leptin and Hyperglycemia

Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.

Topics: Autoimmune Diseases; Bone and Bones; Dyslipidemias; Fatty Liver; Glucose; Humans; Hyperglycemia; Hypertension; Kidney; Leptin; Lipid Metabolism; Lipodystrophy; Quality of Life; Recombinant Proteins; Reproduction; Syndrome

Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.

Topics: Adiponectin; Adipose Tissue; Animals; Disease Progression; Gene Expression Regulation; Humans; Hyperglycemia; Hypertension; Inflammation; Insulin-Like Growth Factor I; Leptin; Ligands; Metabolic Syndrome; Mice; Neoplasms; Obesity; Peroxisome Proliferator-Activated Receptors; Rats; Receptor for Advanced Glycation End Products; Signal Transduction; Vascular Endothelial Growth Factor A; Wnt Proteins

Sepsis has become a global health problem with rising incidence and high mortality, creating a substantial social and economic burden. Early diagnosis and treatment can improve outcome, but reliable sepsis biomarkers are lacking. This review summarizes current evidence of the pathophysiological mechanisms linking adipose tissue to sepsis and presents experimental and clinical data on adipokines and sepsis along with important insights into the obesity paradox in sepsis survival.. Sepsis is characterized by significant alterations in circulating cytokines and adipokines, biologically active molecules produced by the adipose tissue, being implicated in metabolic and inflammatory processes. Although data are inconclusive regarding classic adipokines such as leptin and adiponectin, recent evidence have highlighted the striking elevation of resistin and visfatin in critical illness and sepsis as well as their association with sepsis severity and outcomes. Given that inflammatory and metabolic pathways are involved in sepsis, studying adipokines presents an attractive, innovative, and promising research field that may provide more powerful diagnostic and prognostic biomarkers as well as novel therapeutic targets, empowering the therapeutic armamentarium for sepsis management in order to improve survival.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers; Cytokines; Humans; Hyperglycemia; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Sepsis; Severity of Illness Index

Leptin resistance refers to states in which leptin fails to promote its anticipated effects, frequently coexisting with hyperleptinaemia. Leptin resistance is closely associated with obesity and also observed in physiological situations such as pregnancy and in seasonal animals. Leptin resensitisation refers to the reversion of leptin-resistant states and is associated with improvement in endocrine and metabolic disturbances commonly observed in obesity and a sustained decrease of plasma leptin levels, possibly below a critical threshold level. In obesity, leptin resensitisation can be achieved with treatments that reduce body adiposity and leptinaemia, or with some pharmacological compounds, while physiological leptin resistance reverts spontaneously. The restoration of leptin sensitivity could be a useful strategy to treat obesity, maintain weight loss and/or reduce the recidivism rate for weight regain after dieting. This review provides an update and discussion about reversion of leptin-resistant states and modulation of the molecular mechanisms involved in each situation.

Topics: Adiposity; Animals; Blood Pressure; Body Weight; Diet; Eating; Energy Intake; Female; Fertility; Humans; Hyperglycemia; Leptin; Male; Mice; Obesity; Phosphorylation; Photoperiod; Pregnancy; Pregnancy, Animal; Signal Transduction; Thermogenesis; Weight Loss

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

New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of β-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.

Topics: Adipocytes; Adiponectin; Animals; Calcium Channels; Caveolins; Cell Differentiation; Diabetes Mellitus; Dolichols; Glucose Transporter Type 4; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Ion Channels; Leptin; MicroRNAs; Mitochondrial Proteins; Terpenes; Ubiquinone; Uncoupling Protein 3

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

Osteoporosis is a high-prevalence disease, particularly in developed countries, and results in high costs both to the individual and to society through associated fragility fractures. There is an urgent need for identification of novel drug targets and development of new anti-osteoporotic agents. Between 30 and 80% of osteoporotic fractures cannot be prevented despite current treatments achieving relative fracture risk reduction of up to 20%, 50%, and 70% for non-vertebral, hip and spine fractures, respectively. Traditionally, the decline in gonadal hormones has been studied as the sole hormonal determinant for the loss of bone mineral density in osteoporosis. However, recent studies have identified receptors for numerous non-gonadal hormones such as PTH, angiotensin II, leptin, adiponectin, insulin and insulin-like growth factor-1 on the osteoblast lineage cells that directly regulate bone turnover. These hormones are also involved in the pathogenesis of metabolic syndrome risk factors, particularly hypertension, type-II diabetes and obesity. By activating their respective receptors on osteoblastic lineage cells, these hormones appear to act through a common mechanism by down-regulating receptors for activation of nuclear factor kappa B ligand (RANKL) and up-regulating osteoprotegerin (OPG) with inverse responses for adiponectin. Receptors for amylin, gastric inhibitory polypeptide and ghrelin and have also been identified on the osteoblast lineage cells although the roles of these receptors in bone turnover are controversial or poorly studied. Moreover, bone turnover may be independently regulated by modulation of osteoclast-osteoblast function and bone marrow adiposity. Leptin appears to be the only hormone that is a known regulator of both bone mineralisation and bone adiposity.

Topics: Adiposity; Animals; Bone Remodeling; Hormones; Humans; Hyperglycemia; Hypertension; Leptin; Osteoclasts; Osteoporosis; Parathyroid Hormone; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cell Surface; Signal Transduction

The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

Topics: Animals; Diabetes Mellitus; Genetic Therapy; Humans; Hyperglycemia; Hypothalamus; Leptin; Rats; Signal Transduction; Transgenes

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

This review summarizes key aspects of what has been learned about the physiology of pancreatic islets and leptin deficiency from studies in obese ob/ob mice. ob/ob Mice lack functional leptin. They are grossly overweight and hyperphagic particularly at young ages and develop severe insulin resistance with hyperglycemia and hyperinsulinemia. ob/ob Mice have large pancreatic islets. The beta-cells respond adequately to most stimuli, and ob/ob mice have been used as a rich source of pancreatic islets with high insulin release capacity. ob/ob Mice can perhaps be described as a model for the prediabetic state. The large capacity for islet growth and insulin release makes ob/ob mice a good model for studies on how beta-cells can cope with prolonged functional stress.

Topics: Animals; Disease Models, Animal; Glucose; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Mice, Obese; Models, Biological; Oscillometry

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

Obesity is characterized by increased concentration of leptin and disturbance of the feedback between hyperleptinaemia and enhanced appetite. The hyperleptinaemia is often combined with hyperglycaemia and arterial hypertension and seems to be a predictor of acute cardiovascular events. Leptin inhibitors might be used in the future for therapy in case of the metabolic syndrome.

Topics: Animals; Appetite; Humans; Hyperglycemia; Hypertension; Leptin; Metabolic Syndrome

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

This review summarizes key aspects of what has been learned about the physiology of leptin deficiency as it can be observed in obese-hyperglycemic ob/ob mice. These mice lack functional leptin. They are grossly overweight and hyperphagic, particularly at young ages, and develop severe insulin resistance. They have been used as a model for obesity and as a rich source of pancreatic islets with high insulin release capacity. The leptin deficiency manifests also with regard to immune function, the cardiovascular system including angiogenesis, supportive tissue function, malignancies, and reproductive function. ob/ob Mice are well suited for studies on the interaction between leptin and insulin, and for studies on initial aspects of metabolic disturbances leading to type-2 diabetes.

Topics: Animals; Disease Models, Animal; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Leptin; Mice; Mice, Obese; Obesity

Topics: Diagnosis, Differential; Diet Therapy; Exercise Therapy; Humans; Hyperglycemia; Hyperinsulinism; Immunosuppression Therapy; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Plasma Exchange; Receptor, Insulin; Syndrome

Topics: Animals; Bezafibrate; Biguanides; Fatty Acids, Nonesterified; Humans; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Hypertension; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Pioglitazone; Thiazoles; Thiazolidinediones; Tumor Necrosis Factor-alpha

The metabolic processes that are responsible for the pathophysiology of the fetus of the diabetic mother have been elucidated in recent years and include maternal hyperglycinemia, fetal hyperglycinemia, fetal hyperinsulinemia, and increased levels of maternal, placental, and fetal insulin-like growth factors. Counter-regulatory mechanisms, such as insulin-like growth factors binding proteins and leptin also play a role. The fetal hypermetabolic state leads to increased somatic growth, obesity, and metabolic disturbances with short- and long-term consequences.

Topics: Diabetes Mellitus; Embryonic and Fetal Development; Female; Fetus; Humans; Hyperglycemia; Hyperinsulinism; Insulin-Like Growth Factor Binding Proteins; Leptin; Pregnancy; Pregnancy in Diabetics; Somatomedins

Low-calorie sweeteners are often used to moderate energy intake and postprandial glycemia, but some evidence indicates that they may exacerbate these aims.. The trial's primary aim was to assess the effect of daily aspartame ingestion for 12 wk on glycemia. Effects on appetite and body weight were secondary aims.. One hundred lean [body mass index (kg/m2): 18-25] adults aged 18-60 y were randomly assigned to consume 0, 350, or 1050 mg aspartame/d (ASP groups) in a beverage for 12 wk in a parallel-arm design. At baseline, body weight and composition were determined, a 240-min oral-glucose-tolerance test (OGTT) was administered, and measurements were made of appetite and selected hormones. Participants also collected a 24-h urine sample. During the intervention, the 0-mg/d ASP group consumed capsules containing 680 mg dextrose and 80 mg para-amino benzoic acid. For the 350-mg/d ASP group, the beverage contained 350 mg aspartame and the 1050-mg/d ASP group consumed the same beverage plus capsules containing 680 mg dextrose and 700 mg aspartame. Body weight, blood pressure, heart rate, and waist circumference were measured weekly. At weeks 4, 8, and 12, participants collected 24-h urine samples and kept appetite logs. Baseline measurements were repeated at week 12.. With the exception of the baseline OGTT glucose concentration at 60 min (and resulting area under the curve value), there were no group differences for glucose, insulin, resting leptin, glucagon-like peptide 1, or gastric inhibitory peptide at baseline or week 12. There also were no effects of aspartame ingestion on appetite, body weight, or body composition. Compliance with the beverage intervention was ∼95%.. Aspartame ingested at 2 doses for 12 wk had no effect on glycemia, appetite, or body weight among healthy, lean adults. These data do not support the view that aspartame is problematic for the management of glycemia, appetite, or body weight. This trial was registered at www.clinicaltrials.gov as NCT02999321.

Topics: Adult; Appetite; Aspartame; Blood Glucose; Body Composition; Body Weight; Diet; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Leptin; Male; Non-Nutritive Sweeteners; Postprandial Period; Young Adult

To investigate the efficacy of combined therapy of insulin and rosiglitazone on metabolic and inflammatory parameters, insulin sensitivity, and adipocytokine levels in patients with type 1 diabetes mellitus (type 1 DM).. A total of 61 adults with type 1 DM were randomly and prospectively assigned in open-label fashion to take insulin and rosiglitazone 4 mg/day (n = 30) or insulin alone (n = 31) for a period of 18 weeks while undergoing insulin therapy without acute metabolic complications.. Combination therapy did not significantly improve metabolic and inflammatory parameters, insulin sensitivity, and adiponectin levels. While leptin and resistin levels decreased in both groups (group 1: resistin 6.96 ± 3.06 to 4.99 ± 2.64, P = 0.006; leptin 25.8 ± 17.6 to 20.1 ± 12.55, P = 0.006; group 2: resistin 7.16 ± 2.30 to 5.57 ± 2.48, P = 0.031; leptin 16.72 ± 16.1 to 14.0 ± 13.4, P = 0.007) Hgb and fibrinogen levels decreased only in group 1 (Hgb 13.72 ± 1.98 to 13.16 ± 1.98, P = 0.015, and fibrinogen 4.00 ± 1.08 to 3.46 ± 0.90, P = 0.002). Patients in both groups showed weight gain and the incidence of hypoglycemia was not lower.. The diverse favorable effects of TZDs were not fully experienced in patients with type 1 DM. These results are suggesting that insulin sensitizing and anti-inflammatory characteristics of TZDs were likely to be more pronounced in patients who were not totally devoid of endogenous insulin secretion.

Topics: Adipokines; Adiponectin; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fibrinogen; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Insulin Secretion; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Resistin; Rosiglitazone; Thiazolidinediones; 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

Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes.. Our objective was to study 1-year effects of recombinant human methionyl leptin (metreleptin) in 5 patients with RMS and 10-year effects in 2 of these patients.. We conducted an open-label nonrandomized study at the National Institutes of Health.. Patients were adolescents with RMS and poorly controlled diabetes.. Two patients were treated with escalating doses (0.02 up to 0.22 mg/kg/d) of metreleptin for 10 years, including 3 cycles of metreleptin withdrawal and reinitiation. In all 5 patients, 1-year effects of metreleptin (0.22 mg/kg/d) were studied.. Hemoglobin A1c (HbA1c) and body mass index (BMI) z-scores were evaluated every 6 months.. HbA1c decreased from 11.4% ± 1.1% at baseline to 9.3% ± 1.9% after 6 months and 9.7% ± 1.6% after 12 months of metreleptin (P = .007). In patients treated for 10 years, HbA1c declined with each cycle of metreleptin and rose with each withdrawal. BMI z-scores declined from -1.4 ± 1.8 at baseline, to -2.6 ± 1.6 after 12 months of metreleptin (P = .0006). Changes in BMI z-score correlated with changes in HbA1c (P < .0001).. Metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c; part of this improvement was likely mediated via decreased BMI. Metreleptin is a promising treatment option for RMS, but additional therapies are needed to achieve HbA1c targets.

Topics: Adolescent; Blood Glucose; Child; Donohue Syndrome; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin Resistance; Leptin; Male; Receptor, Insulin; Treatment Outcome

Genotype/allele distributions of leptin promoter G-2548A polymorphism, serum leptin and insulin levels and body weight were not significantly different between 72 children (39 male/33 female; age range 1.08-16, median 6 years) with acute leukemia (56 acute lymphoblastic leukemia [ALL]/16 acute non-lymphoblastic leukemia [ANLL]) at diagnosis and 70 age- and sex-matched controls (p > 0.05). The - 2548GG genotype was associated with the highest leptin levels in controls and patients with acute leukemia after 7-day high-dose methylprednisolone (HDMP) therapy (p < 0.05), while no significant association of genotype with leptin levels was detected in patients at diagnosis (p > 0.05). One-week HDMP therapy in patients carrying the - 2548G allele caused a significant increase in leptin levels and body weight (p < 0.001), whereas increases in those carrying the - 2548AA genotype were insignificant (p > 0.05). Decreases in white blood cell counts of patients after therapy were insignificant in - 2548GG (p > 0.05) yet significant in - 2548GA and - 2548AA (p < 0.05) genotypes. These results revealed no association of leptin genotype with the etiology of childhood acute leukemia but a possible association with leptin levels and effects of HDMP therapy.

Topics: Acute Disease; Adolescent; Case-Control Studies; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Glucocorticoids; Humans; Hyperglycemia; Infant; Insulin; Leptin; Leukemia; Male; Methylprednisolone; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Prospective Studies; Time Factors; Treatment Outcome

The steady increase in chronic "glycemic load" is characteristic for modern times. Among myriad of glucose functions, two principals can be emphasized: first, endocrine (in particular, ability to induce insulin secretion) and second, DNA-damaging related to formation of reactive oxygen species (ROS). It was suggested by us earlier that a shift in the ratio of mentioned functions reflects a possible "joker" role of glucose as an important modifier of human pathology. Therefore, we embarked on a study to investigate an individual effect of peroral glucose challenge on serum insulin level and ROS generation by mononuclears (luminol-dependent/latex-induced chemiluminescence) in 20 healthy people aged between 28-75. Concentrations of glucose, blood lipids, carbonylated proteins, malondialdehyde, leptin and TNF-alpha were determined as well. On the basis of received data two separate groups could be distinguished: one (n=8), in which glucose stimulation of ROS generation by mononuclears was increased and relatively prevailed over induction of insulin secretion (state of the so called glucose-induced genotoxicity, GIGT), and another (n=12), in which signs of GIGT were not revealed. People who belonged to the first group were characterized with a tendency to lower body mass index, blood leptin and cholesterol and to higher TNF-alpha concentration. Thus, if joker function of glucose is realized in "genotoxic mode", the phenotype (and probably genotype) of subjects may be rather distinctive to the one discovered in glucose-induced "endocrine prevalence". Whether such changes may serve as a pro-mutagenic or pro-endocrine basis for the rise of different chronic diseases or, rather, different features/aggressiveness of the same disease warrants further study.

Topics: Adult; Aged; Blood Glucose; Blood Proteins; Endocrine System; Female; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Secretion; Leptin; Lipids; Male; Malondialdehyde; Middle Aged; Postprandial Period; Prevalence; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

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

The present study was performed to investigate the effects of the intestinal fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism and the beta(3)-adrenergic receptor (beta3AR) gene Trp64Arg polymorphism on body mass index (BMI), blood pressure, heart rate, glucose and lipid profiles, and serum leptin level in 196 young men aged 21 to 39 years, 186 older normoglycemic men (fasting plasma glucose [FPG] < 110 mg/dL) aged 40 to 65 years, and 122 older hyperglycemic men, including 77 type 2 diabetic patients. Genomic DNA was extracted from the peripheral blood, and these polymorphisms were assessed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. In the older groups, the beta3AR Arg64-allele frequency tended to be lower and the FABP2 Thr/Thr54 genotype frequency tended to be higher in hyperglycemic patients, although these differences did not reach statistical significance. Also, there were no significant differences in the genotype or allele frequency of either variant between the 27 hyperlipidemic and 204 normolipidemic subjects. In the younger group, there were no significant differences in any of the parameters measured between the genotypes of beta3AR or FABP2. In the older normoglycemic subjects, heart rate was significantly lower (P =.037) in beta3AR Arg64-positive subjects, and FPG was significantly higher in subjects with the FABP2 Thr/Thr genotype than the other genotypes (99.8 +/- 5.6 v 96.5 +/- 5.6 mg/dL, P =.010). In the older hyperglycemic group, the beta3AR Arg64-positive group had significantly lower high-density lipoprotein (HDL) cholesterol and free fatty acid (FFA) levels (P =.024 and P =.043, respectively). There were no synergistic effects of these 2 variants on any measured parameter, but only the FABP2 Thr/Thr genotype was related to a higher FPG in the older normoglycemic men. In conclusion, no major difference was associated with the beta3AR Trp64Arg or FABP2 Ala54Thr polymorphism in terms of type 2 diabetes or hyperlipidemia in young to older Japanese men. However, a slight but significant increase in FPG was observed in older Japanese men with the FABP2 Thr/Thr genotype.

Topics: Adult; Aged; Aging; Amino Acid Substitution; Blood Glucose; Blood Pressure; Body Mass Index; Carrier Proteins; Fasting; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Gene Frequency; Genotype; Humans; Hyperglycemia; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Neoplasm Proteins; Polymorphism, Genetic; Receptors, Adrenergic, beta-3; Tumor Suppressor Proteins

The release of leptin by pieces of human adipose tissue incubated in primary culture for 24 or 48 hours in the presence of dexamethasone was reduced by isoproterenol. An inhibition of leptin release was observed at 24 hours in the presence of isoproterenol and was mediated by beta1-adrenergic receptors, since it was blocked by the specific beta1-adrenoceptor antagonist CGP-20712A. The inhibitory effect of 33 nmol/L isoproterenol on leptin release was reversed in the presence of 0.1 nmol/L insulin to a 2-fold stimulation of leptin release. These data suggest that the primary mechanism by which insulin stimulates leptin release is to blunt the inhibitory effects of beta1-adrenergic receptor agonists, and low concentrations of catecholamines actually enhance the stimulation of leptin release by insulin.

Topics: Adipocytes; Adrenergic beta-Antagonists; Adult; Catecholamines; Dexamethasone; Drug Synergism; Female; Humans; Hyperglycemia; Imidazoles; Insulin; Isoproterenol; Leptin; Lipolysis; Male; Obesity

Background: some studies have evaluated the association of the rs1805134 genetic variant of the LEPR gene with obesity. Aims: the objective was to explore the association of the rs1805134 genetic variant of the LEPR gene with obesity measures and metabolic syndrome in obese Caucasian adults. Methods: we conducted a cross-sectional study in 212 obese subjects with body mass index (BMI) greater than 30 kg/m2. Measurements of adiposity parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C-reactive protein, and prevalence of metabolic syndrome were determined. Results: the distribution of rs1805134 was 128 TT (60.4 %), 77 TC (36.3 %), and 7 CC (3.3 %). C-allele carriers showed higher levels of BMI, body weight, body fat mass, waist circumference, insulin, HOMA-IR, triglycerides, total energy intake, and carbohydrate intake than non-C-allele carriers. A logistic regression analysis reported a high percentage of elevated waist circumference (OR = 2.22, 95 % CI = 1.201-4.97; p = 0.02), hyperglycemia (OR = 1.54, 95 % CI = 1.01-5.44; p = 0.01), and metabolic syndrome percentage (OR = 1.41, 95 % CI = 1.04-5.39; p = 0.03) in C-allele carriers. Conclusions: subjects with the C-allele of the rs1805134 variant of the LEPR gene showed a worse metabolic pattern with a higher percentage of metabolic syndrome, central obesity and hyperglycaemia, probably related to higher energy intake.. Antecedentes: algunos estudios han evaluado la asociación de la variante genética rs1805134 del gen LEPR con la obesidad. Objetivos: el objetivo fue explorar la asociación de la variante genética rs1805134 del gen LEPR con los parámetros de obesidad y síndrome metabólico en adultos caucásicos obesos. Métodos: realizamos un estudio transversal en 212 sujetos obesos con índice de masa corporal (IMC) superior a 30 kg/m2. Se determinaron los parámetros de adiposidad, presión arterial, glucemia en ayunas, concentración de insulina, resistencia a la insulina (HOMA-IR), perfil lipídico, proteína C-reactiva y prevalencia de síndrome metabólico. Resultados: la distribución del rs1805134 fue de 128 TT (60,4 %), 77 TC (36,3 %) y 7 CC (3,3 %). Los portadores del alelo C mostraron niveles más altos de IMC, peso corporal, masa grasa corporal, circunferencia de la cintura, insulina, HOMA-IR, triglicéridos, ingesta total de energía y consumo de carbohidratos que los portadores sin alelo C. El análisis de regresión logística mostró un alto porcentaje de pacientes con elevada circunferencia de la cintura (OR = 2,22, IC 95 % = 1,201-4,97; p = 0,02), hiperglucemia (OR = 1,54, IC 95 % = 1,01-5,44; p = 0,01) y síndrome metabólico (OR = 1,41, IC 95 % = 1,04-5,39; p = 0,03) en los portadores del alelo C. Conclusiones: los sujetos con alelo C de la variante rs1805134 del gen LEPR mostraron un peor patrón metabólico con mayor porcentaje de síndrome metabólico, obesidad central e hiperglucemia, probablemente relacionado con una mayor ingesta energética.

Topics: Adult; Body Mass Index; Cross-Sectional Studies; Eating; Humans; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin

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

Hyperglycemia exerts various harmful effects on the vasculature. Studies have shown an association between the levels of the adipokines leptin and adiponectin (APN) and vascular complications in diabetes mellitus. The aim of our study was to investigate the molecular mechanisms mediated by APN and leptin that are involved in hyperglycemia-induced vascular remodeling, especially at the level of oxidative stress and actin cytoskeleton dynamics. Rat aorta organ culture was used to investigate the effect of hyperglycemia on APN and leptin protein expression in vascular smooth muscle cells (VSMCs) using Western blot analysis and immunohistochemistry. Hyperglycemia lead to a significant increase in APN synthesis in VSMCs, mainly through caveolae, but this increase failed to provide vascular protection because of the decreased expression of APN receptors, especially AdipoR2, which was assessed by qPCR. In addition, hyperglycemia significantly upregulated leptin expression in VSMCs through caveolae and the RhoA/ROCK pathway. These variations lead to a marked increase in reactive oxygen species (ROS) production, detected by dihydroethidium (DHE) staining, and in NADPH oxidase type 4 (Nox4) expression. Moreover, Nox4 mediated the synthesis of APN in hyperglycemia in VSMCs. Finally, hyperglycemia activated the RhoA/ROCK pathway and subsequently induced the polymerization of globular actin (G-actin) into filamentous actin (F-actin), decreasing the G/F-actin ratio. Taken together, these data show that hyperglycemia increases oxidative stress and changes actin cytoskeleton dynamics in the aorta via caveolae, favoring vascular remodeling.

Topics: Adiponectin; Animals; Caveolae; Disease Models, Animal; Hyperglycemia; Leptin; Male; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Vascular Remodeling

Leptin is best known for its role in adipostasis, but it also regulates blood glucose levels. The molecular mechanism by which leptin controls glucose homeostasis remains largely unknown. Here, we use a zebrafish model to show that Wnt signaling mediates the glucoregulatory effects of leptin. Under normal feeding conditions, leptin regulates glucose homeostasis but not adipostasis in zebrafish. In times of nutrient excess, however, we found that leptin also regulates body weight and size. Using a Wnt signaling reporter fish, we show that leptin activates the canonical Wnt pathway in vivo. Utilizing two paradigms for hyperglycemia, it is revealed that leptin regulates glucose homeostasis via the Wnt pathway, as pharmacological inhibition of this pathway impairs the glucoregulatory actions of leptin. Our results may shed new light on the evolution of the physiological function of leptin.

Topics: Animals; Glucose; Homeostasis; Hyperglycemia; Leptin; Receptors, Leptin; Wnt Signaling Pathway; Zebrafish; Zebrafish Proteins

Obesity-related hyperglycemia, with hepatic insulin resistance, has become an epidemic disease. Central neural leptin signaling was reported to improve hyperglycemia. The aim of this study was to investigate the effect of hepatic leptin signaling on controlling hyperglycemia.. First, the effect of leptin signaling on gluconeogenesis was investigated in primary mouse hepatocytes and hepatoma cells. Second, glucose tolerance, insulin tolerance, blood glucose levels, and hepatic gluconeogenic gene expression were analyzed in obese mice overexpressing hepatic OBRb. Third, expression of mitogen-activated protein kinase phosphatase (MKP)-3, phosphorylation level of signal transducer and activator of transcription (STAT) 3, and extracellular regulated protein kinase (ERK) were analyzed in hepatocytes and mouse liver. Fourth, the role of MKP-3 in hepatic leptin signaling regulating gluconeogenesis was analyzed. Lastly, the role of ERK and STAT3 in the regulation of MKP-3 protein by leptin signaling was analyzed.. Activation of hepatic leptin signaling suppressed gluconeogenesis in both hepatocytes and obese mouse liver, and improved hyperglycemia, insulin tolerance, and glucose tolerance in obese mice. The protein level of MKP-3, which can promote gluconeogenesis, was decreased by leptin signaling in both hepatocytes and mouse liver. Mkp-3 deficiency abolished the effect of hepatic leptin signaling on suppressing gluconeogenesis in hepatocytes. STAT3 decreased the MKP-3 protein level, while inactivation of STAT3 abolished the effect of leptin signaling on reducing the MKP-3 protein level in hepatocytes. Moreover, STAT3 could combine with MKP-3 and phospho-ERK1/2, which induced the degradation of MKP-3, and leptin signaling enhanced the combination.. Hepatic leptin signaling could suppress gluconeogenesis at least partially by decreasing the MKP-3 protein level via STAT3-enhanced MKP-3 and ERK1/2 combination.

Topics: Animals; Blood Glucose; Hyperglycemia; Insulins; Leptin; Liver; Mice; Mice, Obese; Phosphoric Monoester Hydrolases; Proteolysis

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

The hypothalamus is a critical regulator of glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The small GTPase Rap1 in the forebrain is implicated in high-fat diet-induced (HFD-induced) obesity and glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated blood glucose without increasing the body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced hyperglycemia but did not prevent weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in steroidogenic factor-1-positive (SF-1-positive) neurons in the ventromedial hypothalamic nucleus (VMH) known to regulate glucose metabolism. While having no effect on body weight regardless of sex, diet, and age, Rap1 deficiency in the VMH SF1 neurons markedly lowered blood glucose and insulin levels, improved glucose and insulin tolerance, and protected mice against HFD-induced neural leptin resistance and peripheral insulin resistance at the cellular and whole-body levels. Last, acute pharmacological inhibition of brain exchange protein directly activated by cAMP 2, a direct activator of Rap1, corrected glucose imbalance in obese mouse models. Our findings uncover the primary role of VMH Rap1 in glycemic control and implicate Rap1 signaling as a potential target for therapeutic intervention in diabetes.

