -0.4921, p < 0.05, femur neck: r = -0.4972, p < 0.05), while with deterioration of glucose metabolism this correlation disappeared (lumbar spine: r = -0.022, ns; femur neck: r = -0.3136, ns). The adiponectin was the only adipokine which correlated with lumbar spine density in both groups ( r = -0.5081, p < 0.05; -0.2804, p < 0.05), but not with femur density, where this connection disappeared with glucose intolerance ( r = -0.6742, p < 0.01; -0.1723, ns). Relations of bone metabolic markers indicated that bone resorption decreases with worsening of insulin resistance. In conclusion inverse correlations were found between bone density and glucose metabolism, or insulin sensitivity in healthy women in perimenopause, but this connection disappeared with the deterioration of glucose metabolism and progression of insulin resistance measured by the "gold standard" insulin-glucose clamps. Decreasing insulin sensitivity of bones and escape from "metabolic control" may result in frequently observed hyperdensity in Type 2 diabetics.

Topics: Absorptiometry, Photon; Adiponectin; Adult; Biomarkers; Blood Glucose; Body Mass Index; Bone and Bones; Bone Density; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Leptin; Lumbar Vertebrae; Middle Aged; Obesity; Osteoporosis; Perimenopause; Resistin

Insulin resistance is characterized by high insulin levels and decreased responsiveness of tissues to the clearance of glucose from the bloodstream. This study maintained the diabetes-prone C57BL/6J and obese-resistant A/J mice strains on a high-fat diet for twelve weeks to transcriptionally profile the liver for changes caused by high fat diet. In the eighth week of the experiment, the C57BL/6J mice began exhibiting signs of insulin resistance, while the A/J mice did not show any such indications during the course of the experiment. A regression model of partial least squares between serum insulin measurements and the liver gene expression profile for the C57BL/6J mice on a high-fat diet was constructed in an effort to quantitatively link the physiological measurement with the gene expressions. A series of discriminating genes between high fat and chow fed mice was generated for both the C57BL/6J and A/J strains. These discriminatory genes contain information about the mechanisms responsible for the development of insulin resistance, and the compensation for a high fat diet, respectively. The results identified several genes involved in the development of insulin resistance and serve as a framework for other studies involving other organs affected by this systemic disease.

Topics: Abdominal Fat; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, Atherogenic; Dietary Fats; Gene Expression Profiling; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Oligonucleotide Array Sequence Analysis; Transcription, Genetic

Metabolic disorders induced by high-fat feeding in rodents evoke some, if not all, of the features of human metabolic syndrome. The occurrence and severity of metabolic disorders, however, varies according to rodent species, and even strain, as well as the diet. Therefore, in the present study, we investigated the long-term obesogenic and diabetogenic effects of three high-fat diets differing by their fat/carbohydrate ratios. Sprague-Dawley rats were fed a control high-carbohydrate and low-fat diet [HCD; 3:16:6 ratio of fat/carbohydrate/protein; 15.48 kJ/g (3.7 kcal/g)], a high-fat and medium-carbohydrate diet [HFD1; 53:30:17 ratio of fat/carbohydrate/protein; 19.66 kJ/g (4.7 kcal/g)], a very-high-fat and low-carbohydrate diet [HFD2; 67:9:24 ratio of fat/carbohydrate/protein; 21.76 kJ/g (5.2 kcal/g)] or a very-high-fat and carbohydrate-free diet [HFD3; 75:0:25 ratio of fat/carbohydrate/protein; 24.69 kJ/g (5.9 kcal/g)] for 10 weeks. Compared with the control diet (HCD), rats fed with high-fat combined with more (HFD1) or less (HFD2) carbohydrate exhibited higher BMI (body mass index; +13 and +10% respectively; P<0.05) and abdominal fat (+70% in both HFD1 and HFD2; P<0.05), higher plasma leptin (+130 and +135% respectively; P<0.05), lower plasma adiponectin levels (-23 and -30% respectively; P<0.05) and impaired glucose tolerance. Only the HFD1 group had insulin resistance. By contrast, a very-high-fat diet devoid of carbohydrate (HFD3) led to impaired glucose tolerance, insulin resistance and hypoadiponectinaemia (-50%; P<0.05), whereas BMI, adiposity and plasma leptin did not differ from respective values in animals fed the control diet. We conclude that increasing the fat-to-carbohydrate ratio to the uppermost (i.e. carbohydrate-free) in a high-fat diet prevents the development of obesity, but not the prediabetic state (i.e. altered glucose tolerance and insulin sensitivity).