Topics: Animals; Blood Glucose; Diet, High-Fat; Gene Knockdown Techniques; Homeostasis; Hyperglycemia; Hypothalamus; Insulin; Insulin Resistance; Leptin; Mice; Neurons; Obesity; rap1 GTP-Binding Proteins; Steroidogenic Factor 1; Ventromedial Hypothalamic Nucleus

Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepR

Topics: Agouti-Related Protein; AMP-Activated Protein Kinases; Animals; Blood Glucose; Brain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; GABAergic Neurons; Hyperglycemia; Infusions, Intraventricular; Leptin; Male; Mice, Transgenic; Neurons; Receptors, Leptin; Signal Transduction

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

Obesity during pregnancy has been shown to increase the risk of metabolic diseases in the offspring. However, the factors within the maternal milieu which affect offspring phenotypes and the underlying mechanisms remain unknown. The adipocyte hormone leptin plays a key role in regulating energy homeostasis and is known to participate in sex-specific developmental programming. To examine the action of leptin on fetal growth, placental gene expression and postnatal offspring metabolism, we injected C57BL mice with leptin or saline on gestational day 12 and then measured body weights (BWs) of offspring fed on a standard or obesogenic diet, as well as mRNA expression levels of insulin-like growth factors and glucose and amino acid transporters. Male and female offspring born to leptin-treated mothers exhibited growth retardation before and a growth surge after weaning. Mature male offspring, but not female offspring, exhibited increased BWs on a standard diet. Leptin administration prevented the development of hyperglycaemia in the obese offspring of both sexes. The placentas of the male and female foetuses differed in size and gene expression, and leptin injection decreased the fetal weights of both sexes, the placental weights of the male foetuses and placental gene expression of the GLUT1 glucose transporter in female foetuses. The data suggest that mid-pregnancy is an ontogenetic window for the sex-specific programming effects of leptin, and these effects may be exerted via fetal sex-specific placental responses to leptin administration.

Topics: Animals; Female; Fetus; Hyperglycemia; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Phenotype; Placenta; Pregnancy; Recombinant Proteins; Sex Characteristics

Changes in fetal DNA methylation (DNAm) of the leptin (

Topics: Adiposity; Adult; Child, Preschool; Diabetes, Gestational; DNA Methylation; Epigenesis, Genetic; Female; Fetal Blood; Genetic Loci; Humans; Hyperglycemia; Infant, Newborn; Leptin; Male; Obesity; Placenta; Pregnancy; Young Adult

Elafin is an antimicrobial and anti-inflammatory protein. We hypothesize that elafin expression correlates with diabetes. Among non-diabetic and prediabetic groups, men have significantly higher serum elafin levels than women. Men with type 2 diabetes mellitus (T2DM) have significantly lower serum elafin levels than men without T2DM. Serum elafin levels are inversely correlated with fasting blood glucose and hemoglobin A1c levels in men with T2DM, but not women with T2DM. Lentiviral elafin overexpression inhibited obesity, hyperglycemia, and liver steatosis in high-fat diet (HFD)-treated male mice. Elafin-overexpressing HFD-treated male mice had increased serum leptin levels, and serum exosomal miR181b-5p and miR219-5p expression. Transplantation of splenocytes and serum exosomes from elafin-overexpressing HFD-treated donor mice reduced food consumption and fat mass, and increased adipose tissue leptin mRNA expression in HFD-treated recipient mice. Elafin improved leptin sensitivity via reduced interferon-gamma expression and induced adipose leptin expression via increased miR181b-5p and miR219-5p expression. Subcutaneous and oral administration of modified elafin inhibited obesity, hyperglycemia, and liver steatosis in the HFD-treated mice. Circulating elafin levels are associated with hyperglycemia in men with T2DM. Elafin, via immune-derived miRNAs and cytokine, activates leptin sensitivity and expression that subsequently inhibit food consumption, obesity, hyperglycemia, and liver steatosis in HFD-treated male mice.

Topics: Adipose Tissue; Animals; Cytokines; Diet, High-Fat; Disease Models, Animal; Eating; Elafin; Fatty Liver; Female; Gene Expression; Humans; Hyperglycemia; Interferon-gamma; Leptin; Male; Mice, Inbred C57BL; Obesity; Sex Characteristics

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of

Topics: Animals; Dyslipidemias; Glucose; Hyperglycemia; Insulin; Integrases; Leptin; Male; Mice; Mice, Transgenic; Neurons; Receptors, Leptin

Tens of millions suffer from insulin deficiency (ID); a defect leading to severe metabolic imbalance and death. The only means for management of ID is insulin therapy; yet, this approach is sub-optimal and causes life-threatening hypoglycemia. Hence, ID represents a great medical and societal challenge. Here we report that S100A9, also known as Calgranulin B or Myeloid-Related Protein 14 (MRP14), is a leptin-induced circulating cue exerting beneficial anti-diabetic action. In murine models of ID, enhanced expression of S100A9 alone (i.e. without administered insulin and/or leptin) slightly improves hyperglycemia, and normalizes key metabolic defects (e.g. hyperketonemia, hypertriglyceridemia, and increased hepatic fatty acid oxidation; FAO), and extends lifespan by at least a factor of two. Mechanistically, we report that Toll-Like Receptor 4 (TLR4) is required, at least in part, for the metabolic-improving and pro-survival effects of S100A9. Thus, our data identify the S100A9/TLR4 axis as a putative target for ID care.

Topics: Animals; Calgranulin B; Diabetes Mellitus, Experimental; Diphtheria Toxin; Fatty Acids; Humans; Hyperglycemia; Insulin; Leptin; Liver; Longevity; Male; Mice; Mice, Knockout; Oxidation-Reduction; Signal Transduction; Streptozocin; Toll-Like Receptor 4

One of the main pathological mechanisms of neurotoxicity in diabetic situation is oxidative stress promoted by hyperglycemia. It has been shown that leptin has neuroprotective effects and may provide neuronal survival signals. This study was designed to reveal the possible neuroprotective effects of leptin in hyperglycemic conditions. Pheochromocytoma (PC12) cell viability was assessed via the MTT test. Cellular reactive oxygen species (ROS) generation was determined by DCFH-DA analysis. The malondialdehyde (MDA) and glutathione (GSH) levels were measured in high-glucose-treated PC12 cells with and without leptin cotreatment. Western blotting was performed to measure apoptosis markers (Cleaved caspase-3 and Bax/Bcl2 ratio). Elevation of glucose levels (100 mmol/L) consecutively increased intracellular ROS and MDA level, and apoptosis in PC12 cells after 24 h leptin administration (12 and 24 nmol/L) decreased the high-glucose-induced cell toxicity, caspase-3 activation, and Bax/Bcl-2 ratio. Also, cotreatment with leptin (12 and 24 nmol/L) significantly reduced oxidative damage to PC12 cells in high-glucose condition, as reflected by the diminution in MDA and ROS levels and the increase in GSH content. Our finding demonstrates that leptin has protective effects against hyperglycemia-induced neural damage. This could be related to the attenuation of oxidative stress and neural apoptosis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Survival; Glucose; Glutathione; Hyperglycemia; Leptin; Malondialdehyde; Neurons; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species

(1) Examine associations of a branched-chain amino acid (BCAA) metabolite pattern with metabolic risk across adolescence; (2) use Least Absolute Shrinkage and Selection Operator (LASSO) to identify novel metabolites of metabolic risk.. We used linear regression to examine associations of a BCAA score with change (∆) in metabolic biomarkers over 5-year follow-up in 179 adolescents 8-14 years at baseline. Next, we applied LASSO, a regularized regression technique well suited for reduction of high-dimensional data, to identify metabolite predictors of ∆biomarkers.. In boys, the BCAA score corresponded with decreasing C-peptide, C-peptide-based insulin resistance (CP-IR), total cholesterol (TC), and low-density-lipoprotein cholesterol (LDL). In pubertal girls, the BCAA pattern corresponded with increasing C-peptide and leptin. LASSO identified asparagine as a predictor of decreasing C-peptide (β = -0.33) and CP-IR (β = -0.012), and acetyl-carnitine (β = 2.098), 4-hydroxyproline (β = -0.050), ornithine (β = -0.353), and α-aminoisobutyric acid (β = -0.793) as determinants of TC in boys. In girls, histidine was a negative determinant of TC (β = -0.033).. The BCAA pattern was associated with ∆glycemia and ∆lipids in a sex-specific manner. LASSO identified asparagine, which influences growth hormone secretion, as a determinant of decreasing C-peptide and CP-IR in boys, and metabolites on lipid metabolism pathways as determinants of decreasing cholesterol in both sexes.

Topics: Acetylcarnitine; Adolescent; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Asparagine; Biomarkers; Blood Glucose; Body Composition; Body Mass Index; C-Peptide; Carnitine; Child; Cholesterol; Female; Humans; Hydroxyproline; Hyperglycemia; Insulin Resistance; Leptin; Male; Metabolome; Ornithine; Prospective Studies; Puberty; Regression Analysis; Risk Factors

Topics: Adolescent; Amino Acids, Branched-Chain; Biomarkers; Child; Colombia; Epidemiology; History, 21st Century; Humans; Hyperglycemia; Leptin; Lipids; Metabolomics; Pediatrics

Six-week-old male KK-A

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Disease Models, Animal; Drinking Water; Drug Combinations; Eating; Glycerylphosphorylcholine; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Hypoglycemic Agents; Leptin; Male; Mice; Mice, Transgenic; Obesity; S-Adenosylmethionine; Triglycerides

Leptin promotes adequate caloric intake and glycemia in healthy lean individuals, harnessing the benefits of the ideal therapy against metabolic syndrome. Yet, new evidence demonstrates an unexpected causal role for leptin in obesity-associated hyperglycemia. Like the betrayal of Julius Caesar by Brutus, insulin did not see that coming from leptin.

Topics: Humans; Hyperglycemia; Insulin; Leptin; Obesity

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

Topics: Agouti-Related Protein; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Eating; Hyperglycemia; Hyperphagia; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Wistar; Thyrotropin-Releasing Hormone

Despite benefits, atypical antipsychotics produce troublesome metabolic adverse effects particularly hyperphagia, weight gain, dyslipidemia, hyperglycemia and insulin resistance which further develop metabolic and cardiac complications. The animal models studied for antipsychotic-induced weight gain only focused on metabolic alteration in antipsychotics treated animals but none has considered psychosis as a predisposing factor which mimics the clinical condition. The present study was aimed to rule out the impact of pharmacologically induced psychosis-like phenotype on metabolic alterations induced by antipsychotics. Female BALB/c mice (weighing 18-23 g) exhibiting schizophrenia-like behavior after 5 days of MK-801 treatment (0.1 mg/kg, i.p.) were administered olanzapine (3 and 6 mg/kg, per oral) and risperidone (2 and 4 mg/kg, per oral) for six weeks. Acute as well as chronic treatment with olanzapine and risperidone treatment significantly reduced locomotion, increased feed intake and body weight in a time-dependent manner, which confirms the face validity of the animal model. Olanzapine (6 mg/kg) treatment significantly altered glucose and lipid homeostasis which was further accompanied by elevated levels of proinflammatory cytokines, ghrelin and leptin. These metabolic and biochemical alterations have demonstrated construct validity. Further, no significant difference was observed in the metabolic parameters in control and schizophrenic mice treated with olanzapine which confers that antipsychotic-induced metabolic alterations are independent of psychosis. Our study concluded that six-week olanzapine (6 mg/kg) treatment in control mice induced most of the clinically relevant physiological, biochemical and metabolic alterations (clinically relevant), that is independent of pharmacologically-induced psychosis.

Topics: Animals; Antipsychotic Agents; Body Weight; Female; Ghrelin; Hyperglycemia; Leptin; Mice; Mice, Inbred BALB C; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

Loss of white adipose tissue (WAT), associated with type 1 diabetes (DM1), contributes to increased chronic systemic inflammation.. The aim of this study was to investigate the effects of leucine supplementation and resistance training (RT) in attenuating WAT loss and improving inflammatory parameters and glucose metabolism in DM1 rats.. Thirty-two male Wistar rats were distributed into four groups: DA (sedentary and supplemented with non-essential amino acids (NEAA)), DL (sedentary and supplemented with leucine), DTA (submitted to RT and supplemented with NEAA) and DTL (submitted to RT and supplemented with leucine). DM1 was induced by streptozotocin (STZ). An 8-week period of RT consisted of climbing a ladder with a progressively increased load, and supplementation was offered in the feed.. Glycemia, polyphagia and polydipsia were lower in DL, DTA and DTL groups compared with the DA group by approximately 20% ( p<.0001), 28% ( p=.004) and 64% ( p<.0001), respectively. Weight of total WAT and retroperitoneal adipose tissue (RPAT) were higher by approximately 21% ( p=.01) and 54% ( p=.0004), respectively, in DL, DTA and DTL groups compared with DA. However, gene expression of adiponectin and leptin in RPAT was only increased by RT (DTA and DTL) compared with DA and DL by approximately 93% ( p<.0001) and 78% ( p=.0002), respectively. Similarly, the levels of adiponectin in the serum, tissue IL-10 (RPAT) and serum IL-10 were only increased in DTA and DTL compared with DA and DL by approximately 31% ( p=.03), 45% ( p=.0009) and 35% ( p=.003), respectively.. Both interventions, isolated or together, reduced hyperglycemia and excessive loss of WAT, but RT was the main factor responsible for attenuating inflammation.

Topics: Adiponectin; Adipose Tissue, White; Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Combined Modality Therapy; Diabetes Mellitus, Type 1; Dietary Supplements; Gene Expression Regulation; Hyperglycemia; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Leucine; Male; Random Allocation; Rats, Wistar; Resistance Training; Weight Loss

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

Metabolic syndrome is a major risk factor for the development of cardiovascular diseases and diabetes, among other conditions. Studies have shown that aging and metabolic syndrome share several metabolic alterations, and that aged individuals, in particular females, are at an increased risk of developing metabolic disorders. Although several studies have investigated the effects of hypercaloric diets in the development of obesity and metabolic syndrome in young animals, few studies have investigated these parameters in aged animals, especially in females. Therefore, the aim of this study was to investigate the effects of a hypercaloric diet in metabolic parameters of young and aged female rats, including its effects on lipid and glycemic profile and on liver lipid content. When compared to young animals, the aged rats presented increased serum levels of triglycerides and decreased serum levels of HDL cholesterol and glycemia, as well as increased hepatic levels of triglycerides and total cholesterol. The hypercaloric diet increased food intake, body weight gain and adiposity index, leading both young and aged animals to a dyslipidemia, represented by increased serum levels of triglycerides. The hypercaloric diet increased the glycemia and the HOMA index only in the young animals. On the other hand, the diet increased the frequency of hepatocellular microvacuolar degeneration only in the aged animals. In summary, it was observed that the females from different ages respond differently to hypercaloric diet intake: while the aged animals were more resistant to the changes in the glycemic profile, they were more susceptible to the hepatic damage caused by this diet.

Topics: Adiposity; Aging; Animals; Blood Glucose; Body Weight; Dyslipidemias; Energy Intake; Female; Hyperglycemia; Leptin; Lipid Metabolism; Liver; Metabolic Syndrome; Rats; Rats, Wistar; Triglycerides

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

Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure and maintain blood glucose stability

Topics: Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Eating; Energy Metabolism; Female; GABAergic Neurons; Gene Editing; Homeostasis; Hyperglycemia; Hyperphagia; Leptin; Male; Mice; Neural Pathways; Neurons; Obesity; Potassium Channels; Presynaptic Terminals; Receptors, Leptin; Satiety Response

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.

Topics: 3T3-L1 Cells; Adipogenesis; Adiponectin; Adipose Tissue, White; Animals; Dietary Fats; Dyslipidemias; Fatty Liver; Gene Deletion; Genetic Predisposition to Disease; Glucose Transporter Type 4; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipogenesis; Macrophages; Male; Metabolic Syndrome; Mice; Neuregulins; Obesity; Receptor, ErbB-4; Subcutaneous Fat

Metabolic syndrome (MetS) is associated with osteoporosis due to the underlying inflammatory and hormonal changes. Annatto tocotrienol has been shown to improve medical complications associated with MetS or bone loss in animal studies. This study aimed to investigate the effects of annatto tocotrienol as a single treatment for MetS and osteoporosis in high-carbohydrate high-fat (HCHF) diet-induced MetS animals. Three-month-old male Wistar rats were randomly divided into five groups. The baseline group was euthanized at the onset of the study. The normal group received standard rat chow and tap water. The remaining groups received HCHF diet and treated with three different regimens orally daily: (a) tocopherol-stripped corn oil (the vehicle of tocotrienol), (b) 60 mg/kg annatto tocotrienol, and (c) 100 mg/kg annatto tocotrienol. At the end of the study, measurements of MetS parameters, body compositions, and bone mineral density were performed in animals before sacrifice. Upon euthanasia, blood and femur of the rats were harvested for the evaluations of bone microstructure, biomechanical strength, remodelling activities, hormonal changes, and inflammatory response. Treatment with annatto tocotrienol improved all MetS parameters (except abdominal obesity), trabecular bone microstructure, bone strength, increased osteoclast number, normalized hormonal changes and inflammatory response in the HCHF animals. In conclusion, annatto tocotrienol is a potential agent for managing MetS and osteoporosis concurrently. The beneficial effects of annatto tocotrienol may be attributed to its ability to prevent the hormonal changes and pro-inflammatory state in animals with MetS.

Topics: Adiponectin; Animals; Bixaceae; Bone Resorption; Cancellous Bone; Carotenoids; Diet, High-Fat; Dietary Carbohydrates; Hyperglycemia; Hypertension; Inflammation; Leptin; Male; Metabolic Syndrome; Osteoblasts; Plant Extracts; Rats, Wistar; Tocotrienols; X-Ray Microtomography

Topics: Aging; Animals; Animals, Newborn; Blood Glucose; Brain; Brain Chemistry; Brain-Derived Neurotrophic Factor; Female; Fetus; Fluorodeoxyglucose F18; Genotype; Glucose; Glucose Intolerance; Humans; Hyperglycemia; Infant; Infant, Newborn; Leptin; Male; Obesity; Positron-Emission Tomography; Rats; Rats, Zucker

To assess the associations between sleep duration and cardiometabolic risk factors in Chinese school-aged children and to explore the possible mediating role of adipokines.. Sleep duration was collected in 3166 children from the Beijing Child and Adolescent Metabolic Syndrome study. Glucose homeostasis and other cardiometabolic risk factors were assessed. Serum adipokines including leptin, total and high-molecular-weight (HMW) adiponectin, resistin, fibroblast growth factor 21 (FGF21), and retinol binding protein 4 (RBP4) were determined.. Among the 6- to 12-year-old children, after adjusting for covariates including puberty, short sleep duration was associated with increased body mass index (BMI), waist circumference, fasting glucose, insulin and homeostasis model assessment of insulin resistance (all p < .0001), higher triglyceride and lower high-density lipoprotein cholesterol (p < .05), along with increased leptin (p < .0001), FGF21 (p < .05) and decreased HMW-adiponectin (p ≤ .01); the association with leptin remained significant after further adjustment for BMI. However, these associations, except for glucose (p < .0001), disappeared after further adjusted for leptin. For the 13-18 years old group, short sleep duration was associated with higher BMI, waist circumference, and RBP4 (all p < .05), but the association with RBP4 was attenuated after adjusting for BMI (p = .067).. Short sleep duration is strongly associated with obesity and hyperglycemia (in 6-12 years old), along with adverse adipokine secretion patterns among Chinese children. The associations with cardiometabolic risk factors appear to be more pronounced in younger children, and could be explained, at least partially, by leptin levels.

Topics: Adipokines; Adiponectin; Adolescent; Asian People; Blood Glucose; Body Mass Index; Cardiovascular Diseases; Child; China; Cholesterol, HDL; Female; Fibroblast Growth Factors; Humans; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Resistin; Retinol-Binding Proteins, Plasma; Risk Factors; Sleep; Time Factors; Triglycerides; Waist Circumference

Gestational diabetes mellitus is a significant risk factor for metabolic syndrome and cardiovascular disease.. To assess the relationships between components of the metabolic syndrome and cytokine and adhesion molecule levels in women with GDM during pregnancy and after delivery.. A prospective case-control study on a sample of 126 pregnant women (63 with and 63 without gestational diabetes mellitus). In an intra-subject analysis, 41 women with history of gestational diabetes mellitus and 21 controls were re-assessed in the postpartum period. Clinical data and levels of cytokines and adhesion molecules were recorded during weeks 24-29 of pregnancy and 12 months after delivery.. In the postpartum period, there were significantly higher levels of tumor necrosis factor alpha in both cases and controls, and of adiponectin in controls. Cases showed higher leptin levels, with no significant differences during and after pregnancy. No significant differences were seen in adhesion molecules and interleukin-6 between cases and controls during pregnancy and in the postpartum period, but levels of both were higher in cases. During pregnancy and after delivery, adiponectin decreased in cases and increased in controls. Significant positive correlations were seen between adiponectin and fasting blood glucose levels and vascular cell adhesion molecule-1, and also between leptin and tumor necrosis factor alpha levels.. The results suggest that increased inflammation and transient hyperglycemia during pregnancy would represent a latent form of metabolic syndrome, with an increased risk for type 2 diabetes mellitus and future cardiovascular disease.

Topics: Adiponectin; Adult; Blood Glucose; Cardiovascular Diseases; Case-Control Studies; Cell Adhesion Molecules; Cytokines; Diabetes, Gestational; Disease Susceptibility; Female; Humans; Hyperglycemia; Inflammation; Leptin; Metabolic Syndrome; Postpartum Period; Prediabetic State; Pregnancy; Prospective Studies; Tumor Necrosis Factor-alpha; Young Adult

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

Parental history with obesity or diabetes will increase the risk for developing metabolic diseases in offspring. However, literatures as to transgenerational inheritance of metabolic dysfunctions through male lineage are relatively scarce. In the current study, we aimed to evaluate influences of paternal hyperglycemia on metabolic phenotypes in offspring. Male SD rats were i.p. injected with streptozotocin (STZ) or citrate buffer (CB, as control). STZ-injected rats with glucose levels higher than 16.7 mM were selected to breed with normal female rats. Offspring from STZ or CB treated fathers (STZ-O and CB-O) were maintained in the identical condition. We monitored body weight and food intake, and tests of glucose and insulin tolerance (GTTs and ITTs), fasting-refeeding and cold exposure were performed. Expression of factors involved in hypothalamic feeding and brown adipose tissue (BAT) thermogenic activity was performed by real-time PCR and Western blot. Adult STZ-O were heavier than CB-O. Impairment of GTTs was observed in STZ-O compared with CB-O at 22 and 32 weeks of age; ITTs results showed decreased insulin sensitivity in STZ-O. Daily food intake and accumulated food intake during 12-h refeeding after fasting were significantly higher in STZ-O. UCP1 levels were downregulated in BAT from STZ-O at room temperature and cold exposure. Finally, STZ-O rats showed suppressed leptin signaling in the hypothalamus as evidenced by upregulated SOCS3, reduced phosphorylation of STAT3, impaired processing POMC and decreased α-MSH production. Our study revealed that paternal hyperglycemia predisposes offspring to developing obesity, which is possibly associated with impaired hypothalamic leptin signaling.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; alpha-MSH; Animals; Diabetes Mellitus, Experimental; Epididymis; Female; Gene Expression Regulation; Hyperglycemia; Hyperphagia; Hypothalamus; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Signal Transduction

The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing β cells of the pancreas. Previous studies assessing the role of leptin receptors in β cells used Cre-. We used a mouse model in which endogenous expression of. Male and female. Collectively, these data suggest that direct action of leptin on β cells is insufficient to restore normal insulin secretion and glucose tolerance in mice without leptin receptor signaling elsewhere.

Topics: Animals; Cells, Cultured; Female; Hyperglycemia; Hyperinsulinism; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Inbred C57BL; Receptors, Leptin

Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and β cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.

Topics: Animals; Cell Proliferation; Dietary Supplements; Energy Metabolism; Fatty Liver; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Imidazoles; Insulin-Secreting Cells; Leptin; Lipodystrophy; Mice; Pyrazines; Safety-Based Drug Withdrawals; Time Factors; Tomography, X-Ray Computed

Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor-expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores.

Topics: Adipocytes; Animals; Behavior, Animal; Blood Glucose; Brain; Female; Glucose; Glucose Tolerance Test; Hyperglycemia; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pain; Phenotype; Proto-Oncogene Proteins c-fos; Receptors, Leptin; Sympathetic Nervous System

High fat-high sucrose (HF-HS) diet, known as the western diet, has been shown to induce the onset of obesity via increasing metabolic inflammation, insulin resistance and adipose tissue dysfunction. Hyperleptinemia, hyperglycemia and dyslipidemia are also the primary observations of obesogenic diet induced obesity. We have previously reported anti-adipogenic and insulin sensitizing effects of blue mussels (BM) using 3T3-L1 cells. BM is a rich source of omega-3 polyunsaturated fatty acids, phytosterols and other micronutrients that has been shown to elicit benefits under obese conditions using in-vitro cell culture models. However, no studies to date have established the anti-obesity effects, safety and efficacy of BM in an in-vivo animal model. In the present study, we fed a HF-HS diet supplemented with different concentrations of BM freeze-dried powder (1.25, 2.5 and 5% w/w) to C57BL/6 mice for 12weeks. A HF-HS diet caused rapid weight gain, hyperglycemia, dyslipidemia, hyperleptinemia, and increased plasma levels of inflammatory cytokines; interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Incorporating 2.5% BM in the HF-HS diet prevented weight gain, dyslipidemia, hyperglycemia and reduced the levels of inflammatory cytokines and leptin mRNA expression. Furthermore, plasma from 2.5% BM increased cholesterol efflux capacity of J774 macrophage cells, compared to plasma from HF-HS diet. There was no effect of 1.25% BM on any tested parameters, while 5% BM was not palatable after four weeks. In conclusion, our findings have established the efficacy and safety of BM using C57BL/6 mice, demonstrating that BM has the potential to target obesity and related complications.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Biomarkers; Cholesterol; Cytokines; Diet, High-Fat; Diet, Western; Dietary Sucrose; Dietary Supplements; Dyslipidemias; Hyperglycemia; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leptin; Macrophages; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Models, Animal; Mytilus edulis; Obesity; RNA, Messenger; Tumor Necrosis Factor-alpha; Weight Gain

Hyperglucagonemia is present in many forms of diabetes and contributes to hyperglycemia, and glucagon suppression can ameliorate diabetes in mice. Leptin, a glucagon suppressor, can also reverse diabetes in rodents. Lipid nanoparticle (LNP) delivery of small interfering RNA (siRNA) effectively targets the liver and is in clinical trials for the treatment of various diseases. We compared the effectiveness of glucagon receptor (Gcgr)-siRNA delivered via LNPs to leptin in two mouse models of diabetes.. Gcgr siRNA encapsulated into LNPs or leptin was administered to mice with diabetes due to injection of the β-cell toxin streptozotocin (STZ) alone or combined with high fat diet (HFD/STZ).. In STZ-diabetic mice, a single injection of Gcgr siRNA lowered blood glucose levels for 3 weeks, improved glucose tolerance, and normalized plasma ketones levels, while leptin therapy normalized blood glucose levels, oral glucose tolerance, and plasma ketones, and suppressed lipid metabolism. In contrast, in HFD/STZ-diabetic mice, Gcgr siRNA lowered blood glucose levels for 2 months, improved oral glucose tolerance, and reduced HbA1c, while leptin had no beneficial effects.. While leptin may be more effective than Gcgr siRNA at normalizing both glucose and lipid metabolism in STZ diabetes, Gcgr siRNA is more effective at reducing blood glucose levels in HFD/STZ diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucagon; Homeostasis; Hyperglycemia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Receptors, Glucagon; RNA, Small Interfering

The hypothalamic-pituitary-adrenal (HPA) axis has been postulated to play a major role in mediating the antidiabetic effects of leptin. We tested if the pituitary is essential for the chronic central nervous system mediated actions of leptin on metabolic and cardiovascular function in insulin-dependent diabetic and non-diabetic rats. Male 12-week-old hypophysectomized Sprague-Dawley rats (Hypo, n = 5) were instrumented with telemetry probes for determination of mean arterial pressure (MAP) and heart rate (HR) 24-hrs/day and an intracerebroventricular (ICV) cannula was placed into the brain lateral ventricle for continuous leptin infusion. In additional groups of Hypo and control rats (n = 5/group), diabetes was induced by single injection of streptozotocin (50 mg/kg, IP). Hypo rats were lighter, had lower MAP and HR (83±4 and 317±2 vs 105±4 mmHg and 339±4 bpm), with similar caloric intake per kilogram of body weight and fasting plasma glucose levels (84±4 vs 80±4 mg/dl) compared to controls. Chronic ICV leptin infusion (7 days, 0.62 μg/hr) in non-diabetic rats reduced caloric intake and body weight (-10%) in Hypo and control rats and markedly increased HR in control rats (~25 bpm) while causing only modest HR increases in Hypo rats (8 bpm). In diabetic Hypo and control rats, leptin infusion reduced caloric intake, body weight and glucose levels (323±74 to 99±20 and 374±27 to 108±10 mg/dl), respectively; however, the effects of leptin on HR were abolished in Hypo rats. These results indicate that hypophysectomy attenuates leptin's effect on HR regulation without altering leptin's ability to suppress appetite or normalize glucose levels in diabetes.

Topics: Animals; Blood Glucose; Blood Pressure; Bradycardia; Central Nervous System; Diabetes Mellitus, Experimental; Energy Intake; Heart Rate; Hyperglycemia; Hyperphagia; Hypophysectomy; Infusions, Intraventricular; Insulin; Leptin; Male; Pituitary Gland; Rats; Rats, Sprague-Dawley; Streptozocin

The phosphoinositide phosphatase, myotubularin-related protein 14 (MTMR14), has been reported to play an important role in the regulation of muscle performance, autophagy, and aging in mice. We previously showed that MTMR14-knockout (KO) mice gain weight earlier than their wild-type (WT) littermates even on a normal chow diet (NCD), suggesting that this gene might also be involved in regulating metabolism. In the present study, we evaluated the effect of MTMR14 deficiency on high-fat diet (HFD)-induced obesity, lipid accumulation, metabolic disorders, and inflammation in WT and MTMR14-KO mice fed with NCD or HFD. To this end, MTMR14-KO mice fed with HFD showed significantly increased body weight, blood glucose levels, serum triglyceride (TG) levels, and total cholesterol (TC) levels as compared to their age-matched WT control. Additionally, lipid accumulation also increased in the KO mice. Simultaneously, the expression of metabolism-associated genes (Glut4, adiponectin, and leptin) was different in the liver, muscle, and fatty tissue of MTMR14-KO mice fed with HFD. More importantly, the expression of several inflammation-associated genes (TNF-α, IL-6, IL-1β, and MCP-1) dramatically increased in the liver, muscle, and fatty tissue of MTMR14-KO mice relative to control. Taken together, these results suggest that MTMR14 deficiency accelerates HFD-induced metabolic dysfunction and inflammation. Furthermore, the results showed that exacerbated metabolic dysfunction and inflammation may be regulated via the PI3K/Akt and ERK signaling pathways.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Diet, High-Fat; Gene Expression Regulation; Glucose Transporter Type 4; Hyperglycemia; Hyperlipidemias; Leptin; Lipid Metabolism; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Obesity; Phosphoric Monoester Hydrolases; Random Allocation; Weight Gain

Insulin and IGF1 signaling are important for adipose tissue development and function; however, their role in mature adipocytes is unclear. Mice with a tamoxifen-inducible knockout of insulin and/or IGF1 receptors (IR/IGF1R) demonstrate a rapid loss of white and brown fat due to increased lipolysis and adipocyte apoptosis. This results in insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia, and cold intolerance. This phenotype, however, resolves over 10-30 days due to a proliferation of preadipocytes and rapid regeneration of both brown and white adipocytes as identified by mTmG lineage tracing. This cycle can be repeated with a second round of receptor inactivation. Leptin administration prior to tamoxifen treatment blocks development of the metabolic syndrome without affecting adipocyte loss or regeneration. Thus, IR is critical in adipocyte maintenance, and this loss of adipose tissue stimulates regeneration of brown/white fat and reversal of metabolic syndrome associated with fat loss.

Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Cell Differentiation; Cell Proliferation; Fatty Liver; Gene Deletion; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Lipodystrophy; Metabolic Syndrome; Mice; Organ Specificity; Receptor, IGF Type 1; Receptor, Insulin; Regeneration; Tamoxifen

Cinnamon has a history of use for medicinal purposes and its major benefits have been linked to cinnamaldehyde. The present study aimed to investigate the hypoglycemic action of cinnamaldehyde against fatty-sucrosed diet/streptozotocin (FSD/STZ)-rat model of gestational diabetes. Female albino rats were divided into three groups. Group I fed with normal diet (ND) while group II and III were fed with FSD for eight weeks (five weeks pre-gestational and three weeks gestational). Rats of group III were administered with a daily oral dose of 20mg/kg cinnamaldehyde one week before mating onward. At the 7th day of gestation, FSD-fed rats were injected intraperitoneally with STZ (25mg/kg b.wt.) to induce gestational diabetes. Pre-mating treatment of cinnamaldehyde controls hyperphagia and glucose intolerance during the gestational period than in diabetic rats. It also reduced levels of fructosamine, total cholesterols, triglycerides, leptin, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and nitric oxide (NO), while it significantly increased levels of high-density lipoprotein (HDL)-cholesterol, adiponectin, liver glycogen, reduced glutathione (GSH) and catalase activity at term pregnancy. In addition, cinnamaldehyde administration up-regulated the mRNA expression of peroxisome proliferated activated receptor-gamma (PPARγ) and also ameliorated the number of viable fetuses, implantation loss sites, fetal glucose and insulin levels. In conclusion, cinnamaldehyde has safe hypoglycemic action on gestational diabetes by potentiating insulin secretion and sensitivity through activating the antioxidant defense system, suppressing pro-inflammatory cytokines production, upregulating PPARγ gene expression and alleviating the reproductive performance.

Topics: Acrolein; Adipose Tissue; Animals; Antioxidants; Biomarkers; Blood Glucose; Body Weight; Cholesterol; Cytokines; Diabetes, Gestational; Feeding Behavior; Female; Fetus; Fructosamine; Glucose Tolerance Test; Glycogen; Hyperglycemia; Inflammation Mediators; Insulin; Leptin; Liver; Oxidative Stress; PPAR gamma; Pregnancy; Pregnancy Outcome; Rats; RNA, Messenger; Triglycerides

Modified Lingguizhugan Decoction (MLD) came from famous Chinese medicine Linggui Zhugan Decoction. The MLD is used for the treatment of metabolic syndrome in the clinical setting. Our study focuses on the comprehensive treatment of MLD incorporated with dietary restriction and exercise in a rat model of the metabolic syndrome (MS).. Rats were divided into five groups: control group (Cont), high-fat diet group (HFD), high-fat diet incorporated with dietary restriction group (HFD-DR), exercise incorporated with dietary restriction group (HFD-DR-Ex) and MLD incorporated with dietary restriction and exercise group (HFD-DR-Ex-MLD). Treatments were conducted for 1 week after feeding high-fat diet for 12 weeks. The effects of treatments on high fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance in rats of MS were examined. In addition, the tumor necrosis factor-α (TNF-α), leptin and protein kinase B (PKB) in rats serum and liver were also examined by enzyme-linked immunosorbent assay (ELISA).. After a week's intervention by dietary restriction, dietary restriction incorporated with exercise or MLD, compared with HFD rats, the relative weight of liver and fat, levels of triglyceride, total cholesterol, low-density lipoprotein, free fatty acid, aspartate aminotransferase, glutamic-pyruvic transaminase and alkaline phosphatase, insulin, were significantly decreased (p < 0.05 or 0.01). This treatment also inhibited abnormal increases of TNF-α, leptin and PKB in serum and liver.. MLD incorporated with dietary restriction and exercise treatment exhibit effects in alleviating high-fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance, which are possibly due to the down-regulation of TNF-α, leptin and PKB.

Topics: Adipose Tissue; Animals; Blood Pressure; Caloric Restriction; Drugs, Chinese Herbal; Hyperglycemia; Hyperlipidemias; Hypertension; Insulin; Leptin; Lipids; Liver; Magnoliopsida; Male; Metabolic Syndrome; Obesity; Physical Conditioning, Animal; Phytotherapy; Poria; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Obesity, diabetes and fatty liver disease are extremely common in leptin-resistant patients. Dysfunction of leptin or its receptor is associated with obesity. The present study aimed to assess the effects of intramuscular injection of exogenous leptin or its receptor on fat deposition and leptin-insulin feedback regulation. Forty-five 40-day old female Sprague Dawley (SD) rats were injected thrice with leptin or its receptor intramuscularly. Adiposity and fat deposition were assessed by assessing the Lee's index, body weight, food intake, and total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride levels, as well as histological properties (liver and adipose tissue). Serum glucose, leptin, and insulin amounts were evaluated, and glucose tolerance assessed to monitor glucose metabolism in SD rats; pancreas specimens were analyzed immunohistochemically. Hypothalamic phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphatidylinositol-3-kinase (PI3K) signaling, and hepatic sterol regulatory element binding protein-1 (SREBP-1) were qualified by Western blotting. Leptin receptor immunogen reduced fat deposition, increased appetite, and lowered serum leptin levels, enhancing STAT3 signaling in hypothalamus and down-regulating hepatic SREBP-1. In contrast, SD rats administered leptin immunogen displayed significantly increased body weight and fat deposition, with up-regulated SREBP-1, indicating adiposity occurrence. SD rats administered leptin immunogen also showed glucose intolerance, β- cell reduction in the pancreas, and deregulation of JAK2-STAT3/PI3K signaling, indicating that Lep rats were at risk of diabetes. In conclusion, intramuscular injection of exogenous leptin or its receptor, a novel rat model approach, can be used in obesity pathogenesis and therapeutic studies.

Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Disease Models, Animal; Eating; Fatty Liver; Female; Glucose Intolerance; Hyperglycemia; Immunity; Injections, Intramuscular; Insulin; Insulin-Secreting Cells; Janus Kinase 2; Leptin; Lipids; Liver; Phosphatidylinositol 3-Kinase; Phosphorylation; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Sterol Regulatory Element Binding Protein 1

Consumption of sugar-sweetened beverages promotes the development of metabolic syndrome (MetS) and type 2 diabetes mellitus in humans. One factor related to the appearance of MetS components is the dysfunction of the adrenal gland. In fact, the experimental generation of hyperglycemia has been associated with morphological and microvascular changes in the adrenal glands of rats. We hypothesized that high sucrose consumption from infancy promotes histological disruption of the adrenal glands associated with the appearance of metabolic syndrome indicators. Male Wistar rats were separated at weaning (21 days old) into two groups: free access to tap water (control group, C) or 30 % sucrose diluted in water (sugar-fed group). After 12 weeks, high sucrose consumption promoted an increase in visceral fat accumulation, adipose cell number, and insulin resistance. Also, a rise in the concentration of triglycerides, very low-density lipoprotein, insulin and leptin was observed. In control rats, a histomorphometric asymmetry between the right and left adrenal glands was found. In the sugar-fed group, sucrose consumption produced a major change in adrenal gland asymmetry. No changes in corticosterone serum level were observed in either group. Our results suggest that a high sucrose liquid-diet from early life alters the morphology of adrenocortical zones, leading to MetS indicators.

Topics: Adrenal Glands; Age Factors; Animals; Dietary Sucrose; Hyperglycemia; Insulin; Intra-Abdominal Fat; Leptin; Male; Metabolic Syndrome; Microvessels; Rats; Rats, Wistar; Triglycerides

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Lamin Type A; Leptin; Lipodystrophy; Male; Mutation; Syndrome; Triglycerides

Leptin can reverse hyperglycemia in rodent models of type 1 diabetes. However, these models have used chemical or immune mediated β-cell destruction where insulin depletion is incomplete. Thus it is unknown which actions of leptin are entirely insulin independent, versus those which require insulin. To directly assess this we maximized blockage of insulin action using an insulin receptor antagonist in combination with streptozotocin-diabetic mice; leptin treatment was still able to reduce blood glucose. Next, we leptin-treated adult insulin knockout (InsKO) mice. Remarkably, leptin-treated InsKO mice were viable for up to 3 weeks without insulin therapy. Leptin treatment reduced plasma corticosterone, glucagon, β-hydroxybutyrate, triglycerides, cholesterol, fatty acids and glycerol. However, leptin-treated InsKO mice exhibited overt fed hyperglycemia and severe fasting hypoglycemia. Therefore, leptin can normalize many metabolic parameters in the complete absence of insulin, but blood glucose levels are volatile and the length of survival finite.

Topics: 3-Hydroxybutyric Acid; Animals; Blood Glucose; Cholesterol; Corticosterone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fatty Acids; Glucagon; Glycerol; Hyperglycemia; Hypoglycemia; Insulin; Leptin; Mice; Mice, Knockout; Peptides; Receptor, Insulin; Triglycerides

Adipokines have many homeostatic roles, including modulation of glucose metabolism, but their role in the pathophysiology of hyperglycemia associated with acute and critical illnesses in general, and acute pancreatitis (AP) in particular, is largely unknown. This study aimed to investigate the relationship between a panel of adipokines and hyperglycemia in the early course of AP, as well as the role of adipokines as predictors of AP severity.Adiponectin, leptin, omentin, resistin, and visfatin were measured on a daily basis in the first 72 hours after hospital admission. A first set of analyses was undertaken with admission glycemia stratified by severity, and a second set of analyses was undertaken based on persistence of early hyperglycemia. All of the analyses were adjusted for confounders.A total of 32 patients with AP were included in this study. None of the studied adipokines was significantly associated with glucose level on admission. Leptin was significantly (P = 0.003) increased in patients with persistent hyperglycemia. Adiponectin was significantly associated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score in patients with persistent hyperglycemia (P = 0.015), visfatin with APACHE II score in patients with persistent hyperglycemia (P = 0.014), and omentin with APACHE II score in all of the patients regardless of the presence or absence of hyperglycemia (P = 0.021).Leptin is significantly associated with persistent hyperglycemia in the early course of AP. Omentin has a potential to become an accurate predictor of AP severity.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Humans; Hyperglycemia; Leptin; Male; Middle Aged; Pancreatitis; Prospective Studies; Severity of Illness Index; Young Adult

The aim of this study was to assay the effects of Coreopsis tinctoria Nutt. flower extracts on hyperglycemia of diet-induced obese mice and the underlying mechanisms. Coreopsis tinctoria flower was extracted with ethanol and water, respectively. The total phenol, flavonoid levels, and the constituents of the extracts were measured. For the animal experiments, C57BL/6 mice were fed with a chow diet, high-fat diet, or high-fat diet mixed with 0.4% (w/w) water and ethanol extracts of Coreopsis tinctoria flower for 8 weeks. The inhibitory effects of the extracts on α-glucosidase activity and the antioxidant properties were assayed in vitro. We found that the extracts blocked the increase of fasting blood glucose, serum triglyceride (TG), insulin, leptin, and liver lipid levels and prevented the development of glucose tolerance impairment and insulin resistance in the C57BL/6 mice induced by a high-fat diet. The extracts inhibited α-glycosidase activity and increased oxidant activity in vitro. In conclusion, Coreopsis tinctoria flower extracts may ameliorate high-fat diet-induced hyperglycemia and insulin resistance. The underling mechanism may be via the inhibition of α-glucosidase activity. Our data indicate that Coreopsis tinctoria flower could be used as a beverage supplement and a potential source of drugs for treatment of diabetics.

Topics: Animals; Biomarkers; Blood Glucose; Coreopsis; Diet, High-Fat; Disease Models, Animal; Ethanol; Female; Flowers; Glycoside Hydrolase Inhibitors; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Mice, Inbred C57BL; Obesity; Phytotherapy; Plant Extracts; Plants, Medicinal; Solvents; Time Factors; Water

Salidroside is a functionally versatile natural compound from the perennial flowering plant Rhodiola rosea L. Here, we examined obese mice treated with salidroside at the dosage of 50 mg/kg/day for 48 days. Mice treated with salidroside showed slightly decreased food intake, body weight and hepatic triglyceride content. Importantly, salidroside treatment significantly improved glucose and insulin tolerance. It also increased insulin singling in both liver and epididymal white adipose tissue (eWAT). In addition, salidroside markedly ameliorated hyperglycemia in treated mice, which is likely due to the suppression of gluconeogenesis by salidroside as the protein levels of a gluconeogenic enzyme G6Pase and a co-activator PGC-1α were all markedly decreased. Further analysis revealed that adipogenesis in eWAT was significantly decreased in salidroside treated mice. The infiltration of macrophages in eWAT and the productions of pro-inflammatory cytokines were also markedly suppressed by salidroside. Furthermore, the leptin signal transduction in hypothalamus was improved by salidroside. Taken together, these euglycemic effects of salidroside may due to repression of adipogenesis and inflammation in eWAT and stimulation of leptin signal transduction in hypothalamus. Thus, salidroside might be used as an effective anti-diabetic agent.

Topics: Adipose Tissue, White; Animals; Body Weight; Eating; Epididymis; Glucose-6-Phosphatase; Glucosides; Hyperglycemia; Hypothalamus; Inflammation; Leptin; Liver; Male; Mice; Mice, Obese; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phenols; Triglycerides

To determine the roles of insulin and insulin-like growth factor 1 (IGF-1) action in adipose tissue, we created mice lacking the insulin receptor (IR), IGF-1 receptor (IGF1R), or both using Cre-recombinase driven by the adiponectin promoter. Mice lacking IGF1R only (F-IGFRKO) had a ∼25% reduction in white adipose tissue (WAT) and brown adipose tissue (BAT), whereas mice lacking both IR and IGF1R (F-IR/IGFRKO) showed an almost complete absence of WAT and BAT. Interestingly, mice lacking only the IR (F-IRKO) had a 95% reduction in WAT, but a paradoxical 50% increase in BAT with accumulation of large unilocular lipid droplets. Both F-IRKO and F-IR/IGFRKO mice were unable to maintain body temperature in the cold and developed severe diabetes, ectopic lipid accumulation in liver and muscle, and pancreatic islet hyperplasia. Leptin treatment normalized blood glucose levels in both groups. Glucose levels also improved spontaneously by 1 year of age, despite sustained lipodystrophy and insulin resistance. Thus, loss of IR is sufficient to disrupt white fat formation, but not brown fat formation and/or maintenance, although it is required for normal BAT function and temperature homeostasis. IGF1R has only a modest contribution to both WAT and BAT formation and function.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Hyperglycemia; Hyperlipidemias; In Vitro Techniques; Insulin; Insulin-Secreting Cells; Leptin; Lipodystrophy; Mice; Mice, Knockout; Oxygen Consumption; Radioimmunoprecipitation Assay; Receptor, IGF Type 1; Receptor, Insulin; Succinate Dehydrogenase

The present study was planned to assess IGF-1, leptin and cholinesterase levels in maternal blood of both normoglycaemics and hyperglycaemics preeclampsia. Twenty five normotensive pregnant women at the time of delivery were selected in as group I and sub grouped according to blood glucose less than or more than 85 mg/dL as I A (<85mg/dL) and I B (>85mg/dL). Study group (group II, n=25) comprised of preeclamptic women and was further divided into group II A (<85mg/dL) and group II B (>85mg/dL). Routine biochemical investigations along with IGF-1, leptin and cholinesterase levels were analyzed in maternal and cord blood of preeclamptic and normotensive pregnant women. Serum IGF-1 levels were significantly lower in preeclamptic women and more so in those with hyperglycemia. Cord blood IGF-1 levels were nearly doubled in hyperglycemic preeclamptics as compared to normoglycemic preeclamptics. Leptin levels were higher in preeclamptic women and more in hyperglycemic preeclamptics. Cholinesterase levels were lowered in preeclamptic mothers and higher in hyperglycemics. Cord blood cholinesterase levels were reduced in preeclamptics, more so in hyperglycaemics as compared to group I. Diet recommendation, avoidance of excessive weight gain and healthy life style, exercise and nutritional interventions may be beneficial in these women.

Topics: Biomarkers; Blood Glucose; Cholinesterases; Diet; Female; Fetal Blood; Humans; Hyperglycemia; Insulin-Like Growth Factor I; Leptin; Life Style; Pre-Eclampsia; Pregnancy

Manilkara zapota is a tropical evergreen tree belonging to the Sapotaceae family; its parts are used in alternative medicine to treat coughs and colds and possess diuretic, antidiarrheal, antibiotic, antihyperglycemic, and hypocholesterolemic effects. There are no studies on metabolic profile after using the fruit, and this study aimed at evaluating the effects of the leaf and pulp of M. zapota fruit on the metabolic profile of Wistar rats. Male rats were treated for 50 days with M. zapota leaf juice or fruit juice, after which their biochemical and body composition profiles were analyzed (glycemia, triglycerides, high-density lipoprotein cholesterol (HDL-c), insulin, leptin, aspartate transaminase, alanine aminotransferase, Lee Index, and body mass index). Our results indicate significantly lower levels of glycemia, insulin, leptin, cholesterol, and triglycerides and augmented levels of HDL-c in animals treated with the leaves or fruit of this plant. The percentage of weight gain also declined in animals treated with M. zapota fruit pulp. The use of the M. zapota may be helpful in the prevention of obesity, diabetes, dyslipidemia, and their complications.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dyslipidemias; Fruit; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Leptin; Lipids; Male; Manilkara; Metabolome; Obesity; Phytotherapy; Plant Extracts; Plant Leaves; Rats, Wistar; Weight Gain

The aim of this study was to evaluate the effects of maternal obesity on pancreas structure and carbohydrate metabolism in early adult life, focusing on the F1 and F2 generations after F0 maternal pregestational, gestation, and lactation high-fat diet (HF).. C57 BL/6 female mice (F0) were fed standard chow (SC) or an HF diet for 8 wk before mating and during the gestation and lactation periods to provide the F1 generation (F1-SC and F1-HF). At 3 mo old, F1 females were mated to produce the F2 generation (F2-SC and F2-HF). The male offspring from all groups were evaluated at 3 mo old.. F0-HF and F1-HF dams were overweight before gestation and had a higher body mass gain and energy intake during gestation, although only F0-HF dams presented pregestational hyperglycemia. The F1-HF offspring had higher body mass, energy intake, fasting glucose levels, and were glucose intolerant compared with F1-SC offspring. These parameters were not significantly altered in F2-HF offspring. Both F1-HF and F2-HF offspring showed hyperinsulinemia, hyperleptinemia, decreased adiponectin levels, increased pancreatic mass, and islet volume density with elevated α- and β-cell mass, hypertrophied islet characterized by an altered distribution of α- and β-cells and weak pancreatic-duodenal homeobox (Pdx)1 immunoreactivity.. Maternal HF diet consumed during the preconception period and throughout the gestation and lactation periods in mice promotes metabolism and pancreatic programming in F1 and F2 male offspring, implying intergenerational effects.

Topics: Adiponectin; Animals; Blood Glucose; Body Mass Index; Diet, High-Fat; Disease Models, Animal; Energy Intake; Female; Hyperglycemia; Hyperinsulinism; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Lactation; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

Rats fed with high-fat-high-sucrose (HFHS) diet are known to manifest metabolic syndrome including hyperinsulinemia, hyperleptinemia, hyperglycemia, diabetic dyslipidemia, and hepatic steatosis. The aim of the current study is to determine the temporal relationships between the development of hepatic steatosis and the onset of insulin and leptin resistance in hypothalamus and liver in male Wistar rats (six weeks of age) fed chow or HFHS diet for up to 8 weeks. Fasting plasma glucose, lipids/lipoproteins, insulin and leptin levels were quantified, histopathologic score of hepatic steatosis and inflammation were assessed, and the responses of common checkpoints of insulin and leptin signalling responsible for lipogenesis and gluconeogenesis were analyzed. In addition, acute insulin or leptin administration was performed at different stages of HFHS dieting to determine the responsiveness of the respective signalling pathways. Hyperinsulinemia, hyperglycemia, dyslipidemia, and increased homeostasis model assessment of basal insulin resistance occurred 1-week after HFHS dieting, coinciding with upregulation of suppressor of cytokine signalling 3 in both hypothalamus and liver. However, hepatosteatosis, accompanied with increased expression of sterol regulatory element binding protein 1c and phosphoenolpyruvate carboxykinase, did not manifest until 4- to 8-week after HFHS dieting. Lowered insulin sensitivity (shown by decreased insulin receptor substrate 1 and protein kinase B phosphorylation) occurred approximately 2 weeks prior to leptin resistance (shown by impaired signal transducer and activator of transcription 3 activation) in both the liver and hypothalamus. Acute insulin/leptin administration also demonstrated the impaired insulin or leptin signalling transduction. These data suggest that lowered insulin sensitivity and leptin resistance occurred at least 2-3 weeks earlier than the manifestation of hepatosteatosis in rats fed HFHS diet.

Topics: Animals; Blood Glucose; Diet, High-Fat; Dietary Sucrose; Dyslipidemias; Fatty Liver; Hyperglycemia; Hyperinsulinism; Hypothalamus; Inflammation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Lipoproteins; Liver; Male; Rats, Wistar

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (β = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 × 10(-11); N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (β = -0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (β = -0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

Topics: Adult; Cohort Studies; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation; Glucose; Humans; Hyperglycemia; Infant, Newborn; Leptin; Male; Maternal-Fetal Exchange; Mendelian Randomization Analysis; Pregnancy

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

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

Leptin receptor, which is encoded by the diabetes (db) gene and is highly expressed in the choroid plexus, regulatesenergy homeostasis, the balance between food intake and energy expenditure, fertility and bone mass. Here, using CRISPR/Cas9 technology, we created the leptin receptor knockout rat. Homozygous leptin receptor null rats are characterized by obesity, hyperphagia, hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Due to long-term poor glycemic control, the leptin receptor knockout rats also develop some diabetic complications such as pancreatic, hepatic and renal lesions. In addition, the leptin receptor knockout rats show a significant decrease in bone volume and bone mineral density of the femur compared with their wild-type littermates. Our model has rescued some deficiency of the existing rodent models, such as the transient hyperglycemia of db/db mice in the C57BL/6J genetic background and the delayed onset of glucose intolerance in the Zucker rats, and it is proven to be a useful animal model for biomedical and pharmacological research on obesity and diabetes.

Topics: Animals; Blood Glucose; Bone Density; Clustered Regularly Interspaced Short Palindromic Repeats; Dyslipidemias; Femur; Gene Knockout Techniques; Glucose Intolerance; Homeostasis; Hyperglycemia; Hyperphagia; Leptin; Models, Animal; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Leptin

In the present study, we investigated whether maternal exposure to a cafeteria diet affects the metabolism and body composition of offspring and whether such an exposure has a cumulative effect during the lifetime of the offspring. Female rats were fed a control (CON) or a cafeteria (CAF) diet from their own weaning to the weaning of their offspring. At 21 d of age, male offspring were divided into four groups by diet during gestation and after weaning (CON-CON, CON-CAF, CAF-CON and CAF-CAF). Blood was collected from dams (after weaning) and pups (at 30 and 120 d of age) by decapitation. CAF dams had significantly greater body weight and adipose tissue weight and higher concentrations of total cholesterol, insulin and leptin than CON dams (Student's t test). The energy intake of CAF rats was higher than that of CON rats regardless of the maternal diet (two-way ANOVA). Litters had similar body weights at weaning and at 30 d of age, but at 120 d, CON-CAF rats were heavier. At both ages, CAF rats had greater adipose tissue weight than CON rats regardless of the maternal diet, and the concentrations of TAG and cholesterol were similar between the two groups, as were blood glucose concentrations at 30 d of age. However, at 120 d of age, CAF rats were hyperglycaemic, hyperinsulinaemic and hyperleptinaemic regardless of the maternal diet. These findings suggest that maternal obesity does not modulate the metabolism of male offspring independently, modifying body weight only when associated with the intake of a cafeteria diet by the offspring.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Female; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Metabolic Diseases; Obesity; Pregnancy; Pregnancy Complications; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Wistar; Triglycerides; Weaning

This study sought to determine the role of white adipose tissue (WAT) metabolism in the prevention of insulin resistance (IR) by physical training (PT).. Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n=15), CHOW-TR (chow diet, trained; n=18), CAF-SED (cafeteria diet, sedentary; n=15) and CAF-TR (cafeteria diet, trained; n=18). PT consisted of running sessions of 60 min at 60% of maximal speed conducted five days per week for eight weeks.. PT prevented body weight and fat mass accretion in trained groups and prevented hyperglycemia, hyperinsulinemia, glucose intolerance and IR in the CAF-TR. The CAF-SED group presented higher leptin and free fatty acid and lower adiponectin serum levels compared with other groups. Lipolytic activity (in mmol/10(6) adipose cells) stimulated by isoproterenol increased in CHOW-TR (16347±3005), CAF-SED (18110±3788) and CAF-TR (15837±2845) compared with CHOW-SED (8377±2284). The CAF-SED group reduced FAS activity compared with CHOW-SED and CHOW-TR, reduced citrate synthase activity and increased DGAT2 content compared with other groups. Both trained groups reduced G6PDH activity and increased the expression of p-AMPK (Thr172) compared with sedentary groups. CAF-SED group had lower levels of AMPK, p-AMPK (Thr172), ACC and p-ACC (Ser79) compared with other groups.. The prevention of IR by PT is mediated by adaptations in WAT metabolism by improving lipolysis, preventing an increase in enzymes responsible for fatty acid esterification and by activating enzymes that improve fat oxidation instead of fat storage.