Topics: Abdominal Fat; Adiponectin; Animals; Body Mass Index; Diabetes Mellitus, Type 2; Diet; Dietary Carbohydrates; Dietary Fats; Glucose Tolerance Test; Insulin Resistance; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley

Little information is available on leptin concentrations in individuals with IGT. This study aims to determine and correlate leptin levels to anthropometric measures of obesity in pre-diabetic, (IFG and IGT), type 2 diabetic and normoglycaemic Saudis.. 308 adult Saudis (healthy controls n = 80; pre-diabetes n = 86; Type 2 diabetes n = 142) participated. Anthropometric parameters were measured and fasting blood samples taken. Serum insulin was analysed, using a solid phase enzyme amplified sensitivity immunoassay and also leptin concentrations, using radio-immunoassay. The remaining blood parameters were determined using standard laboratory procedures.. Leptin levels of diabetic and pre-diabetic men were higher than in normoglycaemic men (12.4 [3.2-72] vs 3.9 [0.8-20.0] ng/mL, (median [interquartile range], p = 0.0001). In females, leptin levels were significantly higher in pre-diabetic subjects (14.09 [2.8-44.4] ng/mL) than in normoglycaemic subjects (10.2 [0.25-34.8] ng/mL) (p = 0.046). After adjustment for BMI and gender, hip circumference was associated with log leptin (p = 0.006 with R2 = 0.086) among all subjects.. Leptin is associated with measures of adiposity, hip circumference in particular, in the non-diabetic state among Saudi subjects. The higher leptin level among diabetics and pre-diabetics is not related to differences in anthropometric measures of obesity.

Topics: Adiposity; Adult; Aged; Anthropometry; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity; Prediabetic State; Saudi Arabia

The antidiabetic effect of bariatric surgery has been interpreted as a conceivable result of surgically induced weight loss and decreased caloric intake. However, glycemic control often occurs within days, before significant weight loss has been reached. The aim of our work was to investigate the hormones that control glycemic status in diabetes mellitus after a duodenal-jejunal exclusion in an animal model of nonobese type 2 diabetes.. Twelve (12- to 14-week-old) rats (Goto-Kakizaki) randomly underwent one of the following procedures: gastrojejunal bypass (group 1, n = 6) or no intervention (controls) (group 2, n = 6). Both groups were fed with the same type and amount of diet. At basal time (preoperative) and after intervention (1 week and 1 month), weight and fasting glycemia were measured. An oral glucose tolerance test (OGTT) was realized at same times. Hormone levels (insulin, glucagons-like peptide 1 [GLP-1], glucose-dependent insulinotropic peptide [GIP], glucagon, and leptin) were measured after 20 minutes of oral glucose overload. Age-matched Goto-Kakizaki rats were used as controls for all variables.. Rats in group 1 and group 2 remained with the same weight during the protocol. The OGTT showed an improvement in glycemic levels in group 1; glucose levels were better at 1 week and 1 month after the surgery in all times of OGTT (basal, 10 minutes, and 120 minutes). Basal glucose levels at time 0 in basal time, at 1 week, and at 1 month were lower in group 1 than group 2. Postoral glucose overload levels of glucagon, insulin, GLP-1, and GIP remained unchanged during the treatment in both groups. In group 1, leptin levels had a significant decrease at 1 week and 1 month after surgery (basal time (6.1 +/- 1.6 ng/mL) versus 1 week (0.9 +/- 0.9 ng/mL) versus 1 month (0.7 +/- 0.6 ng/mL) (P < .05).. Gastrojejunal bypass in a nonobese diabetic model improves glycemic control with a significant decrease in leptin levels, without changes in enteroinsular axis (GLP-1, GIP, glucagons, and insulin levels).