Topics: Adipocytes; Adiponectin; Adipose Tissue, White; Adiposity; Animals; Fatty Acids, Nonesterified; Glucose Intolerance; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Isoproterenol; Leptin; Lipolysis; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Physical Conditioning, Animal; Physical Exertion; Weight Gain

Pantothenate kinase (PANK) is the first enzyme in CoA biosynthesis. Pank1-deficient mice have 40% lower liver CoA and fasting hypoglycaemia, which results from reduced gluconeogenesis. Single-nucleotide polymorphisms in the human PANK1 gene are associated with insulin levels, suggesting a link between CoA and insulin homeostasis. We determined whether Pank1 deficiency (1) modified insulin levels, (2) ameliorated hyperglycaemia and hyperinsulinaemia, and (3) improved acute glucose and insulin tolerance of leptin (Lep)-deficient mice.. Serum insulin and responses to glucose and insulin tolerance tests were determined in Pank1-deficient mice. Levels of CoA and regulating enzymes were measured in liver and skeletal muscle of Lep-deficient mice. Double Pank1/Lep-deficient mice were analysed for the diabetes-related phenotype and global metabolism.. Pank1-deficient mice had lower serum insulin and improved glucose tolerance and insulin sensitivity compared with wild-type mice. Hepatic and muscle CoA was abnormally high in Lep-deficient mice. Pank1 deletion reduced hepatic CoA but not muscle CoA, reduced serum glucose and insulin, but did not normalise body weight or improve acute glucose tolerance or protein kinase B phosphorylation in Lep-deficient animals. Pank1/Lep double-deficient mice exhibited reduced whole-body metabolism of fatty acids and amino acids and had a greater reliance on carbohydrate use for energy production.. The results indicate that Pank1 deficiency drives a whole-body metabolic adaptation that improves aspects of the diabetic phenotype and uncouples hyperglycaemia and hyperinsulinaemia from obesity in leptin-deficient mice.

Topics: Animals; Energy Metabolism; Glucose; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Liver; Male; Mice; Obesity; Phosphotransferases (Alcohol Group Acceptor)

Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The aim of the present study was to investigate the effects of chronic HF diet feeding on exocrine pancreatic digestive enzyme transcript levels in DIO C57BL/6J mice. C57BL/6J mice were fed diets containing either 10 or 45% energy (E%) derived from fat for 12 weeks (n 10 mice per diet group). Pancreatic tissue and blood samples were collected at 0, 4 and 12 weeks. The expression of a panel of exocrine pancreatic digestive enzymes was analysed using quantitative RT-PCR and Western blot analysis. The HF (45 E%) diet-fed C57BL/6J mice developed obesity, hyperleptinaemia, hyperglycaemia and hyperinsulinaemia. The transcript levels of pancreatic lipase (PL), pancreatic lipase-related protein 2 (PLRP2) and pancreatic phospholipase A2 (PLA2) were initially elevated; however, they were down-regulated to basal control levels at week 12. The transcript levels of colipase were significantly affected by diet and time. The protein levels of PL and PLRP2 responded to HF diet feeding. The transcript levels of amylase and proteases were not significantly affected by diet and time. The transcript levels of specific lipases in hyperinsulinaemic, hyperleptinaemic and hyperglycaemic DIO C57BL/6J mice are down-regulated. However, these mice compensate for this by the post-transcriptional regulation of the levels of proteins that respond to dietary fat. This suggests a complex regulatory mechanism involved in the modulation of fat digestion.

Topics: Animals; Colipases; Diet, High-Fat; Gene Expression Regulation, Enzymologic; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Lipase; Male; Mice; Mice, Inbred C57BL; Obesity; Pancreas, Exocrine; Phospholipases A2, Secretory; Protein Processing, Post-Translational; Random Allocation; RNA Processing, Post-Transcriptional; RNA, Messenger

Metabolic syndrome (MetS) correlates with systemic inflammation. A relation of MetS to periodontitis has been reported. This study aims to evaluate whether periodontitis is associated with untreated MetS, plasma adiponectin, and leptin among Thai people.. One hundred twenty-five participants (aged 35 to 76 years) were recruited. Demographic and biologic data, bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL) of all teeth were examined. Plasma adiponectin and leptin levels were measured.. Forty-four participants (35.2%) were healthy, and 81 (64.8%) had MetS. All periodontal conditions (BOP, PD, and CAL) were significantly worse in patients with MetS than healthy participants. After adjustment for confounders, MetS was strongly associated with severe periodontitis (odds ratio [OR] = 3.60, 95% confidence interval [CI]: 1.34 to 9.65). MetS with four to five components had a higher association with periodontitis than did MetS with three components (OR = 5.49, 95% CI: 1.75 to 17.19), whereas each separate component had no association with periodontitis, except for high diastolic blood pressure. Periodontitis was also associated with age (OR = 1.08, 95% CI: 1.01 to 1.14) and education (OR = 3.76, 95% CI: 1.05 to 13.40). The risk of MetS was predicted by body mass index and plasma adiponectin (OR = 1.90, 95% CI: 1.24 to 2.92 and OR = 0.93, 95% CI: 0.88 to 0.98, respectively).. There may be a relationship between untreated MetS and periodontitis in Thai people. Periodontal diagnosis should be regularly conducted in patients with MetS.

Topics: Adiponectin; Adult; Age Factors; Aged; Blood Pressure; Body Mass Index; Diabetes Complications; Educational Status; Female; Humans; Hyperglycemia; Hypertension; Hypertriglyceridemia; Hypoalphalipoproteinemias; Leptin; Male; Metabolic Syndrome; Middle Aged; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Thailand; Waist Circumference

High fat programming, by exposure to a high saturated fat diet during fetal and/or lactational life induces metabolic derangements and alters islet cell architecture in neonate and weanling rats.. The present study assessed metabolic changes and islet cell dynamics in response to high fat maintenance during specific developmental periods in adolescent rats, with some parameters also studied in neonate and weanling rats.. The experimental groups comprised neonates, weanlings and adolescents maintained on a high fat diet during specific periods of fetal, lactational and/or postnatal life. Control neonates, weanlings and adolescents were maintained on a standard laboratory (control or low fat) diet. Fetal high fat programmed (i.e., maintained on a high fat diet exclusively during fetal life) neonates were insulin resistant.. Weanlings maintained on a high fat diet throughout fetal and lactational life had increased pancreas weights. Fetal high fat programmed adolescents presented a normal phenotype mimicking the control adolescents. Adolescents maintained on a postnatal high fat diet had increased body weights, hyperglycemia, hyperinsulinemia, hyperleptinemia and insulin resistance displaying beta cell hypertrophy and increased islet cell proliferation. Adolescents maintained on a fetal and postnatal high fat diet had increased body weights, hyperleptinemia, hyperinsulinemia and insulin resistance.. High fat programming induces various diabetogenic phenotypes which present at different life stages. The postnatal period from birth to adolescence represents an extension for high fat programming of metabolic disease.

Topics: Acinar Cells; Age Factors; Animals; Animals, Newborn; Animals, Suckling; Blood Glucose; Cell Proliferation; Dietary Fats; Fatty Acids; Female; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Insulin-Secreting Cells; Lactation; Leptin; Organ Size; Prediabetic State; Pregnancy; Rats, Wistar; Weaning

Increased leptin levels have been suggested to contribute to cardiac hypertrophy and attenuate cardiac lipid accumulation in obesity, although it has been difficult to separate leptin's direct effects from those caused by changes in body weight and adiposity. To determine whether leptin attenuates cardiac lipid accumulation in obesity or directly causes left ventricular hypertrophy (LVH), we generated a novel mouse model in which the long form of the leptin receptor (LepR) was "rescued" only in cardiomyocytes of obese db/db mice. Reexpression of cardiomyocyte leptin receptors in db/db mice did not cause LVH but reduced cardiac triglycerides and improved cardiac function. Compared with lean wild-type (WT) or db/db-cardiac LepR rescue mice, db/db mice exhibited significantly lower E/A ratio, a measurement of early to late diastolic filling, which averaged 1.5 ± 0.07 in db/db vs. 1.9 ± 0.08 and 1.8 ± 0.11 in WT and db/db-cardiac LepR rescue mice, respectively. No differences in systolic function were observed. Although db/db and db/db-cardiac LepR rescue mice exhibited similar increases in plasma triglycerides, insulin, glucose, and body weight, cardiac triglycerides were significantly higher in db/db compared with WT and db/db cardiac LepR rescue mice, averaging 13.4 ± 4.2 vs. 3.8 ± 1.6 vs. 3.8 ± 0.7 mg/g, respectively. These results demonstrate that despite significant obesity and increases in plasma glucose and triglycerides, db/db cardiac LepR rescue mice are protected against myocardial lipid accumulation. However, we found no evidence that leptin directly causes LVH.

Topics: Animals; Crosses, Genetic; Heart Ventricles; Heterozygote; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Hypertrophy, Left Ventricular; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Myocardium; Obesity; Receptors, Leptin; Recombinant Proteins; Signal Transduction; Triglycerides

The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lep(ob/ob);Fto(-/-)). Lep(ob/ob);Fto(-/-) mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lep(ob/ob);Fto(-/-) mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lep(ob/ob);Fto(-/-)mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents.

Topics: Adipose Tissue; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Body Weight; Disease Models, Animal; Fatty Liver; Female; Genetic Predisposition to Disease; Hepatocytes; Hyperglycemia; Islets of Langerhans; Leptin; Lipid Metabolism; Male; Metabolic Syndrome; Mice; Mice, Knockout; Mixed Function Oxygenases; Oxo-Acid-Lyases

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

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

Topics: Animals; Animals, Newborn; Blood Glucose; Cell Proliferation; Diabetes, Gestational; Disease Models, Animal; Female; Glucagon; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Organ Size; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Weight Gain

This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic β-cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice.

Topics: Adiponectin; Adiposity; Animals; Biomarkers; Blood Glucose; Cyclooctanes; Diabetes Mellitus, Experimental; Fatty Liver; Fruit; Glycated Hemoglobin; Hyperglycemia; Insulin; Leptin; Lignans; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Plant Extracts; Polycyclic Compounds; Resistin; Resveratrol; Schisandra; Stilbenes; Vitis

We showed that early weaned rats developed obesity, hyperleptinemia, leptin and insulin resistance at adulthood. Here, we studied the potential beneficial effects of Ilex paraguariensis aqueous solution upon body composition, glycemia, lipid and hormonal profiles, leptin signaling and NPY content.. To induce early weaning, lactating rats' teats were blocked with a bandage to interrupt lactation during the last 3 days (EW group), while control offspring had free access to milk throughout lactation (C group). In postnatal day (PN) 150, EW offspring were subdivided into: EW and EW+ mate groups treated, respectively, with water or yerba mate aqueous solution (1 g/kg BW/day, gavage) during 30 days. C offspring received water for gavage. In PN180, offspring were killed.. EW+ mate group presented lower body weight (-10 %), adipose mass (retroperitoneal:-40 % and epididymal:-44 %), total body fat (-43 %), subcutaneous fat (-46 %), visceral adipocyte area (-21 %), triglyceridemia (-31 %) and hypothalamic NPY content (-37 %) compared to EW group. However, hyperglycemia and lower HDL-c levels observed in EW group were not reverted with mate treatment. Although the hyperleptinemia, lower hypothalamic JAK2 and pSTAT3 content of EW group were not corrected by mate treatment, the hyperphagia and higher hypothalamic SOCS-3 content were normalized in EW+ mate group, indicating that the central leptin resistance could be restored.. Thus, the therapy with yerba mate solution was capable to reverse abdominal obesity, leptin resistance and hypertriglyceridemia, suggesting an important role of this bioactive component in the management of obesity in this programming model.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Dyslipidemias; Female; Hyperglycemia; Hypothalamus; Ilex paraguariensis; Insulin Resistance; Janus Kinase 2; Lactation; Leptin; Neuropeptide Y; Obesity; Plant Extracts; Rats; STAT3 Transcription Factor; Subcutaneous Fat; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Weaning

Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose-response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-induced diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose-response study revealed that leptin reverses STZ-induced diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice that underwent transplantation of 50 or 125 islets. Although these islet doses were insufficient to ameliorate hyperglycemia alone, coadministration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-induced diabetic mice.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Hyperglycemia; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Leptin; Male; Mice; Mice, Inbred C57BL

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.

Topics: Animals; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Secreting Cells; Gluconeogenesis; Hyperglycemia; Hypoglycemic Agents; Infusions, Intraventricular; Injections, Intraventricular; Leptin; Liver; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Rats; Rats, Wistar; Receptors, Leptin; Recombinant Proteins; Signal Transduction; Ventromedial Hypothalamic Nucleus

The dogma that life without insulin is incompatible has recently been challenged by results showing the viability of insulin-deficient rodents undergoing leptin monotherapy. Yet, the mechanisms underlying these actions of leptin are unknown. Here, the metabolic outcomes of intracerebroventricular (i.c.v.) administration of leptin in mice devoid of insulin and lacking or re-expressing leptin receptors (LEPRs) only in selected neuronal groups were assessed. Our results demonstrate that concomitant re-expression of LEPRs only in hypothalamic γ-aminobutyric acid (GABA) and pro-opiomelanocortin (POMC) neurons is sufficient to fully mediate the lifesaving and antidiabetic actions of leptin in insulin deficiency. Our analyses indicate that enhanced glucose uptake by brown adipose tissue and soleus muscle, as well as improved hepatic metabolism, underlies these effects of leptin. Collectively, our data elucidate a hypothalamic-dependent pathway enabling life without insulin and hence pave the way for developing better treatments for diseases of insulin deficiency.

Topics: Adipose Tissue, Brown; Animals; Diabetes Mellitus, Experimental; GABAergic Neurons; Glucose; Hyperglycemia; Hypothalamus; Insulin; Kaplan-Meier Estimate; Leptin; Liver; Mice; Muscle, Skeletal; Neurons; Receptors, Leptin

Obesity and diabetes are associated with increased breast cancer risk and worse disease progression once cancer is diagnosed; however, the exact etiology behind these observations remains to be fully elucidated. Due to the global obesity/diabetes pandemic, it is imperative to understand how these diseases promote and enhance breast cancer and other common cancers. In this study we demonstrate that hyperglycemia promotes breast cancer by altering leptin/IGF1R and AKT/mTOR signaling. To our knowledge, we show for the first time that in breast epithelial cells, hyperglycemia alone directly impacts leptin signaling. Hyperglycemia increased proliferation of both non-tumorigenic and malignant mammary epithelial cells. These observations coincided with increased leptin receptor and IGF1R receptor, as well as, increased levels of GRB2, pJAK2, pSTAT3, pIRS1/2, pAKT, and p-mTOR. Moreover, pJAK2 was almost completely colocalized with leptin receptor under high glucose conditions. These results demonstrate how hyperglycemia can potentially increase the risk of breast cancer in premalignant lesions and enhance cancer progression in malignant cells.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Fluorescent Antibody Technique; Glucose; Humans; Hyperglycemia; Immunoblotting; Leptin; MCF-7 Cells; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Signal Transduction; TOR Serine-Threonine Kinases

The effects of maternal moderate-low physical training on postnatal development, glucose homeostasis and leptin concentration in adult offspring subjected to a low-protein diet during the perinatal period were investigated. Male Wistar rats (aged 150 d old) were divided into four groups according to maternal group: untrained (NTp, n 8); trained (Tp, n 8); untrained with a low-protein diet (NT+LPp, n 8); trained with a low-protein diet (T+LPp, n 8). The trained mothers were subjected to a protocol of moderate physical training over a period of 4 weeks (treadmill, 5 d/week, 60 min/d, at 65 % VO(2max)) before mating. At pregnancy, the intensity and duration of exercise was progressively reduced (50-20 min/d, at 65-30 % VO(2max)). The low-protein diet groups received an 8 % casein diet, and their peers received a 17 % casein diet during gestation and lactation. The pups' birth weight and somatic growth were recorded weekly up to the 150th day. Fasting blood glucose, cholesterol, serum leptin concentration, glucose and insulin tolerance tests were evaluated. The Tp animals showed no changes in somatic and biochemical parameters, while the NT+LPp group showed a greater abdominal circumference, hyperglycaemia, hypercholesterolaemia, glucose intolerance and lower plasma leptin. In the T+LPp animals, all of those alterations were reversed except for plasma leptin concentration. In conclusion, the effects of a perinatal low-protein diet on growth and development, glucose homeostasis and serum leptin concentration in the offspring were attenuated in pups from trained mothers.

Topics: Animals; Behavior, Animal; Birth Weight; Diet, Protein-Restricted; Female; Fetal Development; Fetal Growth Retardation; Hypercholesterolemia; Hyperglycemia; Insulin Resistance; Lactation; Leptin; Male; Maternal Behavior; Maternal Nutritional Physiological Phenomena; Motor Activity; Muscle, Skeletal; Pregnancy; Random Allocation; Rats; Rats, Wistar; Weight Gain

We investigated possible involvements of bile acids (BA) and leptin in hepatogenous insulin resistance being present in up to 90% of cirrhotic patients.. Blood was analysed in 10 cirrhotic patients (8m/2f, 48 ± 10.4 yrs) and 10 controls (8m/2f, 43 ± 9.3 yrs) after oral nutrition and during 1 h of parenteral feeding. In patients, leptin was additionally analysed from mesenteric and arterial blood.. Cirrhosis patients showed typical signs of hepatogenous insulin resistance (hyperinsulinaemia, normoglycaemia, hyperglucagonaemia). Both fasting BA (r = .714, p = 0.047) and fasting leptin (r = .867, p = 0.001) correlated to HOMA and predicted insulin response after oral feeding (R²adj = .783, p = 0.002). But during parenteral nutrition only leptin predicted insulin response (p = 0.005). The prandial glucose response was negatively correlated to the BA increase after oral nutrition (r = -.733, p = 0.028) and to the change in leptin during parenteral nutrition (r = -.738, p = 0.037) pointing towards a nutritional route-dependent positive impact on glucose tolerance of both substances. Prandial glucagon response was correlated to BA under both feeding conditions (p < 0.05). We found no relevant intestinal release of leptin during fasting or feeding conditions.. Our results suggest a substantial involvement of BA and leptin by improving postprandial glucose tolerance related to liver cirrhosis.

Topics: Adipose Tissue, White; Adult; Bile Acids and Salts; Female; Glucagon; Glucose; Humans; Hyperglycemia; Insulin Resistance; Intestinal Mucosa; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Parenteral Nutrition; Postprandial Period

Postnatal calorie and growth restriction (PNGR) in the first generation (F1) rat female offspring causes a lean and glucose tolerant phenotype associated with hypoinsulinemia and reduced glucose-stimulated insulin secretion (GSIS). Despite the absence of gestational hyperglycemia in the F1 PNGR female, naturally born second generation (F2) PNGR female adult offspring reportedly exhibit obesity, hyperglycemia with insulin resistance. The objective of this study was to determine the role of the intrauterine environment on the heritability of the trans-generational phenotypic expression in the F2 PNGR female adult offspring.. We performed embryo transfer (ET) of the F2 embryos from the procreating F1 pregnant PNGR or control (CON) females to gestate in control recipient rat mothers. Employing stable isotopes glucose metabolic kinetics was determined.. Birth weight, postnatal growth pattern and white adipose tissue in female F2 ET-PNGR were similar to ET-CON. Similarly, no differences in basal glucose and insulin concentrations, GSIS, glucose futile cycling and glucose clearance were seen. When compared to F2 ET-CON, F2 ET-PNGR showed no overall difference in glucose or hepatic glucose production (HGP) AUCs with minimal hyperglycemia (p<0.04) as a result of unsuppressed endogenous HGP (p<0.02) observed only during the first phase of IVGTT.. We conclude that the lean, glucose tolerant and hypoinsulinemic phenotype with reduced GSIS in the F1 generation is nearly normalized when the embryo-transferred F2 offspring gestates in a normal metabolic environment. This observation supports a role for the intra-uterine environment in modifying the heritability of the trans-generational PNGR phenotype.

Topics: Animals; Animals, Newborn; Area Under Curve; Birth Weight; Blood Glucose; Caloric Restriction; Embryo Transfer; Female; Glucose Tolerance Test; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Uterus

Polyphenols have been reported to prevent chronic diseases such as cardiovascular diseases, cancers, diabetes and neurodegenerative diseases. The objective of the study was to conduct a screening for potential anti-obesity polyphenolic plant extracts using a diet-induced animal model. Rats were fed a high-fat-sucrose (HFS) diet with or without supplementation of different polyphenolic plant extracts (almond, apple, cinnamon, orange blossom, hamamelis, lime blossom, grape vine, and birch) for 56-64 days.. Body weight gain was lower in rats supplemented with apple, cinnamon, hamamelis and birch extracts as compared to HFS non-supplemented group. Moreover, apple and cinnamon extracts prevented the increase in fat mass promoted by the HFS diet. Insulin resistance, estimated by the homostatic model assessment-insulin resistance (HOMA-IR) index, was reduced in rats fed apple, cinnamon, hamamelis and birch extracts. Apple extract also prevented the HFS-induced hyperglycaemia and hyperleptinaemia.. Only apple and cinnamon extracts were finally considered as potentially important anti-obesogenic extracts, due to their body fat-lowering effects, while the improvement of obesity-related metabolic complications by apple polyphenols highlights this extract as a promising functional food ingredient for the management of obesity and its metabolic complications.

Topics: Adipose Tissue, White; Adiposity; Animals; Anti-Obesity Agents; Antioxidants; Cinnamomum zeylanicum; Dietary Sucrose; Dietary Supplements; Fruit; Hyperglycemia; Insulin Resistance; Leptin; Male; Malus; Obesity; Plant Bark; Plant Extracts; Polyphenols; Random Allocation; Rats; Rats, Wistar; Weight Gain

Obesity and diabetes are closely associated with hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the diet-induced obese C57BL/6 mouse was used to test the hypothesis that chronically elevated metabolic parameters associated with the development of obesity such as cholesterol and glucose can aggravate basal HPA axis activity. Because the lipocalin-type prostaglandin D(2) synthase (L-PGDS) knockout (KO) mouse is a model of accelerated insulin resistance, glucose intolerance, and obesity, it was further hypothesized that HPA activity would be greater in this model. Starting at 8 weeks of age, the L-PGDS KO and C57BL/6 mice were maintained on a low-fat or high-fat diet. After 20 or 37 weeks, fasting metabolic parameters and basal HPA axis hormones were measured and compared between genotypes. Correlation analyses were performed to identify associations between obesity-related chronic metabolic changes and changes in the basal activity of the HPA axis. Our results have identified strong positive correlations between total cholesterol, LDL-cholesterol, glucose, and HPA axis hormones that increase with age in the C57BL/6 mice. These data confirm that obesity-related elevations in cholesterol and glucose can heighten basal HPA activity. Additionally, the L-PGDS KO mice show early elevations in HPA activity with no age-related changes relative to the C57BL/6 mice.

Topics: Adrenocorticotropic Hormone; Animals; Corticosterone; Genotype; Hypercholesterolemia; Hyperglycemia; Hypothalamo-Hypophyseal System; Insulin Resistance; Intramolecular Oxidoreductases; Leptin; Lipocalins; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pituitary-Adrenal System

Although several researches have demonstrated that rooibos extract has hypoglycemic effect, the role of aspalathin, a main polyphenol in the extract, remains unclear. Our aims were to find specific mechanisms for anti-diabetic action of aspalathin employing a rat skeletal muscle-derived cell line (L6 myocytes) and a rat-derived pancreatic β-cell line (RIN-5F cells) and to investigate its effect in type 2 diabetic model ob/ob mice.. We investigated in vitro the effect of aspalathin on the glucose metabolism through the studies on molecular mechanisms of glucose uptake using cultured L6 myotubes. We also measured the antioxidative ability of aspalathin against reactive oxygen species (ROS) generated by artificial advanced glycation end product (AGE) in RIN-5F cells. In vivo, ob/ob mice were fed 0.1 % aspalathin-containing diet for 5 weeks, and the effect of aspalathin on fasting blood glucose level, glucose intolerance, and hepatic gene expression was studied.. Aspalathin dose dependently increased glucose uptake by L6 myotubes and promoted AMP-activated protein kinase (AMPK) phosphorylation. Aspalathin enhanced GLUT4 translocation to plasma membrane in L6 myoblasts and myotubes. In RIN-5F cells, aspalathin suppressed AGE-induced rises in ROS. In vivo, aspalathin significantly suppressed the increase in fasting blood glucose levels and improved glucose intolerance. Furthermore, aspalathin decreased expression of hepatic genes related to gluconeogenesis and lipogenesis.. Hypoglycemic effect of aspalathin is related to increased GLUT4 translocation to plasma membrane via AMPK activation. In addition, aspalathin reduces the gene expression of hepatic enzymes related to glucose production and lipogenesis. These results strongly suggest that aspalathin has anti-diabetic potential.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Cell Line; Chalcones; Cholesterol; Diabetes Mellitus, Experimental; Gluconeogenesis; Glucose Intolerance; Glucose Transporter Type 4; Glycogenolysis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Leptin; Lipogenesis; Mice; Mice, Obese; Muscle Fibers, Skeletal; Muscle, Skeletal; Phosphorylation; Rats; Reactive Oxygen Species

In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress. Hyperglycemia-induced ER stress has not been studied in adipocyte differentiation and adipokine expression. Taurine has been known to protect the cells against ER stress. This study examined the effect of taurine on ER stress-induced adipocyte differentiation and adipokine expression to explain the therapeutic effect of taurine on diabetes and obesity. To do this, human preadipocytes were differentiated into adipocytes, in the presence or absence of taurine, under ER stress conditions. Changes in adipokine expression in adipocytes stimulated with IL-1β were investigated in the presence or absence of taurine. Human preadipocytes were treated with thapsigargin (10 nM) or high glucose concentrations (100 mM) as ER stress inducers during differentiation into adipocytes. Thapsigargin inhibited the differentiation of adipocytes in a dose-dependent manner, but the high glucose concentration treatment did not. Taurine 100 mM treatment did not block the inhibition of differentiation of preadipcytes into adipocytes. Furthermore, the high glucose concentration treatment inhibited the expression of adiponectin and increased the expression of leptin in human adipocytes. However, taurine treatment did not affect the expression of two adipokines. In conclusion, the therapeutic mechanism of taurine in diabetes and obesity does not appear to occur by alleviating hyperglycemia-mediated ER stress. To clarify the molecular mechanism by which taurine improves diabetic symptoms and obesity in animal models, the protective effect of taurine against hyperglycemia- or overnutrition-mediated ER stress should be further evaluated under various conditions or types of ER stress.

Topics: Acetylcysteine; Adipocytes; Adiponectin; Cell Differentiation; Endoplasmic Reticulum Stress; Humans; Hyperglycemia; Leptin; Taurine; Taurochenodeoxycholic Acid; Thapsigargin

It is known that Ca therapy may have anti-obesity effects. Since early weaning leads to obesity, hyperleptinaemia and insulin resistance, we studied the effect of dietary Ca supplementation in a rat model. Lactating rats were separated into two groups: early weaning (EW) - dams were wrapped with a bandage to interrupt lactation in the last 3 d of lactation and control (C) - dams whose pups had free access to milk during the entire lactation period (21 d). At 120 d, EW and C offspring were subdivided into four groups: (1) C, received standard diet; (2) CCa, received Ca supplementation (10 g of calcium carbonate/kg of rat chow); (3) EW, received standard diet; (4) EWCa, received Ca supplementation similar to CCa. The rats were killed at 180 d. The significance level was at P < 0·05. Adult EW offspring displayed hyperphagia (28 %), higher body weight (9 %) and adiposity (77 %), hyperleptinaemia (twofold increase), hypertriacylglycerolaemia (64 %), hyperglycaemia (16 %), higher insulin resistance index (38 %) and higher serum 25-hydroxyvitamin D₃ (fourfold increase), but lower adiponectinaemia:adipose tissue ratio (44 %). In addition, they showed Janus tyrosine kinase 2 and phosphorylated signal transducer and activator of transcription 3 underexpression in hypothalamus (36 and 34 %, respectively), suggesting leptin resistance. Supplementation of Ca for 2 months normalised these disorders. The EW group had no change in serum insulin, thyroxine or triiodothyronine, and Ca treatment did not alter these hormones. In conclusion, we reinforced that early weaning leads to late development of some components of the metabolic syndrome and leptin resistance. Dietary Ca supplementation seems to protect against the development of endocrine and metabolic disorders in EW offspring, maybe through vitamin D inhibition.

Topics: Adiposity; Animals; Blood Glucose; Calcitriol; Calcium Carbonate; Calcium, Dietary; Disease Models, Animal; Female; Hyperglycemia; Hyperphagia; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Pregnancy; Rats; Weaning

Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense 'comfort' foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM), although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7-8 weeks) received exogenous corticosterone or wax (placebo) pellets, implanted subcutaneously, and were fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days. Animals given corticosterone and a HFD (cort-HFD) had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired β-cell response to oral glucose load (20% decrease) compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipose Tissue; Adiposity; Animals; Body Composition; Circadian Rhythm; Corticosterone; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Energy Intake; Fasting; Feeding Behavior; Glucocorticoids; Hyperglycemia; Hyperinsulinism; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Muscular Atrophy; Rats; Receptors, Glucocorticoid; Triglycerides; Weight Gain

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

The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance even during pregnancy, while exposure to a high-fat diet (HFD) in utero in mice can induce a type 2 diabetes phenotype that can be transmitted to the progeny. Therefore, we examined whether treatment with a CAR ligand during pregnancy could prevent hypertension, insulin resistance, and hyperlipidemia in the offspring from HFD-induced obese pregnant mice (OH mice). We employed four groups of offspring from HFD-fed and control diet-fed pregnant mice with or without treatment with a CAR ligand. Treatment with a CAR ligand during pregnancy improved glucose tolerance and the levels of triglyceride and adipocytokine and restored the changes induced by HFD with amelioration of hypertension in the adult OH mice. This treatment also increased adiponectin mRNA expression, suppressed leptin expression in adipose tissues of OH mice, and abolished the effect of HFD on the epigenetic modifications of the genes encoding adiponectin and leptin in the offspring during immaturity and adulthood. Our data suggest that CAR might be a potential therapeutic target to prevent metabolic syndrome in adulthood of offspring exposed to an HFD in utero.

Topics: Adiponectin; Animals; Constitutive Androstane Receptor; Diet, High-Fat; Female; Glucose Tolerance Test; Hyperglycemia; Hypertension; Insulin Resistance; Leptin; Mice; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Pyridines; Receptors, Cytoplasmic and Nuclear; Triglycerides

The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ob mice (Ghsr(-/-):ob/ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ob mice did not affect the islet size; the average islet size of Ghsr(-/-):ob/ob mice is similar to that of ob/ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.

Topics: Animals; Gene Deletion; Ghrelin; Glucose; Glucose Tolerance Test; Homeostasis; Hyperglycemia; Leptin; Male; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, Ghrelin

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

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

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

Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNFα), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNFα on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35 min of global ischaemia) followed by 45 min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNFα associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC.

Topics: Animals; Cardiomegaly; Diabetes Mellitus, Type 1; Dietary Carbohydrates; Disease Susceptibility; Heart; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Ischemic Postconditioning; Leptin; Mice; Mice, Knockout; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Obesity; Organ Size; Severity of Illness Index; Streptozocin; Tumor Necrosis Factor-alpha

The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

Topics: Animals; Blood Glucose; Body Composition; Brain; Corticosterone; Diabetes Mellitus, Experimental; Glucagon; Glucose Tolerance Test; Hyperglycemia; Insulin; Leptin; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction

Leptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type 1 diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes.. After the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57Bl/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted.. Hyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wild-type littermates with STZ-induced diabetes.. These observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Enzyme-Linked Immunosorbent Assay; Glucagon; Growth Hormone; Hyperglycemia; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Postprandial Period; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Adiponectin is known to be an anti-diabetic adipocytokine. However, the action mechanism by which it produces this effect remains controversial. In the present study, we investigated the long-term central effect of adiponectin on energy homeostasis, peripheral insulin resistance, β-cell function and mass in rats and aimed to determine the mechanism by which its effect was achieved. Intracerebroventricular infusion of adiponectin (50 ng/h) and artificial cerebrospinal fluid (CSF) was conducted by means of an osmotic pump for 4 weeks on nondiabetic rats and 90% pancreatectomised diabetic rats that were both fed 45% energy fat diets. After 4-weeks of treatment, i.c.v. adiponectin improved hypothalamic insulin/leptin signalling in nondiabetic and diabetic rats compared to i.c.v. CSF but it did not change the phosphorylation of AMP kinase (AMPK) in the hypothalamus. Adiponectin infusion decreased epididymal fats, representing visceral fat, by increasing energy expenditure and fat oxidation. During the euglycaemic hyperinsulinaemic clamp, i.c.v. adiponectin improved whole body insulin sensitivity and decreased hepatic glucose output in the hyperinsulinaemic state by attenuating hepatic insulin resistance. Central infusion of adiponectin did not modulate glucose-stimulated insulin secretion during the hyperglycaemic clamp compared to i.c.v. CSF infusion but it enhanced insulin sensitivity at a hyperglycaemic state. Although there were no changes in insulin secretion capacity, central adiponectin increased pancreatic β-cell mass in nondiabetic and diabetic rats as a result of decreasing β-cell death. In conclusion, long-term central infusion of adiponectin enhanced energy homeostasis by increasing energy expenditure via activating hypothalamic leptin and insulin signalling pathways but without potentiating AMPK signalling; it also improved glucose homeostasis by attenuating insulin resistance.

Topics: Adenylate Kinase; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Eating; Energy Metabolism; Gluconeogenesis; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Secreting Cells; Leptin; Liver; Male; Rats; Rats, Sprague-Dawley

Women with gestational diabetes mellitus (GDM) have an enhanced cardiovascular risk factor profile at 3-months postpartum and an elevated risk of future cardiovascular disease, as compared to their peers. Recently, it has emerged that even mild dysglycemia on antepartum oral glucose tolerance test (OGTT) predicts an increased risk of future cardiovascular disease, although it is not known whether there exists an identifiable high-risk subgroup within this patient population. Since gestational impaired glucose tolerance (GIGT) due to isolated hyperglycemia at 1-h during the OGTT (1-h GIGT) bears metabolic similarity to GDM, we hypothesized that, like GDM, 1-h GIGT may predict a high-risk postpartum cardiovascular phenotype.. In this prospective cohort study, 485 women underwent antepartum OGTT, followed by cardiovascular risk factor assessment at 3-months postpartum. The antepartum OGTT identified 4 gestational glucose tolerance groups: GDM (n = 137); 1-h GIGT (n = 39); GIGT at 2- or 3-h (2/3-h GIGT)(n = 50); and normal glucose tolerance (NGT)(n = 259). After adjustment for age, ethnicity, breastfeeding and waist circumference, mean levels of the following cardiovascular risk factors progressively increased from NGT to 2/3-h GIGT to 1-h GIGT to GDM: LDL cholesterol (p = 0.0026); total cholesterol:HDL (p = 0.0030); apolipoprotein B (p = 0.004); apolipoprotein B:apolipoprotein A1 (p = 0.026); leptin (p = 0.018); and C-reactive protein (p = 0.011).. Amongst women without GDM, 1-h GIGT predicts an enhanced postpartum cardiovascular risk factor profile. It thus emerges, that amongst young women with mild dysglycemia in pregnancy, those with 1-h GIGT may comprise an unrecognized patient population at risk for future cardiovascular disease.

Topics: Adult; Apolipoproteins B; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Leptin; Postpartum Period; Pregnancy; Prospective Studies; Risk Factors

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

The aim of the current study was to evaluate the long-term effects of leptin on glucose metabolism, diabetes complications, and life span in an insulin-dependent diabetes model, the Akita mouse.. We cross-mated Akita mice with leptin-expressing transgenic (LepTg) mice to produce Akita mice with physiological hyperleptinemia (LepTg:Akita). Metabolic parameters were monitored for 10 months. Pair-fed studies and glucose and insulin tolerance tests were performed. The pancreata and kidneys were analyzed histologically. The plasma levels and pancreatic contents of insulin and glucagon, the plasma levels of lipids and a marker of oxidative stress, and urinary albumin excretion were measured. Survival rates were calculated.. Akita mice began to exhibit severe hyperglycemia and hyperphagia as early as weaning. LepTg:Akita mice exhibited normoglycemia after an extended fast even at 10 months of age. The 6-h fasting blood glucose levels in LepTg:Akita mice remained about half the level of Akita mice throughout the study. Food intake in LepTg:Akita mice was suppressed to a level comparable to that in WT mice, but pair feeding did not affect blood glucose levels in Akita mice. LepTg:Akita mice maintained insulin hypersensitivity and displayed better glucose tolerance than did Akita mice throughout the follow-up. LepTg:Akita mice had normal levels of plasma glucagon, a marker of oxidative stress, and urinary albumin excretion rates. All of the LepTg:Akita mice survived for >12 months, the median mortality time of Akita mice.. These results indicate that leptin is therapeutically useful in the long-term treatment of insulin-deficient diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Eating; Glucagon; Hyperglycemia; Insulin; Leptin; Longevity; Mice; Mice, Transgenic; Oxidative Stress; Pancreas

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

We have previously shown that either the continuous intake of a palatable hyperlipidic diet (H) or the alternation of chow (C) and an H diet (CH regimen) induced obesity in rats. Here, we investigated whether the time of the start and duration of these feeding regimens are relevant and whether they affect brain glucose metabolism.. Male Wistar rats received C, H, or CH diets during various periods of their life spans: days 30-60, days 30-90, or days 60-90. Experiments were performed the 60th or the 90th day of life. Rats were killed by decapitation. The glucose, insulin, leptin plasma concentration, and lipid content of the carcasses were determined. The brain was sliced and incubated with or without insulin for the analysis of glucose uptake, oxidation, and the conversion of [1-14C]-glucose to lipids.. The relative carcass lipid content increased in all of the H and CH groups, and the H30-60 and H30-90 groups had the highest levels. Groups H30-60, H30-90, CH30-60, and CH30-90 exhibited a higher serum glucose level. Serum leptin increased in all H groups and in the CH60-90 and CH30-90 groups. Serum insulin was elevated in the H30-60, H60-90, CH60-90, CH30-90 groups. Basal brain glucose consumption and hypothalamic insulin receptor density were lower only in the CH30-60 group. The rate of brain lipogenesis was increased in the H30-90 and CH30-90 groups.. These findings indicate that both H and CH diet regimens increased body adiposity independent treatment and the age at which treatment was started, whereas these diets caused hyperglycemia and affected brain metabolism when started at an early age.

Topics: Aging; Animals; Behavior, Animal; Brain; Diet, Atherogenic; Energy Intake; Feeding Behavior; Glucose; Glycolysis; Hyperglycemia; Hypothalamus; Insulin; Leptin; Lipogenesis; Male; Nerve Tissue Proteins; Neurons; Obesity; Rats; Rats, Wistar; Receptor, Insulin; Receptors, Leptin

Leptin is mainly secreted from adipose tissue and is known to be associated with cardiovascular diseases. However, there are not many studies on the association between serum leptin and metabolic syndrome. The objective of this study was to determine the association between serum leptin and metabolic syndrome among the Korean adult population. The study population consisted of 3,272 Koreans (men: 1,915, women: 1,357) 30 to 84 years of age who had visited the Health Examination Center. Leptin levels were divided into quintiles and metabolic syndrome was defined by NCEP ATP III. The serum leptin levels increased as the number of components present for metabolic syndrome increased. Controlling for age, smoking, exercise, and LDL cholesterol, subjects with high leptin levels were more likely to have an elevated risk of metabolic syndrome than those with lower levels in both men and women. Subjects in the highest leptin quintile were found to have a higher risk of having metabolic syndrome than those in the lowest quintile (OR = 11.51 for men; OR = 4.65 for women). After further adjustment of the BMI, the risk of metabolic syndrome still increased slightly for men but not for women in increasing leptin categories. This association of leptin levels and metabolic syndrome did not change after stratification into obese and nonobese weight status. Serum leptin is associated with metabolic syndrome in Korean populations independent of body mass index. Thus, the reduction of circulating leptin may confer cardiovascular and metabolic protective effects regardless of weight status.

Topics: Abdominal Fat; Adult; Body Mass Index; Female; Humans; Hyperglycemia; Hypertension; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Odds Ratio; Republic of Korea; Triglycerides; Waist Circumference

The importance of hypertension treatment has expanded beyond blood pressure management to include additional risk factors, mainly diabetes. It was considered of interest to test the effect of telmisartan, an angiotensin receptor 1 antagonist and peroxisome proliferator activator receptor-gamma partial agonist, on Cohen-Rosenthal diabetic hypertensive nonobese (CRDH) rats, a unique model combining both pathologies. Its effect was examined on fat-derived and inflammatory agents in CRDH. To determine the extent of the drug's peroxisome proliferator activator receptor-gamma modulating beneficial metabolic actions, results were compared with those obtained with valsartan and rosiglitazone in CRDH and Cohen diabetic rat (CDR). Telmisartan and valsartan were given in drinking water at 3 and 12 mg/kg/d, whereas rosiglitazone (3 mg/kg/d) was given as food admixture for a period of 5 months. Blood pressure, glucose, insulin, adiponectin, leptin, and tumor necrosis factor alpha were examined. Telmisartan and valsartan significantly (P < .01) reduced blood pressure, whereas telmisartan and rosiglitazone considerably reduced blood glucose levels to normoglycemic levels (P < .01) in these 2 strains. Insulin levels were not affected by telmisartan and valsartan but were slightly reduced by rosiglitazone in CDR. In contrast to valsartan, adiponectin was significantly (60%, P < .01) increased by telmisartan in both CDR and CRDH, whereas rosiglitazone induced a 60% and 180% increase in CRDH and CDR animals, respectively, on day 30 of treatment. Co-treatment with GW9662 averted telmisartan-induced rise of adiponectin. Tumor necrosis factor alpha declined in telmisartan-treated rats, less so with rosiglitazone, but not valsartan. Telmisartan also induced downsizing of epididymal adipocytes compared with valsartan. Leptin levels were significantly increased by valsartan (P < .05) but reduced by telmisartan and rosiglitazone. The telmisartan-induced increase in adiponectin was most probably associated with a decrease in glucose and tumor necrosis factor alpha levels. Therefore, in addition to its hypotensive effect, telmisartan demonstrated beneficial thiazolidinedione-like effects.

Topics: Adiponectin; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Blood Pressure; Humans; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Leptin; PPAR gamma; Rats; Rats, Inbred SHR; Rosiglitazone; Telmisartan; Thiazolidinediones; Tumor Necrosis Factor-alpha; Weight Gain

We tested whether leptin can ameliorate diabetes independent of weight loss by defining the lowest dose at which leptin treatment of ob/ob mice reduces plasma glucose and insulin concentration. We found that a leptin dose of 12.5 ng/hr significantly lowers blood glucose and that 25 ng/hr of leptin normalizes plasma glucose and insulin without significantly reducing body weight, establishing that leptin exerts its most potent effects on glucose metabolism. To find possible mediators of this effect, we profiled liver mRNA using microarrays and identified IGF Binding Protein 2 (IGFBP2) as being regulated by leptin with a similarly high potency. Overexpression of IGFBP2 by an adenovirus reversed diabetes in insulin-resistant ob/ob, Ay/a, and diet-induced obese mice, as well as insulin-deficient streptozotocin-treated mice. Hyperinsulinemic clamp studies showed a 3-fold improvement in hepatic insulin sensitivity following IGFBP2 treatment of ob/ob mice. These results show that IGFBP2 can regulate glucose metabolism, a finding with potential implications for the pathogenesis and treatment of diabetes.

Topics: Adenoviridae; Animals; Blood Glucose; Gene Transfer Techniques; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin-Like Growth Factor Binding Protein 2; Leptin; Liver; Mice; Mice, Knockout; Oligonucleotide Array Sequence Analysis; RNA, Messenger

Increased inflammation may contribute to type 1 diabetes (T1D) complications.. The objective of the study was to investigate the association of inflammation with obesity, hyperglycemia and dyslipidemia in youth with T1D.. This was a cross-sectional study of youth with and without T1D.. The study was conducted in Colorado and South Carolina.. SEARCH Case-Control participants with T1D [n = 553, mean age 15 yr (range 10-22), median duration 2.7 yr] and without diabetes [n = 215, mean age 15 yr (range 10-22)].. This was an observational study.. IL-6, high-sensitivity C-reactive protein (hsCRP), fibrinogen, and leptin were measured.. Inflammatory markers were evaluated by diabetes status, quartiles of glycated hemoglobin, and obesity using multiple linear regression analyses, adjusted for age, sex, study site, race/ethnicity, T1D duration, body mass index, and pubertal status. Compared with controls, youth with T1D had higher IL-6 and fibrinogen levels at all levels of glycemia and obesity, and hsCRP levels were significantly higher in youth with T1D in the top three quartiles of glycated hemoglobin (> or = 7.2%) and among normal-weight subjects. Leptin was lower in youth with poor glycemic control. Higher hsCRP and fibrinogen were correlated with higher total and LDL cholesterol, and apolipoprotein B in youth with T1D, whereas higher fibrinogen was correlated with higher LDL and apolipoprotein B in controls.. T1D is characterized by excess inflammation, independent of adiposity and glycemic control. Even T1D youth in good glycemic control had higher levels of IL-6 and fibrinogen than controls. Elevated inflammatory markers were associated with an atherogenic lipid profile, which may contribute to accelerated atherosclerosis in youth with T1D.

Topics: Adolescent; Anthropometry; Biomarkers; Body Mass Index; C-Reactive Protein; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Dyslipidemias; Ethnicity; Female; Fibrinogen; Glycated Hemoglobin; Humans; Hyperglycemia; Inflammation; Interleukin-6; Leptin; Male; Obesity; Puberty; Young Adult

We previously showed that adipose differentiation related protein (Adfp)-deficient mice display a 60% reduction in hepatic triglyceride (TG) content. In this study, we investigated the role of ADFP in lipid and glucose homeostasis in a genetic obesity model, Lep(ob/ob) mice. We bred Adfp(-/-) mice with Lep(ob/ob) mice to create Lep(ob/ob)/Adfp(-/-) and Lep(ob/ob)/Adfp(+/+) mice and analyzed the hepatic lipids, lipid droplet (LD) morphology, LD protein composition and distribution, lipogenic gene expression, and VLDL secretion, as well as insulin sensitivity of the two groups of mice. Compared with Lep(ob/ob)/Adfp(+/+) mice, Lep(ob/ob)/Adfp(-/-) mice displayed an increased VLDL secretion rate, a 25% reduction in hepatic TG associated with improvement in fatty liver grossly and microscopically with a change of the size of LDs in a proportion of the hepatocytes and a redistribution of major LD-associated proteins from the cytoplasmic compartment to the LD surface. There was no detectable change in lipogenic gene expression. Lep(ob/ob)/Adfp(-/-) mice also had improved glucose tolerance and insulin sensitivity in both liver and muscle. The alteration of LD size in the liver of Lep(ob/ob)/Adfp(-/-) mice despite the relocation of other LDPs to the LD indicates a nonredundant role for ADFP in determining the size and distribution of hepatic LDs.

Topics: Animals; Carrier Proteins; Fasting; Fatty Liver; Glucose; Hepatocytes; Homeostasis; Hyperglycemia; Insulin Resistance; Leptin; Lipoproteins, VLDL; Liver; Male; Membrane Proteins; Mice; Perilipin-2; Perilipin-3; RNA, Messenger; Triglycerides; Up-Regulation

In an acute treatment experiment, metformin (150, 300 mg/kg, per os (p.o.)) markedly reduced the consumption of a high-fat diet (HFD) (45 kcal% fat-containing diet) for 2 h after the HFD was given to the fasted male C57BL/6J (B6) mice. In addition, metformin at a higher dose increased plasma active glucagon-like peptide-1 (GLP-1) levels at 1 h after the HFD was given. On the other hand, pioglitazone (12 mg/kg, p.o.) slightly increased the food intake but did not affect active GLP-1 levels when given at 6 and 12 mg/kg, p.o. In a long-team experiment for 9 weeks, metformin treatment (0.25, 0.5% in the HFD) resulted in reduction of body weight gain and HFD intake. When wet weights of various body fat pads of each mouse were measured at 9 weeks after treatment, metformin markedly decreased these weights. However, pioglitazone treatment (0.01, 0.02% in the HFD) did not have obvious effects on these parameters. Oral glucose tolerance test was carried out after 20-h fasting at 4 weeks post-treatment. Whereas metformin treatment (0.25, 0.5%) markedly improved glucose intolerance, pioglitazone treatment (0.02%) slightly improved this parameter. At 9 weeks, both metformin and pioglitazone markedly improved hyperglycemia and hyperinsulinemia. Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective. These results indicate that metformin reduces body weight gain and improves glucose intolerance in HFD-induced obese diabetic B6 mice.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Energy Intake; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Mice; Mice, Inbred C57BL; Obesity; Pioglitazone; Thiazolidinediones; Weight Gain

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

Obesity and type 2 diabetes are national and worldwide epidemics. Because currently available antiobesity and antidiabetic drugs have limited efficacy and/or safety concerns, identifying new medicinal agents, such as ginsenoside Rb1 (Rb1) as reported here, offers exciting possibilities for future development of successful antiobesity and antidiabetic therapies.. Changes in feeding behavior after acute intraperitoneal administration of Rb1 and the effects of intraperitoneal Rb1 for 4 weeks on body weight, energy expenditure, and glucose tolerance in high-fat diet (HFD)-induced obese rats were assessed. We also examined the effects of Rb1 on signaling pathways and neuropeptides in the hypothalamus.. Acute intraperitoneal Rb1 dose-dependently suppressed food intake without eliciting signs of toxicity. This inhibitory effect on feeding may be mediated by central mechanisms because Rb1 stimulated c-Fos expression in brain areas involved in energy homeostasis. Consistent with this, Rb1 activated the phosphatidylinositol 3-kinase/Akt signaling pathway and inhibited NPY gene expression in the hypothalamus. Four-week administration of Rb1 significantly reduced food intake, body weight gain, and body fat content and increased energy expenditure in HFD-induced obese rats. Rb1 also significantly decreased fasting blood glucose and improved glucose tolerance, and these effects were greater than those observed in pair-fed rats, suggesting that although Rb1's antihyperglycemic effect is partially attributable to reduced food intake and body weight; there may be additional effects of Rb1 on glucose homeostasis.. These results identify Rb1 as an antiobesity and antihyperglycemic agent.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Chromatography, High Pressure Liquid; Dietary Fats; Energy Intake; Fasting; Feeding Behavior; Ginsenosides; Glucose Tolerance Test; Hyperglycemia; Injections, Intraperitoneal; Intestinal Absorption; Leptin; Male; Obesity; Phosphatidylinositol 3-Kinases; Rats; Rats, Long-Evans; Taste

The purpose of this study was to assess the effects of low-dose ursolic acid (UA) on glycemic regulation and immune responses in streptozotocin-nicotinamide (STZ/NA)-induced diabetic mice. Diabetic mice were supplemented with two different doses of UA (0.01 and 0.05%, w/w) or metformin (0.5%, w/w) for 4 weeks. Compared with the untreated diabetic group, UA and metformin significantly improved blood glucose, glycosylated hemoglobin, glucose tolerance, insulin tolerance and plasma leptin levels as well as aminotransferase activity. The plasma and pancreatic insulin concentrations were significantly higher in both UA groups than in the untreated diabetic group. Supplementation with metformin increased the pancreatic insulin level without a change in the plasma insulin level. The relative thymus weights were lower in the untreated diabetic group compared to the non-diabetic group; however, the UA or metformin group had significantly improved thymus weights. Mice receiving UA or metformin supplementation had increased CD4(+)CD8(+) subpopulations in the thymus compared to the untreated diabetic mice. Concanavalin A-stimulated splenic T-lymphocyte proliferation and single-positive (CD4(+) and CD8(+)) subpopulations were significantly higher in the UA-supplemented diabetic groups than in the untreated diabetic group, but lipopolysaccharide-stimulated B-lymphocyte proliferation and the CD19(+) subpopulation were not significantly different among the groups. In the STZ/NA-induced diabetic mice, metformin increased the splenic T-lymphocyte CD4(+) and CD8(+) cell numbers without any change in T-lymphocyte proliferation. Both doses of UA lowered splenic IL-6 levels, whereas metformin increased IFN-γ, IL-6 and TNF-α levels compared to the untreated diabetic mice. These results suggest that low-dose UA may be used as a hypoglycemic agent and immune modulator in non-obese type 2 diabetic mice.

Topics: Animals; Atrophy; Blood Glucose; Body Weight; Cell Proliferation; Cytokines; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Glucose Tolerance Test; Glycated Hemoglobin; Hyperglycemia; Insulin; Leptin; Lymphocytes; Male; Mice; Mice, Inbred ICR; Niacinamide; Pancreas; Spleen; Thymus Gland; Transaminases; Triterpenes; Ursolic Acid

To analyse in a cohort of healthy subjects and in a group of morbidly obese patients, we studied the association amongst 25(OH) D and plasma concentrations of adipocytokines, inflammatory cytokines and insulin resistance. We also aimed to determine whether vitamin D-deficient patients showed a greater inflammatory profile. In the observational study that the authors conducted, plasma concentrations of 25(OH) D, leptin, resistin, adiponectin and interleukine-18 were determined in 134 healthy men and 127 women. In the population consisting of 44 patients with morbid obesity, plasma concentrations of 25(OH) D, leptin, resistin, adiponectin, interleukine-18, soluble tumor necrosis factor receptors 1 and 2 and C-reactive protein were analysed. In the healthy population, plasma 25(OH) D showed a negative correlation with body mass index, body fat, waist, hip circumference and with leptin. However, no significant associations were found amongst 25(OH) D and plasma concentrations of resistin, adiponectin or interleukine-18. Patients with vitamin D deficiency showed higher body mass index, fat mass percentage and higher leptin concentrations compared with subjects with normal 25(OH) D concentrations. In the morbidly obese subjects, 25(OH) D did not correlate with leptin, resistin, adiponectin, interleukine-18, soluble tumor necrosis factor receptors 1 and 2 or with C-reactive protein. In patients with morbid obesity, no differences were found in adipokines and inflammatory cytokines concentrations regarding 25(OH) D status. No associations were found either between 25(OH) D and plasma glucose and insulin resistance or with lipid profile. Plasma 25(OH) D concentrations are associated with adiposity markers but not with adipocytokines implicated in inflammation. This lack of association does not support a major role of 25(OH) D in the pro-inflammatory environment observed in morbidly obese subjects. In addition, subjects with vitamin D deficiency are not characterized by a greater inflammatory state.

Topics: Adipokines; Adiponectin; Adult; Biomarkers; Body Composition; C-Reactive Protein; Comorbidity; Female; Humans; Hyperglycemia; Insulin Resistance; Interleukin-18; Leptin; Male; Middle Aged; Obesity, Morbid; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Resistin; Vitamin D

Apoptotic myocyte cell death, diastolic dysfunction, and progressive deterioration in left ventricular pump function characterize the clinical course of diabetic cardiomyopathy. A key question concerns the mechanism(s) by which hyperglycemia (HG) transmits danger signals in cardiac muscle cells. The growth factor adapter protein p66ShcA is a genetic determinant of longevity, which controls mitochondrial metabolism and cellular responses to oxidative stress. Here we demonstrate that interventions which attenuate or prevent HG-induced phosphorylation at critical position 36 Ser residue (phospho-Ser36) inhibit the redox function of p66ShcA and promote the survival phenotype. Adult rat ventricular myocytes obtained by enzymatic dissociation were transduced with mutant-36 p66ShcA (mu-36) dominant-negative expression vector and plated in serum-free media containing 5 or 25 mM glucose. At HG, adult rat ventricular myocytes exhibit a marked increase in reactive oxygen species production, upregulation of phospho-Ser36, collapse of mitochondrial transmembrane potential, and increased formation of p66ShcA/cytochrome-c complexes. These indexes of oxidative stress were accompanied by a 40% increase in apoptosis and the upregulation of cleaved caspase-3 and the apoptosis-related proteins p53 and Bax. To test whether p66ShcA functions as a redox-sensitive molecular switch in vivo, we examined the hearts of male Akita diabetic nonobese (C57BL/6J) mice. Western blot analysis detected the upregulation of phospho-Ser36, the translocation of p66ShcA to mitochondria, and the formation of p66ShcA/cytochrome-c complexes. Conversely, the correction of HG by recombinant adeno-associated viral delivery of leptin reversed these alterations. We conclude that p66ShcA is a molecular switch whose redox function is turned on by phospho-Ser36 and turned off by interventions that prevent this modification.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cardiomyopathies; Caspase 3; Catalase; Cells, Cultured; Cytochromes c; Disease Models, Animal; Genetic Therapy; Hyperglycemia; Leptin; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mitochondria, Heart; Mutation; Myocytes, Cardiac; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1; Superoxide Dismutase; Transduction, Genetic; Tumor Suppressor Protein p53

Long-term benefits of central leptin gene therapy in insulin-deficient diabetes are not known despite its therapeutic effects in obesity animal models such as ob/ob and diet-induced obese mice. Adult male mice were injected intraperitoneally with streptozotocin (STZ, 200mg/kg) to induce insulitis. A week later, only diabetic STZ-pretreated mice (blood glucose >350 mg/dl) received intracerebroventricularly (icv) an injection of recombinant adeno-associated virus vector (rAAV) encoding either green fluorescent protein (control), or leptin gene (rAAV-lep). Body weight (BW), food intake, blood glucose, insulin and survival rate responses were monitored post-icv injection at regular intervals for 52 weeks. The STZ pre-injected diabetic mice remained hyperphagic, gradually lost BW and died by week 6 after receiving control vector. In marked contrast, injection of rAAV-lep to raise hypothalamic leptin levels, rescued the STZ-pretreated mice from early mortality, gradually curbed hyperphagia to normalize intake by week 20, and maintained BW at significantly lower than the control range. Blood glucose levels in these mice started to recede dramatically by week 2-3 to normalize by week 8, and euglycemia was sustained during the remaining course of the experiment. rAAV-lep injected mice did not exhibit any discernible untoward gross behavioral changes and diabetic complications and showed a partial return of pancreatic beta-cell function. These results show for the first time that one time central leptin gene therapy is effective and durable in reinstating euglycemia and energy homeostasis for extended periods in the absence of insulin.