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Insulin; Leptin; Male; Rats; Rats, Inbred Strains

Short-term elevations of stress hormones cause an increase in glycemia. However, the effect of intermittent stress on development of type 2 diabetes mellitus is unclear. We hypothesized that recurrent intermittent restraint stress would deteriorate glycemia. Male, prediabetic Zucker diabetic fatty (ZDF) rats were restrained 1 hour per day, 5 days per week for 13 weeks and compared with unstressed, age-matched diabetic controls and lean nondiabetic rats. To differentiate the effects of recurrent restraint stress per se vs restraint-induced inhibition of food intake, a pair-fed group of rats was included. Surprisingly, recurrent restraint and pair feeding delayed fed and fasting hyperglycemia, such that they were lowered 50% by restraint and 30% by pair feeding after 13 weeks. Rats that were previously restrained or pair fed had lower glucose levels during a glucose tolerance test, but restraint further improved the return of glucose to baseline compared to pair feeding (P<.05). This was despite pair-fed rats having slightly lowered food intake and body weights compared with restrained rats. Restraint and pair feeding did not alter insulin responses to an intraperitoneal glucose tolerance test (IPGTT) or fasting insulin, and did not lower plasma lipids. Interestingly, restraint normalized basal corticosterone to one third that in control and pair-fed rats, prevented increases in pretreatment corticosterone seen with pair feeding, and led to habituation of restraint-induced corticosterone responses. After 13 weeks of treatment, multiple regression analysis showed that elevations in basal corticosterone could explain approximately 20% of the variance in fed glucose levels. In summary, intermittent restraint and its adaptations delayed hyperglycemia and improved glucose control in Zucker diabetic fatty rats. These benefits can be partially explained by restraint-induced lowering of food intake, but additional improvements compared to pair feeding may involve lower overall corticosterone exposure with repeated restraint. Paradoxically, these novel investigations suggest some types of occasional stress may limit development of diabetes.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; Eating; Glucagon; Glucose Tolerance Test; Hormones; Hyperglycemia; Insulin; Leptin; Lipids; Male; Organ Size; Rats; Rats, Zucker; Regression Analysis; Restraint, Physical; Stress, Psychological

The aim of the present study was to investigate the relationships between metabolic syndrome and atherosclerosis in 57 Japanese type 2 diabetic patients. Metabolic syndrome was diagnosed based on the criteria raised by the Japan Internal Medicine Society. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment. Ultrasonographically measured carotid atherosclerosis, brachial-ankle pulse wave velocity (ba-PWV), and ankle brachial index (ABI) were used to assess the degree of atherosclerosis. Of 57 patients, 25 were diagnosed as having metabolic syndrome. The patients with metabolic syndrome had significantly higher levels of waist circumference, insulin, insulin resistance index of homeostasis model assessment, systolic and diastolic blood pressures, and serum triglycerides, and lower concentrations of adiponectin. However, there was no significant difference in age, sex, glycosylated hemoglobin (hemoglobin A1c), fasting glucose, leptin, and tumor necrosis factor system activities including tumor necrosis factor alpha between the 2 groups. Furthermore, no significant difference was observed in the degree of carotid atherosclerosis (intimal-medial thickness in plaque-free segments: 0.72+/-0.03 vs 0.72+/-0.02 mm, P=.435; carotid stenosis in plaque segments: 6.6%+/-3.0% vs 6.6%+/-1.7%, P=.497), ba-PWV (1676+/-56 vs 1654+/-44, P=.380), and ABI (1.16+/-0.01 vs 1.15+/-0.01, P=.245) between the 2 groups. From these results, it can be suggested that metabolic syndrome, an insulin-resistant state, is not associated with carotid atherosclerosis, ba-PWV, or ABI in Japanese type 2 diabetic patients.

Topics: Adult; Aged; Atherosclerosis; Blood Glucose; Body Mass Index; Brachial Artery; Carotid Arteries; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Japan; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Regional Blood Flow; Tumor Necrosis Factor-alpha; Ultrasonography

The adipocyte influences eating behavior and metabolism via cytokine secretion. We report our findings of adipokine secretion in a cohort of diabetic and nondiabetic morbidly obese patients before and after Roux-en-Y gastric bypass (RYGB).. Ten morbidly obese subjects who underwent uncomplicated RYGB were studied: five were diabetic and nine were female. Nonfasting plasma levels of adiponectin, resistin, leptin, and tumor necrosis factor-alpha were determined preoperatively and 6 mo postoperatively. C-reactive protein (CRP) was followed as a marker of the metabolic syndrome.. The patient age was 42 +/- 11 y, and the preoperative BMI was 50 +/- 6 kg/m(2). The 6 mo BMI fell to 33 +/- 5 kg/m(2) (P < 0.0001), and there were no differences between diabetics and nondiabetics with respect to amount of weight loss. In nondiabetic patients, there were significant increases compared with preoperative levels for adiponectin, resistin, and tumor necrosis factor-alpha; leptin was significantly decreased while CRP was unchanged. CRP and leptin levels were both significantly lower (P < 0.05), while all other protein levels were unchanged in diabetic patients.. At 6 mo postoperation, RYGB significantly altered most adipokine levels for nondiabetic patients. Only CRP and leptin were changed in diabetic patients. All patients lost a significant amount of weight over 6 mo, suggesting a different metabolic effect between nondiabetic and diabetic patients after RYGB.