Topics: Animals; Blood Glucose; Dependovirus; Diabetes Mellitus, Experimental; Genetic Therapy; Green Fluorescent Proteins; Hyperglycemia; Hyperphagia; Injections, Intraventricular; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Streptozocin

Fetal or early postnatal stressors may predispose infants to develop diabetes, metabolic syndrome, or stroke. We hypothesized that postnatal stress will predispose animals to develop metabolic syndrome and impair the physiologic response to hypoxic-ischemic brain injury. We characterized the short- and long-term physiologic responses to postnatal stress by examining corticosterone (CS), glucose metabolism, and brain injury in neonatal and adult rats exposed to hypoxia-ischemia (H-I). Rat pups were divided into three levels of postnatal stress from postnatal day (P) 3 to P7. All rats underwent unilateral brain injury on either P7 or P134. We measured brain injury, growth, blood pressure, urine/plasma CS, plasma leptin, insulin, and glucose before and after H-I. Postnatal stress increased neonatal CS production, exacerbated neonatal white matter injury, and was associated with adult hyperglycemia after H-I despite increased insulin production. There were no group differences in adult weight, blood pressure, or leptin. Postnatal stress exacerbated brain injury and produced adult hyperglycemia, triggered after hypoxia exposure, consistent with the hypotheses that neonates exposed to early stress are more vulnerable to hypoxia and may be predisposed to develop metabolic syndrome in adulthood. Prolonged maternal separation produced more hyperglycemia than did brief daily handling.

Topics: Animals; Animals, Newborn; Blood Glucose; Blood Pressure; Body Weight; Brain Injuries; Corticosterone; Female; Humans; Hyperglycemia; Hypoxia-Ischemia, Brain; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley; Stress, Physiological

To investigate the relationship between the levels of serum leptin and oxidative stress in patients with hyperglycemia crisis.. A total of 96 patients with diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) were treated on a low-dose insulin protocol using intravenous infusion of insulin with the established rate of 0.1 Uxkg(-1)xh(-1), with the patients on intravenous fluids and receiving nutrition by mouth and vein. The levels of serum leptin, 8-iso-prostaglandin F(2 alpha) (8-iso-PGF(2 alpha)), the activities of superoxide dismutase (SOD), total antioxidant capacity (TAC) and the contents of malondialdehyde (MDA) in 96 patients with hyperglycemia crisis on admission and after insulin therapy with resolution of hyperglycemia and ketoacidosis (72 hours) were measured. Another 35 healthy individuals served as normal control.. The activities of SOD, TAC and the levels of leptin before treatment were lower in patients with hyperglycemia crisis than in normal controls, and the levels of MDA and 8-iso-PGF(2 alpha) were more markedly elevated than those in normal controls (all P<0.05). The activities of SOD, TAC and the levels of leptin in patients after treatment were significantly higher than those in patients before treatment, and the levels of MDA and 8-iso-PGF(2 alpha) were significantly lower than those in patients on admission (all P<0.05). There was significant positive correlation between leptin and MDA in patients before treatment (r=0.38, P<0.05), and the level of leptin was negatively correlated with MDA and 8-iso-PGF(2 alpha) in patients after treatment (r(1)=-0.35, r(2)=-0.37, both P<0.05). In stepwise regression analysis, MDA and 8-iso-PGF(2 alpha) showed a significant association with leptin.. The levels of leptin are significantly lowered in patients with hyperglycemia crisis. Oxidative stress may participate in determining the leptin level in hyperglycemia crisis.

Topics: Adult; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Oxidative Stress; Regression Analysis

Epidemiological data and results from animal studies indicate that imbalances in maternal nutrition impact the expression of metabolic disorders in the offspring. We tested the hypothesis that consumption of excess saturated fats during pregnancy and lactation contributes to adult metabolic dysfunction and that these disturbances can be further influenced by the postweaning diet. Adult male offspring from chow-fed dams were compared with males from dams fed a diet high in saturated fat (45 kcal/100 kcal) before mating, pregnancy, and lactation. Offspring were weaned to a standard chow diet or high fat diet. Animals were killed at 120 days after a 24-h fast. Body weight, energy intake, fat deposition, serum leptin, and insulin were significantly higher in offspring from control or high-fat dams if fed a high-fat diet from weaning to adulthood. Only fat-fed offspring from fat-fed dams were hyperglycemic. Leptin receptor, proopiomelanocortin, and neuropeptide Y (NPY) were also significantly increased in offspring exposed to excess saturated fat during gestation and into adulthood, whereas NPY(1) receptor was downregulated. Signal transducer and activator of transcription 3 mRNA level was significantly higher in offspring from high-fat-fed dams compared with controls; however, no change was detected in cocaine and amphetamine-regulated transcript or suppressor of cytokine signaling 3. An increase in agouti-related protein expression did not reach significance. A significant reduction in phosphatidylinositol 3-kinase regulatory subunit (p85alpha) coupled to an upregulation of protein kinase B was observed in offspring from high-fat-fed dams transitioned to chow food, whereas p85alpha expression was significantly increased in high-fat offspring weaned to the high-fat diet. These data support the hypothesis that early life exposure to excess fat is associated with changes in hypothalamic regulation of body weight and energy homeostasis and that postweaning diet influences development of metabolic dysfunction and obesity.

Topics: Adiposity; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Dietary Fats; Energy Metabolism; Female; Gene Expression Regulation; Gestational Age; Hyperglycemia; Hypothalamus; Insulin; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Diseases; Neuropeptides; Nutritional Status; Obesity; Phosphatidylinositol 3-Kinases; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; RNA, Messenger; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Weaning

Biotransformation of blueberry juice by the Serratia vaccinii bacterium gave rise to adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and glucose uptake in muscle cells and adipocytes, but inhibited adipogenesis. This study investigated the antiobesity and antidiabetic potential of biotransformed blueberry juice (BJ) in KKA(y) mice, rodent model of leptin resistance.. BJ was incorporated in drinking water of KKA(y) mice. Parameters of body weight, food intake, plasma glucose, insulin, leptin, and adiponectin were measured. Before and after therapy, animals were subjected to an oral glucose tolerance test. At the end of treatment, liver, muscle, kidney, epididymal fat pad, abdominal fat pad, and dorsal fat pad were collected and weighed.. Incorporating BJ in drinking water protected young KKA(y) mice from hyperphagia and significantly reduced their weight gain. Moreover, BJ protected young KKA(y) mice against the development of glucose intolerance and diabetes mellitus. Chronic BJ administration in obese and diabetic KKA(y) mice reduced food intake and body weight. This effect could not fully explain the associated antidiabetic effect because BJ-treated mice still showed lower blood glucose level when compared with pair-fed controls. The adipokines pathway also seems to be involved because BJ significantly increased adiponectin levels in obese mice.. This study shows that BJ decreases hyperglycemia in diabetic mice, at least in part by reversing adiponectin levels. BJ also protects young pre-diabetic mice from developing obesity and diabetes. Thus, BJ may represent a novel complementary therapy and a source of novel therapeutic agents against diabetes mellitus.

Topics: Adiponectin; Animals; Beverages; Blueberry Plants; Body Weight; Diabetes Mellitus; Hyperglycemia; Hyperphagia; Hypoglycemic Agents; Leptin; Male; Mice; Obesity

Hyperglycemia-induced superoxide production in the mitochondria is known to be the primary cause of diabetic micro- and macro-vascular complications and mitochondrial membranal damage. This study in streptozotocin-induced diabetic Wistar rats investigated the anti-hyperglycemic and mitochondrial membrane protection effects of baicalin, a flavonoid known for its radical scavenging activity.. The following oral treatments were given to diabetic rats for 30 days: (1) metformin 500 mg/kg, (2) baicalin 120 mg/kg, and (3) metformin 500 mg/kg & baicalin 120 mg/kg, with vehicle-treated diabetic and non-diabetic groups serving as controls.. Transmission electron microscopy imaging of pancreatic beta-cells revealed loss of integrity of the inner membrane of the mitochondria in the diabetic rats, which was not observed in the baicalin-treated group. In addition, baicalin and the combined treatment of metformin and baicalin had significantly reduced (p < 0.05) the number of mitochondria with a damaged membrane compared to the diabetic control as well as the metformin-treated group in the hepatic tissues. Baicalin had also increased the plasma leptin content (p < 0.05) versus the diabetic control, which in turn had effected the total expression of hepatic mitochondria per cell indicating its effects in SIRT1 activity. The increase in mitochondrial number was further complemented with similar trends in the hepatic citrate synthase activity.. Baicalin had reduced the hyperglycemia-induced mitochondrial membrane damage, as well as enhanced the effects of metformin, as was observed in the results from the metformin and baicalin treated groups.

Topics: Animals; Citrate (si)-Synthase; Diabetes Complications; Diabetes Mellitus, Experimental; Flavonoids; Free Radical Scavengers; Hepatocytes; Hyperglycemia; Hypoglycemic Agents; Insulin-Secreting Cells; Leptin; Liver; Male; Metformin; Microscopy, Electron, Transmission; Mitochondria; Mitochondria, Liver; Mitochondrial Membranes; Oxidative Stress; Rats; Rats, Wistar

To study the effect of intrauterine hyperglycemia on leptin level and offspring development in rats.. Female and male adult Wistar rats were mated, streptozotocin (STZ, 50 mg/kg) was administered intraperitoneally on 5th day of gestation to induce diabetic model, diabetic pups (DP) were exposed to intrauterine hyperglycemia; control pups (CP) were exposed to controls, which was injected with citrate buffer, 8 pups were choosed from each group. Weight gain between 3 - 10 weeks were recorded. Plasma leptin was detected by enzyme-linked immunosorbent assay (ELISA) when the rats were 11 weeks old, and the expression of leptin receptor in hypothalamus was measured at protein level by histomorphology and mRNA level measured by realtime PCR [expressed with integral absorbance (IA)] in 11 weeks in order to discuss the relation of leptin and offspring development.. The fasting blood glucose level was significantly higher in diabetic mother compared with the controls [(28.3 +/- 5.1) mmol/L vs. (6.3 +/- 1.4) mmol/L, P < 0.05]. However, there was no difference between the fasting blood glucose level in DP group and CP group [(5.1 +/- 0.8) mmol/L vs. (5.3 +/- 0.6) mmol/L, P > 0.05]. The growth rate between 3-10 weeks was significantly higher in DP group 649.7% than CP group 479.2%, P < 0.05. The base insulin level was lower in DP group [(0.76 +/- 0.37) microg/L vs. (1.06 +/- 0.14) microg/L, P < 0.05]; while there was no difference in plasma leptin and the expression of leptin receptor in hypothalamus [(113 +/- 37) microg/L vs. (128 +/- 40) microg/L, P > 0.05]. The growth rate was not associated with plasma leptin in DP group (r = -0.501, P = 0.311) but associated in CP group (r = -0.553, P = 0.001). The protein level of DP group (4125 +/- 414) did not significantly differ from that of CP group (4244 +/- 511). The median of mRNA of leptin receptor in hypothalamus in DP group did not altered significantly compared with that of CP group (1.25 vs 1.80, P > 0.05).. Intrauterine hyperglycemia accelerated growth rate of offsprings between 3 and 10 weeks, however, plasma leptin was not discreased, which indicated leptin resistance. Intrauterine hyperglycemia did not influence the expression of leptin receptor in hypopthalamus in offsprings, this suggested the leptin resistance may be not caused by the quantity of leptin receptors.

Topics: Animals; Hyperglycemia; Insulin; Leptin; Rats, Wistar; Streptozocin

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

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

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

The present study was carried to develop and analyze the consequences of hypercaloric pellet-diet cycle that promotes obesity in rats. Male Wistar rats were randomly distributed into two groups that received either normal diet (ND; n =32; 3,5 Kcal/g) or a hypercaloric diet (HD; n =32; 4,6 Kcal/g). The ND group received commercial Labina rat feeding while the HD animals received a cycle of five hypercaloric diets over a 14-week period. The effects of the diets were analyzed in terms of body weight, body composition, hormone-metabolite levels, systolic arterial pressure and glucose tolerance at the 5% significance level. The hypercaloric pellet diet cycle promoted an increase in body weight and fat, systolic arterial pressure and a high serum level of glucose, triacylglycerol, insulin and leptin. The HD group also presented an impaired glucose tolerance. In conclusion, the results of this study show that the hypercaloric pellet-diet cycle promoted obesity in Wistar rats and displayed several characteristics that are commonly associated with human obesity, such as high arterial pressure, insulin resistance, hyperglycaemia, hyperinsulinaemia, hyperleptinaemia and dyslipidaemia.

Topics: Analysis of Variance; Animals; Blood Pressure; Body Composition; Body Weight; Dietary Fats; Disease Models, Animal; Dyslipidemias; Energy Intake; Humans; Hyperglycemia; Hyperinsulinism; Hypertension; Leptin; Male; Obesity; Random Allocation; Rats; Rats, Wistar

To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer.. We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m(-2)), hypertension (blood pressure > or =140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose > or =6.1 mmol l(-1) or post-load glucose in capillary plasma > or =8.9 mmol l(-1)).. None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20-5.52; P (trend)=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1-9 were 1.56 (95% CI 0.93-2.62; P=0.090), 1.83 (95% CI 1.00-3.36; P=0.051) and 1.50 (95% CI 0.83-2.71; P=0.18), respectively.. Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Colorectal Neoplasms; Epidemiologic Methods; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Sweden

Substantial evidence suggests that poor intrauterine milieu elicited by maternal nutritional disturbance may programme susceptibility in the fetus to later development of chronic diseases, such as obesity, hypertension, cardiovascular disease and diabetes. One of the most interesting features of fetal programming is the evidence from several studies that the consequences may not be limited to the first-generation offspring and that it can be passed transgenerationally. In the present study, female rats (F0) were fed either a normal-protein diet [control diet (C); 19 g of protein/100 g of diet] or a low-protein diet [restricted diet (R); 5 g of protein/100 g of diet]. The offspring were termed according to the period and the types of diet the dams were fed, i.e. CC, RC, CR and RR (first letter indicates the diet during gestation and the second the diet during lactation). At 3 months of age, F1 females were bred to proven males, outside the experiment, to produce F2 offspring. At weaning, F2 offspring were divided by gender. RC1 offspring (with the number indicating the filial generation) were born with low birthweight, but afterwards they had catch-up growth, reaching the weight of the CC1 offspring. The increased glycaemia in RC1 offspring was associated with insulin resistance. CR1 and RR1 offspring had impaired growth with no changes in glucose metabolism. RC2 offspring had high BM (body mass) at birth, which was sustained over the whole experiment in male offspring. The F2 generation had more alteration in glucose metabolism than the F1 generation. CR2 and RC2 offspring had hyperglycaemia accompanied by hyperinsulinaemia and insulin resistance in both genders. CR2 offspring had an increase in body adiposity with hyperleptinaemia. In conclusion, low protein during gestation improves BM, fat mass and growth rate in F1 rats, but has adverse effects on glucose and leptin metabolism, resulting in insulin resistance in adult F1 and F2 offspring. Low protein during lactation has adverse effects on glucose, insulin and leptin metabolism, resulting in insulin resistance in adult F2 offspring. These findings suggest that low protein during gestation and/or lactation can be passed transgenerationally to the second generation.

Topics: Animals; Biometry; Blood Glucose; Diet, Protein-Restricted; Female; Fetal Development; Fetal Nutrition Disorders; Growth; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Lactation; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats

The metabolic syndrome is a group of disorders including obesity, insulin resistance, atherogenic dyslipidemia, hyperglycemia, and hypertension. To date, few animal models have been described to recapitulate the phenotypes of the syndrome. In this study, we generated and characterized two lines of triple-knockout mice that are deficient in either apolipoprotein E (Apoe(-/-)) or low-density lipoprotein receptor (Ldlr(-/-)) and express no leptin (Lep(ob/ob)) or apolipoprotein B-48 but exclusively apolipoprotein B-100 (Apob(100/100)). These two lines are referred to as Apoe triple-knockout-Apoe 3KO (Apoe(-/-)Apob(100/100)Lep(ob/ob)) and Ldlr triple-knockout-Ldlr 3KO (Ldlr(-/-)Apob(100/100)Lep(ob/ob)) mice. Both lines develop obesity, hyperinsulinemia, hyperlipidemia, hypertension, and atherosclerosis. However, only Apoe 3KO mice are hyperglycemic and glucose intolerant and are more obese than Ldlr 3KO mice. To evaluate the utility of these lines as pharmacological models, we treated both with leptin and found that leptin therapy ameliorated most metabolic derangements. Leptin was more effective in improving glucose tolerance in Ldlr 3KO than Apoe 3KO animals. The reduction of plasma cholesterol by leptin in Ldlr 3KO mice can be accounted for by its suppressive effect on food intake. However, in Apoe 3KO mice, leptin further reduced plasma cholesterol independently of its effect on food intake, and this improvement correlated with a smaller plaque lesion area. These effects suggest a direct role of leptin in modulating VLDL levels and, likewise, the lesion areas in VLDL-enriched animals. These two lines of mice represent new models with features of the metabolic syndrome and will be useful in testing therapies targeted for combating the human condition.

Topics: Animals; Apolipoprotein B-48; Apolipoproteins E; Disease Models, Animal; Hyperglycemia; Hyperlipidemias; Hypertension; Insulin Resistance; Leptin; Lipoproteins, VLDL; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phenotype; Receptors, LDL

Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner (Wrn) gene. WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four-month-old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during 4 months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia was characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging.

Topics: Adiposity; Animal Feed; Animals; Body Weight; Diabetes Mellitus; Diet; Glucose Intolerance; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; RecQ Helicases; Werner Syndrome Helicase

Obesity and diabetes, termed "diabesity," are serious health problems that are increasing in frequency. However, the molecular mechanisms and neuronal regulation of these metabolic disorders are not fully understood. We show here that Shp2, a widely expressed Src homology 2-containing Tyr phosphatase, plays a critical role in the adult brain to control food intake, energy balance, and metabolism. Mice with a neuron-specific, conditional Shp2 deletion were generated by crossing a pan-neuronal Cre-line (CRE3) with Shp2(flox/flox) mice. These congenic mice, CRE3/Shp2-KO, developed obesity and diabetes and the associated pathophysiological complications that resemble those encountered in humans, including hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin and leptin resistance, vasculitis, diabetic nephropathy, urinary bladder infections, prostatitis, gastric paresis, and impaired spermatogenesis. This mouse model may help to elucidate the molecular mechanisms that lead to the development of diabesity in humans and provide a tool to study the in vivo complications of uncontrolled diabetes.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Crosses, Genetic; Diabetes Complications; Diabetes Mellitus; Eating; Female; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Male; Mice; Mice, Mutant Strains; Mice, Transgenic; Neurons; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction

An adequate supply of taurine during fetal life is important for normal beta-cell development and insulin action. An altered availability of taurine may programme glucose metabolism in utero and result in type 2 diabetes in adult age. We examined whether maternal taurine supplementation in late pregnant rats affects postnatal growth, adult body composition, insulin sensitivity and endogenous insulin secretion in intrauterine growth restricted (IUGR) and normal offspring. Uterine artery ligation or sham operations were performed on gestational day (GD) 19. Taurine supplementation was given to half of the dams from GD 18 until term, resulting in four groups of offspring: sham (n = 22), sham/taurine (n = 22), IUGR (n = 22) and IUGR/taurine (n = 24). The offspring were studied at 12 weeks of age. In offspring with normal birth weight, fetal taurine supplementation markedly stimulated postnatal growth. In sham/taurine females, fat depots, plasma free fatty acid and leptin concentrations were increased, and insulin sensitivity was reduced. Insulin sensitivity was unaltered in IUGR and IUGR/taurine offspring. However, whereas IUGR offspring showed little catch-up growth, 50% of IUGR/taurine animals displayed complete catch-up at 12 weeks of age, and these animals had increased fat depots and reduced insulin sensitivity. In conclusion, taurine supplementation in late gestation resulted in accelerated postnatal growth, which was associated with adult obesity and insulin resistance in both IUGR and normal offspring. This effect was particularly evident in females. These data suggest that fetal taurine availability is an important determinant for postnatal growth, insulin sensitivity and fat accumulation.

Topics: Adipose Tissue; Animals; Animals, Newborn; Body Composition; Body Weight; Female; Gestational Age; Glucose Clamp Technique; Hyperglycemia; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Maternal Nutritional Physiological Phenomena; Obesity; Placental Insufficiency; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Taurine

Because appetite, hypothalamic gene expression, reproductive function, and adrenal function are highly sensitive to acute changes in plasma glucose levels, it has been hypothesized hypothalamic neurons sensitive to glucose play a role in regulating these functions. To assess this hypothesis, we examined these neuronendocrine functions in mice in which the glucokinase gene, which plays an essential role in neuroendocrine glucose sensing, has been ablated. Haploinsufficiency in heterozygous glucokinase knockout mice produced effects similar to those produced by hypoglycemia: impaired reproductive function, elevated plasma corticosterone, increased food intake, and hypothalamic gene expression similar to that observed in fasted or leptin-deficient obese mice (increased hypothalamic neuropeptide Y mRNA and reduced hypothalamic proopiomelanocortin mRNA). Plasma glucose was elevated 2-fold in glucokinase knockout mice, consistent with a maturity-onset diabetes of the young phenotype, but plasma insulin and leptin levels were normal. These data support the hypothesis that glucokinase plays a key role in the neuroendocrine regulation of metabolic economy.

Topics: Animals; Eating; Female; Fertility; Gene Expression Regulation; Glucocorticoids; Glucokinase; Hyperglycemia; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Knockout; Promoter Regions, Genetic; Reproduction

Experimentally-induced hyperglycemia by prolonged glucose infusion allows investigation of the effects of sustained stimulation of the pancreatic beta-cell on insulin secretion and sensitivity. Hormonal responses to a meal following prolonged glucose infusions have not been investigated. To determine if a 48-h glucose infusion alters hormonal responses to a test meal as well as food intake and hunger in normal weight individuals, 16 subjects (8 men, 8 women, age 18-30 years, mean BMI=21.7+/-1.6 kg/m2) were infused for 48 h with either saline (50 ml/h) or 15% glucose (200 mg/m2/min). Subjects ingested a 600 kcal mixed nutrient meal 3 h after infusion termination. Blood samples were taken during the 48 h and for 4 h following food ingestion. The 48-h glucose infusion elicited a metabolic profile of a glucose intolerant obese subjects, with increased plasma glucose, insulin and leptin (all P<0.01) and increased HOMA-IR (P<0.001). During meal ingestion, early insulin secretion was increased (P<0.05) but post-prandial glucose (P<0.01) and insulin (P<0.01) excursions were lower following the glucose infusion. Post-prandial plasma triglyceride concentrations were increased after glucose compared with saline. Food intake and hunger ratings were not different between the two conditions. Plasma leptin levels were inversely correlated with hunger (P<0.03) in both conditions and with food intake (P<0.003) during the glucose condition only. Thus, a 48-h glucose infusion does not impair post-prandial hormonal responses, alter food intake or hunger in normal weight subjects. The glucose-induced increases in plasma leptin result in a stronger inverse relationship between plasma leptin and hunger as well as food intake. These data are the first to demonstrate a relationship between leptin and hunger in normal weight, non-calorically restricted human subjects.

Topics: Adolescent; Adult; Analysis of Variance; Blood Glucose; Eating; Female; Food Preferences; Glucose; Glucose Intolerance; Humans; Hunger; Hyperglycemia; Infusions, Intravenous; Insulin; Leptin; Male; Taste

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

Chronic kidney disease coexists with metabolic syndrome and this relationship may be apparent before overt manifestations of cardiovascular disease. To investigate early stages of the natural history of associations between renal function and metabolic syndrome, we phenotyped 1572 young (mean age=18.4 years), apparently healthy men for metabolic risk factors and estimated their creatinine clearance based on the Cockcroft-Gault equation. High metabolic risk (clustering of at least three metabolic risk factors) was revealed in 8.7% (137) of the subjects and was associated with a 6.9-fold increase in the odds of glomerular hyperfiltration (95% confidence interval (CI): 3.9-11.5) when compared to reference (from none to two metabolic risk factors). Overweight, elevated blood pressure, and low high-density lipoprotein (HDL) cholesterol increased the multivariate-adjusted odds ratio of glomerular hyperfiltration to 6.6 (95% CI: 3.8-11.6), 1.8 (95% CI: 1.0-3.0), and 2.5 (95% CI: 1.5-4.3), respectively. Systolic and diastolic blood pressures clustered together with leptin in the factor analysis and this blood pressure-adiposity component correlated with estimated creatinine clearance (r=0.329, P<0.0001) and explained on its own 10.2% of the variance in the estimated renal function. Our data reveal the silent epidemics of metabolic risk among young, apparently healthy men. Furthermore, the results indicate that high metabolic risk is associated with glomerular hyperfiltration before overt manifestations of cardiovascular disease.

Topics: Adolescent; Adult; Age Factors; Biomarkers; Creatinine; Glomerular Filtration Rate; Humans; Hyperglycemia; Kidney Diseases; Leptin; Male; Metabolic Syndrome; Prevalence; Risk Factors

Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia.. We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l.. The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04).. Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.

Topics: Adult; Blood Glucose; C-Peptide; Female; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Leptin; Polycystic Ovary Syndrome

The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such "adipose milieu" is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or "adipogenotoxicosis." We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFalpha and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase (CYP1B1) were detected by immunohistochemistry. Aromatase (CYP19) activity in mammary fat was measured by (3)H(2)O release from (3)H-1beta-androstenedione. In the postmenopausal BC patients, NO and TNFalpha production by adipose tissue explants increased independent of BMI and in parallel with decreasing leptin and, especially, adiponectin release. In the premenopausal patients, higher CYP1B1 expression and TBRP level were found in mammary fat, while higher aromatase activity was combined with higher CYP1B1 expression as well as NO and IL-6 production. In the postmenopausal group, impaired glucose tolerance was associated with higher IL-6 release production by fat and with higher IL-6/adiponectin ratio. Thus, signs of adipogenotoxicosis in mammary fat can be found in both pre- and postmenopausal BC patients. This condition is likely being maintained through estrogen- and glucose-related factors and mechanisms presumably associated with less favorable types of hormonal carcinogenesis.

Topics: Adipose Tissue; Adult; Aged; Aged, 80 and over; Aromatase; Breast Neoplasms; Cytochrome P-450 Enzyme System; Estrogens; Female; Humans; Hyperglycemia; Inflammation; Leptin; Macrophages; Mammary Glands, Human; Middle Aged; Postmenopause; Premenopause

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

Recently, we found that poly(gamma-glutamic acid)oxovanadium(IV) complex (VO(gamma-pga)) exhibits a potent antidiabetic activity in streptozotocin (STZ)-induced type 1 diabetic mice. This result prompted us to examine its ability to treat the type 2 diabetic model KKA(y) mice with insulin resistance. We studied the in vivo antidiabetic activity of VO(gamma-pga), 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(-1) body mass to the KKA(y) mice for 30 days. VO(gamma-pga) normalized the hyperglycemia within 21 days, whereas VS lowered the blood glucose concentration only by a small degree. In addition, the glucose intolerance, HbA(1c) level, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia were significantly improved in VO(gamma-pga)-treated KKA(y) mice compared with those treated with VS. Based on these observations, VO(gamma-pga) is proposed to be the first orally active oxovanadium(IV)-polymer complex for the efficacious treatment of not only type 2 diabetes but also metabolic syndrome in animals.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Hyperglycemia; Insulin; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Polyglutamic Acid; Vanadates

The link between obesity and diabetes is not fully understood but there is evidence to suggest that hypothalamic signalling pathways may be involved. The hypothalamic neuropeptides, pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and agouti-related protein (AGRP) are central to the regulation of food intake and have been implicated in glucose homeostasis. Therefore, the expression of these genes was quantified in hypothalami from diabetic Zucker fatty (ZDF) rats and nondiabetic Zucker fatty (ZF) rats at 6, 8, 10 and 14 weeks of age. Although both strains are obese, only ZDF rats develop pancreatic degeneration and diabetes over this time period. In both ZF and ZDF rats, POMC gene expression was decreased in obese versus lean rats at all ages. By contrast, although there was the expected increase in both NPY and AGRP expression in obese 14-week-old ZF rats, the expression of NPY and AGRP was decreased in 6-week-old obese ZDF rats with hyperinsulinaemia and in 14-week-old rats with the additional hyperglycaemia. Therefore, candidate genes involved in glucose, and insulin signalling pathways were examined in obese ZDF rats over this age range. We found that expression of the ATP-sensitive potassium (K(ATP)) channel component, Kir6.2, was decreased in obese ZDF rats and was lower compared to ZF rats in each age group tested. Furthermore, immunofluorescence analysis showed that Kir6.2 protein expression was reduced in the dorsomedial and ventromedial hypothalamic nuclei of 6-week-old prediabetic ZDF rats compared to ZF rats. The Kir6.2 immunofluorescence colocalised with NPY throughout the hypothalamus. The differences in Kir6.2 expression in ZF and ZDF rats mimic those of NPY and AGRP, which could infer that the changes occur in the same neurones. Overall, these data suggest that chronic changes in hypothalamic Kir6.2 expression may be associated with the development of hyperinsulinaemia and hyperglycaemia in ZDF rats.