Topics: Adiponectin; Adult; Biomarkers; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Hormones; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity, Morbid; Pilot Projects; Resistin; Tumor Necrosis Factor-alpha; Weight Loss

Social isolation is associated with increased risks of mortality and morbidity. In this study, we show that chronic individual housing accelerated body weight gain and adiposity in KK mice but not C57BL6J mice, and fully developed diabetes in KKA(y) mice. Individually housed KK and KKA(y) mice increased body weight gain over the initial 2 wk without increased daily average food consumption compared with group-housed animals. The individually housed KK and KKA(y) mice then gradually increased food consumption for the next 1 wk. The chronic social isolation-induced obesity (SIO) was associated with hyperleptinemia and lower plasma corticosterone and active ghrelin levels but not hyperinsulinemia. Elevated plasma leptin in the SIO suppressed expression of 5-HT2C receptor in white adipose tissue. The SIO was also associated with decreased expression of beta3-adrenergic receptors in white adipose tissue and hypothalamic leptin receptor, which might be secondary to the enhanced adiposity. Interestingly, social isolation acutely reduced food consumption and body weight gain compared with group-housed obese db/db mice with leptin receptor deficiency. Social isolation-induced hyperglycemia in KKA(y) mice was associated with increased expression of hepatic gluconeogenetic genes independent of insulin. These findings suggest that social isolation promotes obesity due to primary decreased energy expenditure and secondary increased food consumption, which are independent of the disturbed leptin signaling, in KK mice, and develops into insulin-independent diabetes associated with increased expression of hepatic gluconeogenetic genes in KKA(y) mice. Thus, social isolation can be included in the environmental factors that contribute to the development of obesity and type 2 diabetes.

Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Progression; Eating; Energy Metabolism; Gene Expression; Homeostasis; Ion Channels; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Organ Size; Peroxisome Proliferator-Activated Receptors; Receptor, Serotonin, 5-HT2C; RNA, Messenger; Social Isolation; Uncoupling Protein 1; Uncoupling Protein 2

The obese cat is a model for the study of the progression toward type 2 diabetes. In this study, the impact of obesity on the hypothalamic-pituitary-thyroid axis was examined in 21 domestic shorthair cats before and after the development of obesity, which significantly increased body mass index (BMI), % body fat (BF), and girth (P<0.0001 for all). Serum total thyroxine (TT(4)), tri-iodothyronine, free T(4) (FT(4)) by direct dialysis, nonesterified fatty acids (NEFA), and leptin were measured, and FT(4) fraction (FFT(4)) was calculated. Serum thyrotropin (TSH) concentrations were measured in nine animals by validating a heterologous canine TSH assay with recombinant feline TSH as a standard. FT(4), FFT(4), NEFAs, and leptin were significantly higher in obese cats. FT(4) had the strongest positive correlation with obesity indices BF, BMI, girth, NEFA, and leptin. Fatty acids oleate and palmitate were shown to inhibit T(4) binding to pooled cat serum in vitro, suggesting the possibility that this mechanism was also relevant in vivo. Serum TT(4) and TSH did not rise significantly. The implications for thyroid hormone (TH) action are not yet clear, but fatty acids have been proposed to inhibit the cellular uptake of TH and/or pituitary TH receptor binding, leading to TH resistance. Increased leptin may also alter sensitivity to negative feedback of TH. In conclusion, feline obesity is associated with a significant increase in FT(4) within the normal range; future investigation into the cellular thyroid status will be necessary to establish cause and effect in this obesity model.

Topics: Animals; Cats; Diabetes Mellitus, Type 2; Disease Progression; Fatty Acids, Nonesterified; Female; Insulin Resistance; Leptin; Models, Animal; Obesity; Oleic Acid; Ovariectomy; Palmitic Acid; Thyrotropin; Thyroxine; Triiodothyronine

The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti-inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta-cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively.

Topics: 3T3 Cells; Adipocytes; Adult; Aged; Amides; Animals; Arachidonic Acids; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Ethanolamines; Female; Humans; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Models, Biological; Obesity; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; PPAR gamma; Review Literature as Topic; Structure-Activity Relationship

To use longitudinal profiling of plasma adipokines to distinguish diabetogenic vs. non-diabetogenic obesity syndrome in two new mouse models of polygenic obesity.. Male mice of the NONcNZO5 strain develop a polygenic obesity syndrome uncomplicated by diabetes, whereas NONcNZO10 males develop a comparable polygenic obesity that precipitates type 2 diabetes. A multiplex immunoassay for simultaneous measurement of insulin and a panel of mouse adipokines (leptin, resistin, adiponectin, interleukin-6, tumor necrosis factor alpha, macrophage chemoattractant protein-1, plasminogen activator inhibitor-1) were used to profile longitudinal changes in these strains between 4 and 16 weeks of age that might distinguish the non-diabetogenic vs. diabetogenic obesity (diabesity).. Both strains became adipose, with NONcNZO5 males attaining a higher mean body weight with a higher percentage fat content. Weight gain in NONcNZO5 was accompanied by a transient peak in plasma insulin (PI) at 8 weeks followed by a decline into normal range, with normoglycemia maintained throughout. In contrast, NONcNZO10 showed no early PI secretory response because both body weight and plasma glucose increased between 4 and 8 weeks. Only after 12 weeks, with hyperglycemia established, was a delayed PI secretory response observed. Neither plasma leptin nor adiponectin concentrations significantly differentiated the two syndromes over time. However, repeated measures ANOVA showed that NONcNZO10 males maintained significantly higher plasma concentrations of two adipokines, resistin and plasminogen activator inhibitor-1, and the pro-inflammatory cytokine/adipokine macrophage chemoattractant protein-1.. Longitudinal profiling of PI and adipokines in two new mouse models developing moderate obesity demonstrated that specific marker signatures differentiated a non-diabetogenic obesity from a diabetogenic obesity.

Topics: Adiponectin; Animals; Blood Glucose; Body Composition; Body Weight; Chemokine CCL2; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Predisposition to Disease; Insulin; Leptin; Longitudinal Studies; Male; Mice; Mice, Obese; Obesity; Peptide Hormones; Plasminogen Activator Inhibitor 1; Resistin

The aim of this study was to assess the suitability of A/J and C57BL/6J mice of both sexes as models of some components of the human metabolic syndrome (MetS) under nutritional conditions more comparable with the actual worldwide diet responsible for the increased incidence of the MetS.. We fed large cohorts (n = 515) of two strains of mice, A/J and the C57BL/6J, and of both sexes a high-fat diet (HFD; 60% fat) that, in contrast with most previous reports using saturated fats, was enriched in mono- and polyunsaturated fatty acids, thus more closely mimicking most Western diets, or a control diet (10% fat), for 20 weeks.. In sharp contrast to previous reports, weight gain and hyperleptinemia were similar in both strains and sexes. Hyperinsulinemia, glucose tolerance, insulin resistance, and hypercholesterolemia were observed, although with important differences between strains and sexes. A/J males displayed severely impaired glucose tolerance and insulin resistance. However, in contrast with C57BL6/J mice, which displayed overt type 2 diabetes, A/J mice of both sexes remained normoglycemic.. With important differences in magnitude and time course, the phenotypic and metabolic characteristics of both strains and both sexes on this HFD demonstrate that these models are very useful for identifying the mechanisms underlying progression or resistance to subsequent type 2 diabetes.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol; Cohort Studies; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Fatty Acids, Monounsaturated; Female; Glucose Tolerance Test; Insulin; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Pregnancy; Specific Pathogen-Free Organisms; Triglycerides

TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. Pharmacological inhibition of TNF-alpha is currently in use for the treatment of rheumatoid and psoriatic arthritis, and some case reports have shown clinical improvement of diabetes in patients treated with the TNF-alpha blocking monoclonal antibody infliximab. The objective of this study was to evaluate the effect of infliximab on glucose homeostasis and insulin signal transduction in an animal model of diabetes. Diabetes was induced in Swiss mice by a fat-rich diet. Glucose and insulin homeostasis were evaluated by glucose and insulin tolerance tests and by the hyperinsulinemic-euglycemic clamp. Signal transduction was evaluated by immunoprecipitation and immunoblotting assays. Short-term treatment with infliximab rapidly reduced blood glucose and insulin levels and glucose and insulin areas under the curve during a glucose tolerance test. Furthermore, infliximab increased the glucose decay constant during an insulin tolerance test and promoted a significant increase in glucose infusion rate during a hyperinsulinemic-euglycemic clamp. In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Animals; Antibodies, Monoclonal; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Glucose Tolerance Test; Homeostasis; Hypothalamus; Immunoblotting; Immunoprecipitation; Infliximab; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Leptin; Liver; Male; Mice; Muscle, Skeletal; Obesity; Phosphorylation; Tumor Necrosis Factor-alpha