Topics: Agouti-Related Protein; Animals; Diabetes Mellitus; Gene Expression; Glucose; Hyperglycemia; Hyperinsulinism; Hypothalamus; Immunohistochemistry; Inflammation; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pancreas; Potassium Channels, Inwardly Rectifying; Pro-Opiomelanocortin; Rats; Rats, Wistar; Rats, Zucker; Signal Transduction

Noninfectious complications of peritoneal dialysis (PD) are increasing in relative importance due to success in decreasing the rate of PD peritonitis. Mechanical catheter complications are emerging as an important cause of technique failure at the same time as experience with PD is declining in North America. There is also increasing interest in metabolic complications of PD and in glucose-sparing strategies to reduce the risk for hyperglycemia, hyperinsulinemia, and hyperleptinemia. This clinical commentary focuses on these noninfectious complications of PD.

Topics: Glucose; Humans; Hyperglycemia; Hyperinsulinism; Leptin; Peritoneal Dialysis; Peritonitis; Renal Dialysis; Renal Insufficiency

The AMP-activated kinase (AMPK) is a serine threonine kinase that functions as a fuel sensor to regulate energy balance at both cellular and whole-body levels. Here we studied how hepatic AMPKalpha2 isoform affects hepatic glucose production and peripheral glucose uptake in vivo. We generated mice deleted for the AMPKalpha2 gene specifically in the liver (liveralpha2KO). Liveralpha2KO mice were glucose intolerant and hyperglycemic in the fasted state. Hyperglycemia was associated with a 50% higher endogenous glucose production than in controls as assessed in vivo. We then investigated whether this increased glucose production was sensitive to insulin. Insulin, when infused at a rate inducing physiological hyperinsulinemia, totally inhibited endogenous glucose production in liveralpha2KO mice, showing that they had normal insulin sensitivity. This was confirmed in vivo by normal insulin-induced phosphorylation of Akt and transcriptional regulation of the phosphoenolpyruvate carboxykinase, glucose-6 phosphatase, and pyruvate kinase in liver during the fasted/fed transition. Leptin and adiponectin regulate hepatic glucose production, so we then infused these adipokines into liveralpha2KO mice. Neither of these adipokines regulated hepatic glucose production in mice lacking hepatic AMPKalpha2, whereas both did so in control mice. In conclusion, we show that the hepatic AMPKalpha2 isoform is essential for suppressing hepatic glucose production and maintaining fasting blood glucose levels in the physiological range. We also demonstrate that regulation of hepatic glucose production by leptin and adiponectin, but not insulin, requires hepatic AMPKalpha2 activity.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Blotting, Western; Catalysis; Disease Models, Animal; Gene Deletion; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Glucose-6-Phosphatase; Hyperglycemia; Insect Hormones; Insulin; Leptin; Liver; Male; Mice; Mice, Knockout; Mice, Transgenic; Models, Genetic; Models, Statistical; Multienzyme Complexes; Oligopeptides; Phosphoenolpyruvate Carboxykinase (ATP); Phosphorylation; Protein Isoforms; Protein Serine-Threonine Kinases; Pyrrolidonecarboxylic Acid; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transcription, Genetic; Transcriptional Activation

Obesity is typically associated with resistance to leptin, yet the mechanism by which leptin signaling becomes impaired is poorly understood. Here we sought to determine if the development of obesity and leptin resistance correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) in peripheral tissues and whether over-expression of this phosphatase, specifically in liver, could alter the leptin-mediated effects on feeding and glucose metabolism. Obesity was induced in mice through a high-fat diet that resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia. Resistance to leptin was confirmed as exogenous leptin administration reduced food intake in animals on low-fat, but not high-fat diets. Diet-induced resistance to leptin and insulin was associated with increased hepatic levels of PTP1B. Intriguingly, hepatic adenoviral over-expression of PTP1B in ob/ob mice attenuated the ability of exogenous leptin to reduce both plasma glucose levels and food intake. These findings suggest that leptin reduces both plasma glucose and food intake in part through actions on the liver, and hepatic leptin resistance resulting from over-expression of PTP1B may contribute to the development of both diabetes and obesity.

Topics: Adenoviridae; Animals; Base Sequence; Blood Glucose; CHO Cells; Cricetinae; Dietary Fats; DNA Primers; Feeding Behavior; Genetic Vectors; Hyperglycemia; Hyperinsulinism; Leptin; Liver; Male; Mice; Mice, Inbred BALB C; Polymerase Chain Reaction; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases

Cannabinoid CB(1) receptor blockade decreases weight and hyperinsulinemia in obese animals and humans in a way greatly independent from food intake.. The objective of this study was to investigate the regulation and function of the endocannabinoid system in adipocytes and pancreatic beta-cells.. Mouse 3T3-F442A adipocytes and rat insulinoma RIN-m5F beta-cells, pancreas and fat from mice with diet-induced obesity, visceral and sc fat from patients with body mass index equal to or greater than 30 kg/m(2), and serum from normoglycemic and type 2 diabetes patients were studied.. Endocannabinoid enzyme and adipocyte protein expression, and endocannabinoid and insulin levels were measured.. Endocannabinoids are present in adipocytes with levels peaking before differentiation, and in RIN-m5F beta-cells, where they are under the negative control of insulin. Chronic treatment of adipocytes with insulin is accompanied by permanently elevated endocannabinoid signaling, whereas culturing of RIN-m5F beta-cells in high glucose transforms insulin down-regulation of endocannabinoid levels into up-regulation. Epididymal fat and pancreas from mice with diet-induced obesity contain higher endocannabinoid levels than lean mice. Patients with obesity or hyperglycemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls. CB(1) receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F beta-cells kept in high glucose.. Peripheral endocannabinoid overactivity might explain why CB(1) blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.

Topics: 3T3 Cells; Adipocytes; Adiponectin; Adipose Tissue; Adult; Animals; Cannabinoid Receptor Modulators; Cell Line, Tumor; Diabetes Mellitus, Type 2; Endocannabinoids; Epididymis; Female; Gene Expression; Glucose; Homeostasis; Humans; Hyperglycemia; Insulin; Insulinoma; Intra-Abdominal Fat; Islets of Langerhans; Leptin; Male; Mice; Obesity; Pancreas; Pancreatic Neoplasms; PPAR gamma; Rats; Signal Transduction

This study was conducted to explore the association between nonalcoholic fatty liver disease and glucose metabolism as well as insulin resistance using the homeostasis model assessment method (HOMA).. From July 2003 to June 2004, 23 patients with ultrasound-proved fatty liver and either normal (10 patients) or abnormal (13 patients) serum aminotransferase levels were enrolled. Blood tests included a routine biochemistry, a 75-g glucose oral glucose tolerance test (OGTT) with blood sampled at 30-minute intervals during a 120-minute period. Fasting and 120-minute serum leptin, insulin, and C-peptide concentrations were also measured.. Using the Mann-Whitney U test, significant differences were found in gamma glutamyl transpeptidase (28.6+/-7.9 vs. 65.1+/-65.9 U/L, P=0.008), fasting insulin (FI) (13.11+/-7.53 vs. 31.76+/-42.95 muU/mL, P=0.02), fasting C-peptide (3.82+/-3.00 vs. 2.17+/-0.43 ng/mL, P=0.01), fasting leptin (10.34+/-4.05 vs. 24.27+/-24.97 ng/mL, P=0.01), HOMA-IR (3.34+/-1.06 vs. 8.81+/-13.18, P=0.02), and HOMA beta-cell function (120.32+/-52.50 vs. 242.20+/-247.29, P=0.02) between normal and abnormal ALT/AST function groups. From the 75-g OGTT, no significant difference of plasma glucose was noted at 0, 30, 60, and 90 minutes but significant change was noted in 120-minute plasma glucose (99.3+/-21.5 vs. 131.4+/-27.3 mg/dL, P=0.004) of 2 groups.. In conclusion, patients with fatty liver proved by ultrasound sonography might be at high risk of developing type 2 diabetes, especially when they had elevated liver enzymes. OGTT is warranted for the early diagnosis of these high risk patients.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; C-Peptide; Fatty Liver; Female; Food Deprivation; Glucose Tolerance Test; Homeostasis; Humans; Hyperglycemia; Insulin; Leptin; Liver Function Tests; Male; Metabolic Syndrome; Postprandial Period; Ultrasonography

We previously reported that the adiponectin-leptin (A/L) ratio was more efficacious as a parameter of insulin resistance than adiponectin or leptin alone, and a more sensitive and reliable marker of insulin resistance than homeostasis model assessment (HOMA-R) as the fasting plasma glucose (FPG) level elevated in type 2 diabetes mellitus. In this study, we examined the usefulness of the A/L ratio as compared to HOMA-R for assessing insulin resistance in Japanese subjects without hyperglycemia. A total of 411 Japanese adults without hyperglycemia (205 men, aged 49 +/- 10 years; 206 women, aged 48 +/- 10 years) were enrolled. We investigated the correlation between fasting serum insulin level, FPG, leptin or adiponectin, and body mass index (BMI), fat mass (FM), triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, or preheparin serum lipoprotein lipase (LPL) as parameters of insulin resistance. Next, we examined the relationships between parameters of insulin resistance and the A/L ratio or HOMA-R. By simple regression of the correlation between serum insulin level, FPG, leptin or adiponectin, and each parameter of insulin resistance, the best correlation coefficients were seen in leptin (men, r = 0.501; women, r = 0.667) as compared with BMI, in leptin (men, r = 0.658; women, r = 0.747) as compared with FM, in adiponectin (r = -0.285) in men and leptin (r = 0.299) in women as compared with TGs, in adiponectin (men, r = 0.405; women; r = 0.442) as compared with HDL cholesterol, and in adiponectin (men, r = 0.228; women, r = 0.452) as compared with LPL. By simple regression of the correlation between A/L ratio or HOMA-R and each parameter of insulin resistance, the highest correlation coefficients were seen with the A/L ratio except HDL cholesterol in men. Next, we carried out multiple linear regression to analyze the association between A/L ratio or HOMA-R and FM, TGs, HDL cholesterol, and LPL, excluding BMI, simultaneously. In men, the A/L ratio was significantly correlated with FM and TGs, and HOMA-R was significantly correlated with FM. This model explained 34% of the variance in the A/L ratio and 17% of the variance in HOMA-R. In women, the A/L ratio was significantly correlated with FM and LPL, and HOMA-R was significantly correlated with FM and LPL. This model explained 39% of the variance in A/L ratio and 14% of the variance in HOMA-R. In conclusion, the present study suggested that the A/L ratio might be more useful than HOMA-R to accura

Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Female; Humans; Hyperglycemia; Insulin; Insulin Resistance; Japan; Leptin; Lipids; Male; Middle Aged

In pregnant primates, the effect of post-prandial hyperglycemic or insulinemic states on leptin production is not known. Our goal was to conduct a controlled study using an established pregnant baboon model ( PAPIO ANUBIS) to determine whether acute glucose changes would have an effect on maternal or fetal plasma leptin levels.. Two animals were operated on at 138 and 140 days of gestation (term approximately 184 days) by placing 4 cannulae in the maternal aorta, inferior vena cava, fetal carotid artery, and the amniotic cavity. At 145 and 150 days, glucose infusions were started via the maternal femoral vein. Animal 1 received 7.5 gm of glucose over a 2-hour period at 145 th day. Animal 2 received 20 gm of glucose over a 1-hour period at 150th day. Both animals remained ad libitum throughout the experiments. Maternal and fetal blood samples were obtained from the arterial lines before the glucose infusion and at half hour intervals to include 30 minutes post-infusion.. Significant changes from baseline concentrations were observed for maternal and fetal glucose and insulin concentrations in response to both glucose challenges. Maternal and fetal plasma leptin concentrations did not correlate with glucose or insulin changes.. This preliminary study demonstrated that in primates, acute changes in circulating maternal or fetal glucose or insulin concentration do not affect maternal or fetal plasma leptin concentrations. These results suggest that alterations in leptin secretion by the maternal-placental-fetal unit may only occur in pathological states.

Topics: Animals; Blood Glucose; Female; Fetus; Gestational Age; Glucose; Hyperglycemia; Insulin; Leptin; Papio; Pregnancy

Type 1 diabetes mellitus (T1DM) leads to increased serum levels of the soluble leptin receptor (sOB-R) by an as yet unknown cellular mechanism. The aim of our study was to investigate potential metabolic factors that may be associated with the induction of the sOB-R release from its membrane receptor.. Twenty-five children (aged between 1.5 and 17.0 years) were studied at the onset of T1DM. Blood samples were collected before (n = 25), during the first 18 h (mean +/- S.D. 11.1 +/- 4.3 h, n = 16) and 92 h (47.5 +/- 22.5 h; n = 14) after beginning insulin therapy. Serum sOB-R and leptin levels were determined by in-house immunoassays.. The sOBR-level and the molar sOB-R/leptin ratio were significantly higher before than after starting insulin treatment (P < 0.05). In contrast, leptin levels were significantly lower (P < 0.05) before insulin therapy. The correlation between sOB-R and blood glucose (r = 0.49; P < 0.05), as well as sOB-R with parameters of ketoacidosis, such as pH (r = -0.72), base excess (r = -0.70), and bicarbonate (r = -0.69) (P < 0.0001) at diagnosis of T1DM remained significant during the first 18 h of insulin treatment. Multiple regression analysis revealed that base excess predicted 41.0% (P < 0.001), age 16.4% (P < 0.05), and height SDS 13.9% (P < 0.01) of the sOB-R variance.. Metabolic decompensation in children with new onset T1DM is associated with dramatic changes of the leptin axis; serum levels of sOB-R are elevated and of leptin are reduced. The molar excess of sOB-R over leptin (median 11.3) in this condition may contribute to leptin insensitivity. Upregulation of the soluble leptin receptor appears to be a basic mechanism to compensate for intracellular substrate deficiency and energy-deprivation state.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Fatty Acids, Nonesterified; Humans; Hyperglycemia; Infant; Leptin; Receptors, Cell Surface; Receptors, Leptin

Topics: Adult; Age Factors; Child; Humans; Hyperglycemia; Inflammation Mediators; Insulin; Leptin; Meningococcal Infections; Shock, Septic

The protein p27(Kip1) regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition.

Topics: Animals; Cell Cycle Proteins; Cell Nucleus; Cyclin-Dependent Kinase Inhibitor p27; Diabetes Mellitus, Type 2; Disease Models, Animal; Enzyme Inhibitors; Hyperglycemia; Hyperinsulinism; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Phosphoproteins; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Tumor Suppressor Proteins

We have previously demonstrated that two wild-derived stocks of mice, Idaho and Majuro, are significantly longer-lived than mice of a control stock (DC) generated as a four-way cross of commonly used laboratory strains of mice. This study provides independent confirmation of this earlier finding, as well as examining serum glucose, insulin, leptin, glycated hemoglobin (GHb), cataract severity, and glucose tolerance levels in each of the stocks. Both the mean (+20%) and maximum (+13%) life span of the Idaho mice were significantly increased relative to the DC stock, while in the Majuro mice only maximum (+15%) life span was significantly increased. In addition, Majuro mice were hyperglycemic in both the fed and fasted states compared both to laboratory-derived and Idaho stocks, had significantly elevated GHb levels and cataract scores, and were glucose intolerant although serum insulin levels did not differ between stocks. Body weight and body mass index (BMI)-corrected leptin levels were also dramatically (1.5-3-fold) higher in the Majuro mice. The longevity of Id mice was not accompanied by changes in serum glucose and insulin levels, or glucose tolerance compared to DC controls, although GHb levels were significantly lower in the Idaho mice. Taken together, these findings suggest that neither a reduction of blood glucose levels nor an increase in glucose tolerance is necessary for life span extension in mice.

Topics: Animals; Blood Glucose; Body Mass Index; Cataract; Female; Glucose Tolerance Test; Glycated Hemoglobin; Growth; Hyperglycemia; Insulin; Leptin; Longevity; Mice; Mice, Inbred Strains; Survival Analysis

The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

Topics: Adipocytes; Animals; Body Weight; Brain; Circadian Rhythm; CLOCK Proteins; Dietary Fats; Energy Intake; Energy Metabolism; Feeding Behavior; Hepatocytes; Hyperglycemia; Hyperlipidemias; Insulin; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Motor Activity; Mutation; Neuropeptides; Obesity; Trans-Activators; Weight Gain

Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been successfully used to treat lipodystrophic diabetes, a leptin-deficient state. To study whether leptin therapy can be used for treatment of more common cases of type 2 diabetes, we used a mouse model of type 2 diabetes (MKR mice) that show normal leptin levels and are diabetic due to a primary defect in both IGF-I and insulin receptors signaling in skeletal muscle. Here we show that leptin administration to the MKR mice resulted in improvement of diabetes, an effect that was independent of the reduced food intake. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluconeogenesis. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and inhibiting lipogenesis led to an improvement of the lipotoxic condition. Our data suggest that leptin could be a potent antidiabetic drug in cases of type 2 diabetes that are not leptin resistant.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Energy Metabolism; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Liver; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Multienzyme Complexes; Muscle, Skeletal; Protein Serine-Threonine Kinases; Triglycerides

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.

Topics: Adipose Tissue; Alleles; Analysis of Variance; Animal Feed; Animals; Blood Glucose; Blotting, Southern; Blotting, Western; Body Composition; Body Weight; Crosses, Genetic; Diet; DNA; Female; Gene Deletion; Genetic Predisposition to Disease; Genotype; Ghrelin; Heterozygote; Homeostasis; Hyperglycemia; Insulin-Like Growth Factor I; Leptin; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Models, Genetic; Neurons; Obesity; Peptide Hormones; Phenotype; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Recombinant Proteins; Recombination, Genetic; RNA, Messenger; Signal Transduction; Silver Staining; Time Factors

To determine if increased local production of glucocorticoids by the pancreatic islets might play a role in the spontaneous noninsulin-dependent diabetes mellitus of obesity, we compared islet 11beta-HSD-1 mRNA and activity in islets of obese prediabetic and diabetic Zucker Diabetic Fatty (ZDF) (fa/fa) rats and lean wild-type (+/+) controls. In diabetic rat islets, both mRNA and enzymatic activity of the enzyme were increased in proportion to the hyperglycemia. Troglitazone (TGZ) treatment, beginning at 6 weeks of age, prevented the hyperglycemia, the hyperlipidemia, and the increase in 11beta-HSD-1. To determine if the metabolic abnormalities had caused the 11beta-HSD-1 increase, prediabetic islets were cultured in high or low glucose or in 2:1 oleate:palmitate for 3 days. Neither nutrient enhanced the expression of 11beta-HSD-1. We conclude that 11beta-HSD-1 expression and activity are increased in islets of diabetic, but not prediabetic ZDF rats, and that TGZ prevents both the increase in 11beta-HSD-1 and the diabetes.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Animals, Genetically Modified; Blotting, Western; Chromans; Cushing Syndrome; Diabetes Mellitus, Experimental; Fatty Acids; Glucose; Hyperglycemia; Hypoglycemic Agents; Islets of Langerhans; Leptin; Microsomes, Liver; Obesity; Oleic Acid; Palmitates; Phenotype; Prednisone; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones; Troglitazone

Ghrelin is secreted primarily by the stomach, although other tissues such as the pancreas synthesize a minor proportion. The discovery of a new cell type that produces ghrelin in the human pancreas and that this organ expresses GHS-R opens new perspectives in the understanding of the control of glucose metabolism. We have studied 22 children with newly diagnosed type 1 diabetes mellitus at four different points: at diagnosis before insulin therapy, after 48-60 h of insulin therapy, and after 1 and 4 mo of insulin treatment. At each point circulating levels of ghrelin, leptin, IGF-I, IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, and glucose were determined. Ghrelin levels were significantly decreased at diagnosis (573 +/- 68 pg/mL, p < 0.01) compared with controls (867 +/- 38 pg/mL) and remained decreased after insulin therapy (d 2: 595 +/- 68 pg/mL; 1 mo: 590 +/- 61 pg/mL; 4 mo: 538 +/- 67 pg/mL) with no differences before or after insulin treatment. There was a negative correlation between ghrelin levels and body mass index at all of the study points, whereas a negative correlation between ghrelin and glucose concentrations was only observed after insulin therapy. No correlation between ghrelin and HbA1c was found at any point. A positive correlation between ghrelin and IGFBP-1 was found after insulin therapy, but no correlation with other members of the IGF system or leptin was found. In conclusion, these data could indicate a possible link between glucose concentrations and ghrelin; hence, the persisting low ghrelin levels in diabetic children may suggest a defensive mechanism against hyperglycemia.

Topics: Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Ghrelin; Glucose; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Pancreas; Peptide Hormones; Radioimmunoassay; Time Factors

We examined the galanin-like peptide (GALP) gene expression in the arcuate nucleus (ARC) and posterior pituitary (PP) in 6- and 18-week-old male obese fa/fa rats. GALP mRNA in the ARC in fa/fa rats was significantly decreased in 6- and 18-week-old and GALP mRNA in the PP in fa/fa rats was significantly increased in 18-week-old compared to lean Fa/? rats. Insulin treatment in hyperglycemic fa/fa rats partially reversed those changes. These results suggest that the GALP gene expression in fa/fa rats might be regulated in part by leptin-independent mechanisms.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Galanin-Like Peptide; Gene Expression Regulation; Hyperglycemia; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pituitary Gland, Posterior; Pro-Opiomelanocortin; Rats; Rats, Mutant Strains; RNA, Messenger

Resistin was originally reported as an adipose tissue-specific hormone that provided a link between obesity and diabetes. Resistin protein level was elevated in obese mice and decreased by insulin-sensitizing thiazolidinediones. Immunoneutralization of resistin improved insulin sensitivity in diet-induced obese mice, while the administration of exogenous resistin induced insulin resistance. More recently, we have shown that ablation of the resistin gene in mice decreased fasting glucose through impairment of gluconeogenesis, while resistin treatment in these knockout mice increased hepatic glucose production. However, the link between resistin and glucose homeostasis has been questioned by studies demonstrating reduced, rather than increased, resistin mRNA expression in obese and diabetic mice. To better understand the regulation of resistin, we developed a sensitive and specific RIA resistin that could accurately measure serum resistin levels in several mouse models. We show that while resistin mRNA is indeed suppressed in obese mice, the circulating resistin level is significantly elevated and positively correlated with insulin, glucose, and lipids. Both resistin mRNA expression and protein levels in Lep(ob/ob) mice are suppressed by leptin treatment in parallel with reductions in glucose and insulin. In wild-type mice, serum resistin increases after nocturnal feeding, concordant with rising levels of insulin. Resistin mRNA and protein levels decline in parallel with glucose and insulin during fasting and are restored after refeeding. We performed clamp studies to determine whether resistin is causally related to insulin and glucose. Adipose resistin expression and serum resistin increased in response to hyperinsulinemia and further in response to hyperglycemia. Taken together, these findings suggest that the nutritional regulation of resistin and changes in resistin gene expression and circulating levels in obesity are mediated, at least in part, through insulin and glucose.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus; Diet; Fasting; Female; Hormones, Ectopic; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Radioimmunoassay; Resistin; RNA, Messenger

It has been proposed that the hexosamine pathway acts as a nutrient-sensing pathway, protecting the cell against abundant fuel supply, and that accumulation of hexosamines represents a biochemical mechanism by which hyperglycemia and hyperlipidemia induce insulin resistance. We hypothesized that if an increased flux through the hexosamine pathway caused insulin resistance in humans, the hexosamine levels should be increased in adipose and/or muscle tissue in insulin-resistant subjects, such as patients with type 2 diabetes and obese individuals. In addition, we reasoned that if the hexosamine pathway were a nutrient-sensing pathway, hexosamine levels in adipose and skeletal muscle tissue should be correlated with levels of circulating nutrients, such as glucose and free fatty acids (FFAs) and leptin concentrations. In a human cross-sectional study of 55 patients [20 with type 2 diabetes mellitus (DM) and 21 normal-lean (NL) and 14 normal-obese (NO) subjects] who underwent hip replacement surgery, adipose and muscle tissue biopsies were obtained and analyzed for levels of hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine] and hexoses (UDP-glucose and UDP-galactose). Fasting plasma glucose, glycosylated hemoglobin, serum insulin and homeostasis model assessment calculations, serum lipids, and leptin were measured on the same day. Hexosamines were not elevated in adipose and muscle tissue of patients with type 2 DM compared with NL and NO subjects (UDP-GlcNac DM vs. NL vs. NO, 3.3 +/- 2.3 vs. 2.2 +/- 2.1 vs. 3.0 +/- 2.0 nmol/g tissue in adipose tissue and 8.1 +/- 2.9 vs. 7.8 +/- 2.8 vs. 7.6 +/- 2.8 nmol/g tissue in muscle tissue, respectively). Hexosamines in adipose tissue were positively correlated with circulating levels of FFA (UDP-GlcNAc, r = 0.33, P < 0.05; UDP-N-acetylgalactosamine, r = 0.41, P < 0.01). Adipose tissue UDP-GlcNAc was correlated with leptin levels (r = 0.33; P < 0.05). No such relationship was identified in muscle tissue. In conclusion, these findings argue against a pathophysiological role of the hexosamine pathway in insulin resistance in humans but support the hypothesis that the hexosamine pathway in adipose tissue, not in muscle, is a FFA-sensing pathway and could be involved in the regulation of leptin expression.

Topics: Adipose Tissue; Aged; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Hexosamines; Hexuronic Acids; Humans; Hyperglycemia; Insulin Resistance; Leptin; Male; Middle Aged; Muscle, Skeletal; Uridine Diphosphate Sugars

We examined the effect of a high-fat diet on the diabetes-related traits of the Japanese Fancy mouse 1 (JF1), MSM, and C57BL/6J (B6J) mice. MSM and JF1 mice were derived from Mus musculus molossinus. B6J is a commonly used laboratory strain, with the vast majority of genome segments derived from Mus musculus domesticus and Mus musculus musculus, and is susceptible to high-fat diet-induced type 2 diabetes. None of the strains showed symptoms of diabetes or obesity when fed a laboratory chow diet. Under a high-fat diet, JF1 mice developed impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and obesity. B6J mice fed a high-fat diet mildly developed these diabetes-related traits compared to JF1 mice fed a high-fat diet. JF1 mice fed a high-fat diet were classified as having type 2 diabetes and were susceptible to high-fat diet-induced diabetes and obesity. On the other hand, MSM mice were resistant to high-fat diet-induced diabetes. These results indicate that the JF1 strain, with its unique genetic origin, is a useful new animal model of high-fat diet-induced diabetes and obesity. Further investigations using JF1 mice will help to clarify the role of the high-fat diet on human diabetes and obesity.