In diabetes, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis causes effects such as elevation of corticotropin (ACTH) and glucocorticoids. Cholecystokinin and its receptors are involved in the HPA axis and influence the regulation of the HPA axis. We examined adrenocortical function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, that lack the cholecystokinin A receptor. We measured adrenal weight, plasma ACTH, serum and urinary corticosterone, and serum leptin in OLETF rats at 5 to 36 weeks of age. Messenger RNA (mRNA) expression of 11beta-hydroxysteroid dehydrogenase and 5alpha-reductase type 1 in adrenal glands of the rats were examined. Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In OLETF rats at 32 to 36 weeks of age, plasma ACTH was significantly higher (P < .001); serum corticosterone and 24-hour urinary corticosterone were significantly lower (P < .005); and adrenal weight was significantly lower (P < .005) than those in LETO rats. At the same ages, serum leptin in OLETF rats was significantly higher (P < .001) than that in LETO rats. In the younger OLETF rats, these changes were not observed. Overall, there was an inverse correlation between serum corticosterone and serum leptin (r = -0.374, P < .0005), whereas there was a positive correlation between plasma ACTH and serum leptin (r = 0.654, P < .0001). At 5 and 36 weeks of age, mRNA expression of 5alpha-reductase type 1 in the adrenal gland of OLETF rats was significantly higher (P < .05) than that of LETO rats, whereas there was no significant difference in mRNA expressions of 11beta-hydroxysteroid dehydrogenase types 1 and 2. We showed that adrenocortical insufficiency and adrenal atrophy were acquired in OLETF rats, and the possibility of elevated serum leptin relates to this phenomenon.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adrenal Cortex; Adrenal Cortex Function Tests; Adrenal Glands; Adrenal Insufficiency; Adrenocorticotropic Hormone; Aging; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; DNA Primers; Insulin; Leptin; Organ Size; Rats; Rats, Inbred OLETF; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Leptin alters pancreatic exocrine and beta-cell secretion in animal studies. We hypothesized that leptin might be important in the pathogenesis of idiopathic chronic pancreatitis (ICP) and/or the development of diabetes in ICP.. Fifty patients with ICP (25 with diabetes, 25 without diabetes) and 25 healthy controls were included in a prospective, case-control study. Fasting plasma leptin concentration was measured by enzyme-linked immunosorbent assay. Exocrine and endocrine pancreatic functions were assessed by fecal chymotrypsin and serum C-peptide, respectively. Anthropometric parameters and body fat mass (FM) were measured.. Patients with ICP (mean age, 30 years; 33 men) had significantly lower body mass index (19.5 +/- 2.6 kg/m2) and FM (10.6 +/- 4.2 kg) as compared with controls (body mass index, 21.7 +/- 4.1 kg/m2; FM, 19.0 +/- 16.6 kg; P < 0.01). Fecal chymotrypsin (median, 5.2 [range, 0.3-42.6] U/kg) and C-peptide (median, 1.7 [range, 0.2-9.5] ng/mL) were significantly lower in patients than in controls (12.9 [range, 2.5-33.0] U/kg and 3.5 [range, 0.3-10.3] ng/mL; P < 0.01). Plasma leptin concentration was slightly lower but statistically insignificant in patients with ICP (median, 4.0 [range, 2.0-62.5] ng/mL) as compared with controls (median, 5.0 [range, 2.0-63.0] ng/mL). Patients with and those without diabetes were also comparable with regard to their leptin concentration, pancreatic functions, and anthropometric parameters.. Leptin does not seem to have a pathophysiological role in either ICP or the development of diabetes in ICP.

Topics: Adipose Tissue; Adult; Anthropometry; C-Peptide; Case-Control Studies; Chymotrypsin; Diabetes Mellitus, Type 2; Feces; Female; Humans; Leptin; Male; Middle Aged; Pancreas, Exocrine; Pancreatitis, Chronic; Prospective Studies