Topics: Animals; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Genetic Predisposition to Disease; Glucose Intolerance; Hyperglycemia; Insulin; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Organ Size; Triglycerides

The purpose of this investigation was to determine the effects of Phytostanol Phosphoryl Ascorbate (FM-VP4) on insulin resistance, hyperglycemia, plasma lipid levels, body weight, and gastrointestinal absorption of exogenous cholesterol in Zucker (fa/fa) fatty and lean rats. A group of 12 age-matched male obese (n = 6) and lean (n = 6) Zucker rats were administered 250 mg/kg twice a day (as 2% FM-VP4 in drinking water) for 30 consecutive days. Fasted blood samples prior to and following treatment were taken from all rats for glucose, lipid, insulin, and leptin determination. An oral glucose tolerance test was also carried out at the end of the treatment protocol. In addition, male obese (n = 7) and lean (n = 8) Zucker rats were coadministered a single oral gavage of [(3)H]cholesterol plus cold cholesterol with or without FM-VP4 (20 mg/kg) dissolved in Intralipid and the plasma concentration of the radiolabel was determined 10 h following the dose. FM-VP4 30-day treatment did not alter body weight, morning glucose, insulin, lipids, and leptin concentrations. There was no alteration in glucose tolerance in the nondiabetic, normoglycemic lean group; however, there was a highly significant improvement in glucose tolerance in the fatty group following FM-VP4 treatment. In addition, the insulin response to oral glucose showed no significant change in nondiabetic lean rats, whereas there was a change in the insulin secretory profile in the fatty group following FM-VP4 treatment. Furthermore, following a single oral gavage of FM-VP4 resulted in a significant decrease in the percentage of radiolabeled cholesterol absorbed. These findings suggest that FM-VP4 treatment to fatty Zucker rats could result in increased glucose responsiveness of the insulin secreting pancreatic beta cells. Furthermore, our findings suggest that FM-VP4 may only be effective presystemically. Systemic administration of FM-VP4 is warranted to determine the therapeutic potential of this effect.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Cholesterol, Dietary; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Intestinal Absorption; Leptin; Lipids; Male; Obesity; Phytosterols; Rats; Rats, Zucker

To elucidate the function of PPARgamma in leptin-deficient mouse (ob/ob) liver, a PPARgamma liver-null mouse on an ob/ob background, ob/ob-PPARgamma(fl/fl)AlbCre(+), was produced using a floxed PPARgamma allele, PPARgamma(fl/fl), and Cre recombinase under control of the albumin promoter (AlbCre). The liver of ob/ob-PPARgamma(fl/fl)AlbCre(+) mice had a deletion of exon 2 and a corresponding loss of full-length PPARgamma mRNA and protein. The PPARgamma-deficient liver in ob/ob mice was smaller and had a dramatically decreased triglyceride (TG) content compared with equivalent mice lacking the AlbCre transgene (ob/ob-PPARgamma(fl/fl)AlbCre(-)). Messenger RNA levels of the hepatic lipogenic genes, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1, were reduced in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice, and the levels of serum TG and FFA in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice were significantly higher than in the control ob/ob-PPARgamma(fl/fl)AlbCre(-) mice. Rosiglitazone treatment exacerbated the fatty liver in ob/ob-PPARgamma(fl/fl)AlbCre(-) mice compared with livers from nonobese Cre(-) mice; there was no effect of rosiglitazone in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice. The deficiency of hepatic PPARgamma further aggravated the severity of diabetes in ob/ob mice due to decreased insulin sensitivity in muscle and fat. These data indicate that hepatic PPARgamma plays a critical role in the regulation of TG content and in the homeostasis of blood glucose and insulin resistance in steatotic diabetic mice.

Topics: Animals; Blood Glucose; Fatty Acids, Nonesterified; Fatty Liver; Hyperglycemia; Insulin Resistance; Leptin; Lipoprotein Lipase; Lipoproteins, VLDL; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Receptors, Leptin; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Triglycerides

Glucocorticoids have been implicated as pathophysiological mediators of obesity and insulin resistance and are regulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This enzyme regenerates active corticosterone from inactive 11-keto forms. To assess the role of 11beta-HSD1-mediated synthesis of active corticosterone in leptin-related obesity and diabetes, we examined the peripheral effect of leptin on 11beta-HSD1 activity and gene expression in vivo and in vitro in hepatocytes from ob/ob mice and in liver of streptozotocin (STZ)-treated ob/ob mice. We observed an inverse relationship between hepatic 11beta-HSD1 expression and body weight in ob/ob mice and lean littermates. Leptin treatment of ob/ob mice markedly increased hepatic 11beta-HSD1 activity and mRNA expression. This induction of 11beta-HSD1 expression corresponded to reduced levels of circulating corticosterone and weight loss in ob/ob mice treated with leptin, indicating that impaired hepatic 11beta-HSD1 expression may contribute to the pathogenesis of obesity in ob/ob mice. In addition, leptin treatment of STZ-treated ob/ob mice caused marked increases in hepatic 11beta-HSD1 levels associated with decreased body weight and a significant reduction in hyperglycemia due to pancreatic beta-cell damage. Addition of leptin to ob/ob mouse primary hepatocytes led to a dose-dependent increase in 11beta-HSD1 mRNA expression. In contrast, leptin did not influence 11beta-HSD1 expression in primary hepatocytes from db/db mice, indicating that leptin regulation of 11beta-HSD1 expression is probably mediated by the functional leptin receptor. Thus, leptin appears to be an important metabolic signal that directly activates intrahepatic corticosterone production. These findings suggest that the liver-specific interaction of leptin with 11beta-HSD1 is involved in the development of obesity and insulin resistance in ob/ob mice.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Experimental; Female; Hepatocytes; Hydroxysteroid Dehydrogenases; Hyperglycemia; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Recombinant Proteins

We aimed to determine the effect of insulin replacement on serum leptin concentration in lean and obese patients with diabetic ketoacidosis (DKA). We compared serial leptin levels in 52 patients with DKA, 14 obese subjects with hyperglycemia, and 52 nondiabetic control subjects. Leptin levels on admission were significantly decreased in lean and obese patients with DKA and/or hyperglycemia compared with weight- and gender-matched controls. Insulin therapy resulted in a significant increase in leptin levels within 4 h, with peak stimulation at 12 h. Leptin levels on admission and at resolution of hyperglycemia were higher in obese DKA (9.7 +/- 2 ng/ml and 26.5 +/- 5 ng/ml, respectively; P < 0.001) and obese hyperglycemia subjects (11.9 +/- 4 ng/ml vs. 24.4 +/- 2 ng/ml; P < 0.001) than in lean DKA subjects (5.3 +/- 0.3 ng/ml and 10.1 +/- 2 ng/ml; P < 0.001). We conclude that insulin treatment in patients with acute hyperglycemic crises is followed by rapid and significant increase in leptin concentration, and this increase is more discernible in obese subjects. The low serum leptin level on admission in subjects with hyperglycemic crises may be the result of impaired adipocyte glucose utilization due to insulin deficiency and/or to increased catecholamine levels.

Topics: Acute Disease; Adult; Case-Control Studies; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Leptin; Male; Middle Aged; Obesity; Thinness

To characterize the meal patterns of free feeding Sprague-Dawley rats that become obese or resist obesity when chronically fed a high-fat diet.. Male Sprague-Dawley rats (N = 120) were weaned onto a high-fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet-induced obese (DIO)] and lower [diet-resistant (DR)] deciles for body-weight gain were selected for study. A cohort of chow-fed (CF) rats weight-matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system.. DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups.. The hyperphagia of a Sprague-Dawley rat model of chronic diet-induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.

Topics: Animals; Body Composition; Circadian Rhythm; Diet; Eating; Energy Intake; Food; Genetic Predisposition to Disease; Hyperglycemia; Hyperinsulinism; Hyperphagia; Hypertriglyceridemia; Insulin; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Satiation; Weight Gain

Ghrelin, leptin and adiponectin are three hormones which are frequently associated with metabolism, obesity and appetite. Recently, it has been shown that they may possess other physiologic roles, specially in connection with the circulation. Ghrelin infusion increases forearm blood-flow in a dose-dependent manner. Leptin has been shown to be involved not only in thermogenesis but angiogenesis as well. Adiponectin, apart from its insulin-sensitizing action, appears to modulate inflammation by inhibiting monocyte adhesion to endothelial cells. Six monkeys, which had been classified as being in the pre-diabetic state, where administered a triglyceride lowering regimen. Microvascular function was assessed using a laser Doppler flow-meter during a temperature provocation test. Percent change in flow from baseline following temperature elevation, as well as percent change in flow/degree rise in temperature were used to evaluate microvascular reserve and reactivity. Using univariate analysis, it appears that increased perfusion is significantly correlated with adiponectin, followed by leptin. Flow was also positively correlated with ghrelin, but the relationship did not attain significance. As expected, flow was also negatively and significantly correlated with fibrinogen. Trends show that flow was also negatively correlated to circulating triglyceride levels (p=0.08). The data indicate that the three hormones appear to possess microvascular actions that may impact on their other physiologic functions.

Topics: Adiponectin; Animals; Blood Glucose; Fibrinogen; Ghrelin; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Hypolipidemic Agents; Intercellular Signaling Peptides and Proteins; Leptin; Macaca mulatta; Metabolic Syndrome; Microcirculation; Obesity; Peptide Hormones; Prediabetic State; Proteins

Neuropeptide Y (NPY) is a 36 amino acid peptide well known for its role in regulating food intake and energy homeostasis. It has previously been shown that the NPY Y2 receptor is required for a full biological response to leptin in the central nervous system. We have examined the impact of this receptor on plasma levels of lipid and cholesterol in wild type and obese (ob/ob) mice. The results show that an absence of Y2 in female mice has no effect on cholesterol level in normal lean mice but profoundly decreases serum cholesterol and glucose levels in ob/ob mice. We conclude that NPY, interacting with the Y2 receptor, participates in cholesterol and glucose homeostasis of obese mice.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Crosses, Genetic; Female; Hypercholesterolemia; Hyperglycemia; Leptin; Lipids; Lipoproteins; Mice; Mice, Inbred BALB C; Mice, Obese; Mice, Transgenic; Neuropeptide Y; Receptors, Neuropeptide Y; Temperature; Time Factors

To compare umbilical cord leptin concentrations in different ethnic groups and between pregnancies with and without gestational diabetes mellitus (GDM) in Auckland, New Zealand.. A cross-sectional study of 116 European, Polynesian, and South Asian women and their infants with and without GDM. Maternal metabolic measures were recorded at 36 weeks' gestation, umbilical cord samples were collected at birth, and neonatal anthropometric measures were recorded 24 h after delivery.. Compared with Europeans and South Asians, samples of Polynesian umbilical cords had higher leptin concentrations (8.7 and 9.5 vs. 14.9 ng/ml, respectively; P = 0.026). Umbilical cord samples from pregnancies complicated by GDM had higher leptin concentrations than those from normal pregnancies (22.3 vs. 13.8 ng/ml, respectively; P = 0.022). Maternal leptin concentrations at 36 weeks were similar across ethnic groups and with and without GDM. Cord leptin correlated with birth weight, measures of fetal size, and cord insulin in normal pregnancies and those complicated by GDM. In multivariate analyses, cord leptin was related to birth weight (P < 0.001), gestation at delivery (P = 0.038), and ethnic group (P = 0.017) in normal pregnancies and to birth weight (P < 0.001), gestation at delivery (P < 0.001), and sex (P = 0.003) but not maternal diabetes status (P = 0.909) in pregnancies complicated by GDM.. Offspring of Polynesian women are relatively hyperleptinemic, independent of birth size. Offspring of women with GDM are also relatively hyperleptinemic at birth, but this was associated with their increased birth weight. We speculate that this GDM-associated relative hyperleptinemia may be due to fuel-mediated teratogenesis affecting the adipoinsular axis, which in turn could also lead to leptin resistance and obesity in adult life. The reason for the ethnic difference in hyperleptinemia is unclear.

Topics: Adult; Asian People; Birth Weight; Cross-Sectional Studies; Diabetes, Gestational; Female; Humans; Hyperglycemia; Infant Nutritional Physiological Phenomena; Infant, Newborn; Insulin; Leptin; Male; Pregnancy

Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. However, in contrast to other models of lipoatrophic diabetes, there was no accumulation of fat in liver or muscle. Furthermore, plasma leptin levels were markedly decreased, and adenovirus-mediated expression of leptin in liver reversed the hyperglycemia and hyperinsulinemia. The results indicate that IRS-1 and IRS-3 play important complementary roles in adipogenesis and establish the Irs1(-/-)/Irs3(-/-) double knockout mouse as a novel model of lipoatrophic diabetes.

Topics: Adenoviridae; Adipose Tissue; Animals; Diabetes Mellitus, Lipoatrophic; Disease Models, Animal; Fatty Acids, Nonesterified; Glucose; Hyperglycemia; Hyperinsulinism; Immunoenzyme Techniques; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Phosphoproteins; Transfection; Triglycerides

Leptin, an adipocyte-derived factor, has multiple biological roles including mitogenesis. We investigated the effect of normal development, acute and chronic hyperglycemia and hypoglycemia, and selective acute hyperglycemia, or hyperinsulinemia, on fetal ovine white adipose tissue (WAT) leptin mRNA concentrations. Leptin mRNA amounts expressed as a ratio to the internal control ribosomal S2 mRNA decreased threefold with advancing gestational age (P < 0.05). This gestational decrease was opposite to the 10-fold increase in fetal body weight during the same developmental period. Chronic hyperglycemia with hyperinsulinemia led to no change in WAT leptin mRNA concentrations over a 1- to 10-day duration, but it caused a 40% increase over a 14- to 20-day duration (P < 0.05) along with an increase in fetal body weight (P < 0.05). In contrast, hypoglycemia with hypoinsulinemia, while not affecting WAT leptin mRNA from 1 to 34 days, resulted in a 50% decline over a 36- to 76-day duration along with a decline in fetal body weight (P < 0.05). Acute 24-h studies of selective hyperglycemia with euinsulinemia showed no significant change in WAT leptin mRNA, but in response to selective hyperinsulinemia with euglycemia at 24 h, a twofold increase was observed (P < 0.05). We conclude that fetal WAT leptin mRNA amounts are regulated by fetal development and circulating insulin concentrations. We speculate that chronic in utero metabolic perturbations that alter circulating insulin concentrations affect fetal leptin production that may mediate insulin's influence on fetal growth.

Topics: Adipose Tissue; Animals; Female; Gene Expression Regulation, Developmental; Gestational Age; Glucose; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulin; Leptin; Obesity; Pregnancy; RNA, Messenger; Sheep

This study examined the effect of intracerebroventricular leptin on insulin sensitivity in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were cannulated in the lateral ventricle and, after recovery, administered either intravenous STZ (50 mg/kg) to induce diabetes or citrate buffer. Chronic leptin (10 microg/10 microl icv) or vehicle injections were administered daily for 14 days beginning 2 days after establishment of hyperglycemia in the diabetic animals. At the end of the 2 wk of injections, insulin sensitivity was measured by the steady-state plasma glucose (SSPG) method. Blood glucose concentrations were dramatically reduced and normalized by the 4th day in diabetic animals receiving intracerebroventricular leptin treatment. Diabetic animals exhibited insulin resistance, whereas intracerebroventricular leptin significantly enhanced insulin sensitivity, as indicated by decreased SSPG. Circulating leptin levels were not increased in animals injected with intracerebroventricular leptin. Thus the increased peripheral insulin sensitivity appears to be due solely to the presence of leptin in the brain, not to leptin acting peripherally. These data imply that inadequate central leptin signaling may lead to insulin resistance.

Topics: Animals; Blood Glucose; Body Weight; Brain Chemistry; Diabetes Mellitus, Experimental; Eating; Fasting; Hyperglycemia; Injections, Intraventricular; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Wistar; Signal Transduction

To assess the acute regulation of leptin concentrations by insulin, glucose and free fatty acids (FFAs).. Four protocols: saline control experiment (CON); hyperglycemic clamps (approximately 8.3 mmol/l, 120 min) after an overnight fast (12 FAST); after a 36 h fast (36 FAST); and after a 36 h fast during which Intralipid/heparin was given over the last 24 h (36 FAST+FFA).. Lean, young, healthy volunteers; control group (n=6), experimental group (n=6).. Serum leptin concentrations.. Glucose and insulin concentrations were similar during the three clamp protocols. Average FFAs during the last 60 min of the clamp were 671+/-68 microM (CON),109+/-15 microM (12 FAST), 484+/-97 microM (36 FAST) and 1762+/-213 microM (36 FAST+FFA). Leptin concentrations decreased similarly during 36 FAST and 36 FAST+FFA. Leptin concentrations at 120 min (expressed as percentage of mean basal value) were 0.82+/-0.02 (CON), 0.93+/-0.08 (12 FAST) (P=0.29), 1.19+/-0.06 (36 FAST) (P<0.01) and 1.44+/-0.12 (36 FAST+FFA) (P<0.01).. During a one-day fast leptin concentrations decrease regardless of maintainance of an isocaloric balance. During acute hyperinsulinemic hyperglycemia leptin concentrations increase only after a preceding fast. This increase was most pronounced during simultaneous elevation of FFAs. Overall, our findings are compatible with the hypothesis that leptin secretion may be coupled to triglyceride synthesis rather than to the absolute lipid content of the adipocyte. International Journal of Obesity (2001) 25, 138-142

Topics: Adult; Blood Glucose; Fasting; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Heparin; Humans; Hyperglycemia; Hyperinsulinism; Kinetics; Leptin; Male; Triglycerides

Leptin has been proposed to be a sensor of energy storage in adipose tissues, and is capable of mediating a feedback signal to the hypothalamus, which is involved in the regulation of energy homeostasis and body weight. In order to investigate the issue of whether resistance to the activity of leptin on insulin sensitivity is observed in young Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 8 weeks of age, leptin (50 nmol/kg/h) was administered intravenously for 16 h to OLETF and Long-Evans Tokushima Otsuka (LETO) (lean controls) rats, followed by a measurement of insulin-stimulated glucose uptake in hindlimb muscles during hyperinsulinemic euglycemic clamp technique. In the case of LETO rats, the administration of leptin significantly decreased plasma insulin levels prior to the clamp test, but did not change plasma glucose levels. Furthermore, leptin led to an increase in insulin-stimulated glucose uptake in hindlimb muscles. However, in the case of OLETF rats, leptin administration changed neither plasma insulin levels nor insulin-stimulated glucose uptake. These data demonstrate that OLETF rats at 8 weeks of age have already become resistant to high concentration of peripheral leptin.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Drug Resistance; Humans; Hyperglycemia; Insulin; Leptin; Male; Rats; Rats, Inbred OLETF

Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin. Here we compared responses to leptin in two strains of db/db mice: C57BL/6J mice that are hyperglycemic and hyperinsulinemic and C57BL/Ks that are hyperglycemic and normo- or hypoinsulinemic. Chronic intraperitoneal infusion of 10 microgram leptin/day partially reversed hyperglycemia in C57BL/6J male mice but exaggerated the diabetic state of female mice. Bolus intraperitoneal injections of 40 microgram leptin/day did not effect glucose in either strain of male db/db mice, whereas chronic intraperitoneal infusion of 20 microgram leptin/day significantly reduced fasting blood glucose in male mice from both strains, especially C57BL/6J mice. Food intake, body weight, rectal temperature, and body fat did not change. Chronic intraperitoneal infusion of 10 microgram leptin/day significantly reduced body fat in lean db/+ C57BL/6J but not in C57BL/Ks mice. Thus peripherally administered leptin is active in mice that have only short-form leptin receptors, and the response is dependent on the method of leptin administration and the background strain.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Carrier Proteins; Diabetes Mellitus; Fasting; Glucose Tolerance Test; Heterozygote; Homozygote; Hyperglycemia; Hyperinsulinism; Infusions, Parenteral; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Cell Surface; Receptors, Leptin; Species Specificity

Insulin resistance is a feature of many common disorders including obesity and type 2 diabetes mellitus. In these disorders, the beta-cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity, an increase in beta-cell mass, or both. To determine whether the beta-cell response might relate to a circulating growth factor, we have transplanted normal islets under the kidney capsule of normoglycemic insulin-resistant mice with two different models of insulin resistance: lean mice that have a double heterozygous deletion of the insulin receptor and insulin receptor substrate-1 (DH) or the obese, hyperglycemic ob/ob mice. In the grafts transplanted into both hosts, there was a marked increase in beta-cell mitotic activity and islet mass that was comparable with that observed in the endogenous pancreas. By contrast, islets of the DH mouse transplanted into normal mice showed reduced mitotic index. These data suggest the insulin resistance is associated with a circulating islet cell growth factor that is independent of glucose and obesity.

Topics: Animals; Blood Glucose; Body Weight; Growth Substances; Hyperglycemia; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Islets of Langerhans; Islets of Langerhans Transplantation; Leptin; Male; Mice; Mice, Knockout; Mice, Obese; Obesity; Phosphoproteins; Receptor, Insulin; Subrenal Capsule Assay

We have recently shown that the activity of a synthetic peptide corresponding to amino acid residues 116-130 of secreted mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residues 116-122 (Ser-Cys-Ser-Leu-Pro-Gln-Thr, OB3). Substitution of the Leu residue at position 4 of OB3 with its D-isomer ([D-Leu-4]-OB3) enhanced the ability of OB3 (1 mg/day, ip, 7 days) to reduce body weight gain, food and water intake, and serum glucose in female C57BL/6J ob/ob mice. In the present study, we have utilized a pair-feeding approach to demonstrate that the antihyperglycemic action of [D-Leu-4]-OB3 is not solely due to its effects on caloric intake. One group of female C57BL/6J ob/ob mice (n=6) was fed ad libitum, and two additional groups (n=6 per group) were allowed 3.0 g food/mouse daily, an amount previously determined to satisfy [D-Leu-4]-OB3-treated mice. At the end of the 7-day test period, vehicle-injected mice fed ad libitum were approximately 10% heavier than their initial body weights, while pair-fed mice injected with vehicle and [D-Leu-4]-OB3-treated mice lost 5% of their initial body weights. After 1 day of treatment, blood glucose was reduced by 20% in pair-fed vehicle-injected mice, and by 40% in mice given [D-Leu-4]-OB3. Food restriction reduced blood glucose throughout the 7-day study, but not to levels seen in wild-type nonobese C57BL/6J mice of the same sex and age. After 2 days of treatment with [D-Leu-4]-OB3, however, blood glucose was reduced to levels comparable to those seen in wild-type nonobese mice. [D-Leu-4]-OB3 also lowered serum insulin levels by 53% when compared to mice fed ad libitum. Neither pair-feeding nor [D-Leu-4]-OB3 treatment had any apparent effect on thermogenesis. These results suggest that [D-Leu-4]-OB3 exerts its effects on serum glucose not only by suppressing caloric intake, but also through a separate effect on glucose metabolism which may involve increased tissue sensitivity to insulin.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drinking; Eating; Female; Hyperglycemia; Hypoglycemic Agents; Injections, Intraperitoneal; Insulin; Insulin Resistance; Leptin; Matched-Pair Analysis; Mice; Mice, Inbred C57BL; Mice, Obese; Peptide Fragments; Thermogenesis; Time Factors

We examined whether low-dose dexamethasone administration during late pregnancy modifies hepatic and/or peripheral insulin action or glucose-stimulated insulin secretion. Dexamethasone (100 microg/kg maternal body weight/d) was administered via an osmotic minipump from d 14--19 of gestation. Maternal glucose-insulin homeostasis was assessed on d 19 of pregnancy in the postabsorptive state. Insulin secretion and glucose tolerance was assessed after iv glucose, and insulin action examined during insulin infusion at euglycemia. Dexamethasone treatment during late pregnancy elicited fasting hyperinsulinaemia (by 88%; P < 0.001) and hyperglycaemia (by 20%; P < 0.05), and enhanced endogenous glucose production (by 29%; P < 0.001). Insulin secretion and rates of glucose disappearance after iv glucose were greatly impaired (by 44% and 39% respectively; P < 0.05). Suppression of endogenous glucose production by insulin was enhanced by dexamethasone treatment, but insulin's ability to promote glucose clearance was diminished. We demonstrate that excess maternal glucocorticoids during late pregnancy impairs glucose-stimulated insulin secretion and insulin-simulated glucose clearance but enhances insulin's ability to suppress endogenous glucose production. The data also indicate that elevated maternal glucocorticoids impair adaptations of the endocrine pancreas to pregnancy in vivo in that insulin hypersecretion in response to deteriorating peripheral insulin action is no longer apparent, leading to impaired glucose tolerance.

Topics: Animals; Body Weight; Dexamethasone; Eating; Female; Glucocorticoids; Glucose; Hyperglycemia; Hyperinsulinism; Injections, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Liver; Postprandial Period; Pregnancy; Pregnancy Complications; Pregnancy, Animal; Rats; Rats, Wistar

The effects of lithium, magnesium, vanadate, and zinc on leptinemia and leptin secretion by adipose tissue were investigated in streptozotocin- (STZ) induced hyperglycemic mice. After the administration of studied minerals in drinking water for 4 weeks, fasting serum leptin concentrations were elevated, accompanied by normoglycemia in STZ-injected mice, regardless which mineral was provided (P < 0.05). However, the in vitro administration of lithium, magnesium, and vanadate did not significantly influence the leptin secretion of adipose tissue. A low zinc treatment (0.1 mM) augmented, whereas both a pharmacological treatment of zinc (1 mM) and zinc depletion (1 mM TPEN) attenuated, leptin secretion (P < 0.05). The present study shows that STZ-induced hyperglycemic mice have hypoleptinemia and reduced leptin secretion by adipose tissue. Moreover, these defects can be improved by a moderate zinc administration.

Topics: Adipose Tissue; Animals; Blood Glucose; Hyperglycemia; Interleukin-6; Lactates; Leptin; Lithium; Magnesium; Male; Mice; Mice, Inbred C57BL; Minerals; Streptozocin; Tumor Necrosis Factor-alpha; Vanadates; Zinc

Pancreatic beta-cells from obese-hyperglycemic (ob/ob) mice are widely used for studying the mechanisms of insulin release, including its regulation by the cytoplasmic Ca2+ concentration ([Ca2+]i). In this study, we compared changes of [Ca2+]i in single beta-cells isolated from ob/ob mice with those from lean mice using dual-wavelength microfluorometry and the indicator fura-2. There were no differences in the frequency, amplitude, and half-width of the slow oscillations induced by glucose. Most beta-cells from the obese mice responded to 10 mM caffeine with transformation of the oscillations into sustained elevation of [Ca2+]i, a process counteracted by ryanodine. The beta-cells from the obese mice were characterized by ample generation of [Ca2+]i transients, which increased in number in the presence of glucagon. The transients became less frequent when leptin was added at a concentration as low as 1 nM. It is suggested that the excessive firing of [Ca2+]i transients in the ob/ob mice is owing to the absence of leptin and is mediated by activation of the phospholipase C signaling pathway.

Topics: Animals; Caffeine; Calcium; Cytoplasm; Glucagon; Hyperglycemia; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Ryanodine; Signal Transduction; Type C Phospholipases

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.

Topics: Animals; Anxiety; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Fasting; Fluoxetine; Gene Deletion; Gene Expression; Hyperglycemia; Hyperinsulinism; Hyperkinesis; Hypothalamus; Integrases; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Serotonin; Transfection; Viral Proteins

PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.

Topics: 3T3 Cells; Adipose Tissue; Animals; Benzhydryl Compounds; Benzoates; Biphenyl Compounds; Diabetes Mellitus, Type 2; Epoxy Compounds; Fatty Acids; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Leptin; Mice; Mice, Knockout; Nicotinic Acids; Obesity; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Rosiglitazone; Tetrahydronaphthalenes; Thiazoles; Thiazolidinediones; Transcription Factors

The adverse metabolic consequences of obesity are best predicted by the quantity of visceral fat. Excess glucocorticoids produce visceral obesity and diabetes, but circulating glucocorticoid levels are normal in typical obesity. Glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11beta HSD-1). We created transgenic mice overexpressing 11beta HSD-1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11beta HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Abdomen; Adipocytes; Adipose Tissue; Animals; Body Composition; Cell Size; Corticosterone; Dietary Fats; Disease Models, Animal; Eating; Gene Targeting; Humans; Hydroxysteroid Dehydrogenases; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Lipoprotein Lipase; Male; Metabolic Syndrome; Mice; Mice, Transgenic; Obesity; Receptors, Glucocorticoid; Viscera; Weight Gain

Human obesity and high fat feeding in rats are associated with the development of insulin resistance and perturbed carbohydrate and lipid metabolism. It has been proposed that these metabolic abnormalities may be reversible by interventions that increase plasma leptin. Up to now, studies in nongenetic animal models of obesity and in human obesity have concentrated on multiple injection therapy with mixed results. Our study sought to determine whether a sustained, moderate increase in plasma leptin, achieved by administration of a recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) would be effective in reversing the metabolic abnormalities of the obese phenotype. Wistar rats fed a high-fat diet (HF) were heavier (P < 0.05), had increased fat mass and intramuscular triglycerides (mTG), and had elevated plasma glucose, insulin, triglyceride, and free fatty acids compared with standard chow-fed (SC) control animals (all P < 0.01). HF rats also had impaired glucose tolerance and were markedly insulin resistant, as demonstrated by a 40% reduction in insulin-stimulated muscle glucose uptake (P < 0.001). Increasing plasma leptin levels to 29.0 +/- 1.5 ng/ml (from 7.0 +/- 1.4 ng/ml, P < 0.001) for a period of 6 days decreased adipose mass by 40% and normalized plasma glucose and insulin levels. In addition, insulin-stimulated skeletal muscle glucose uptake was normalized in hyperleptinemic rats, an effect that correlated closely with a 60% (P < 0.001) decrease in mTG. Importantly, HF rats that received a control adenovirus containing the beta-galactosidase cDNA and were calorically matched to AdCMV-leptin-treated animals remained hyperglycemic, hyperinsulinemic, insulin resistant, and maintained elevated mTG. We conclude that a gene-therapeutic intervention that elevates plasma leptin moderately for a sustained period reverses diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance, and that these improvements are tightly linked to leptin-induced reductions in mTG.

Topics: Animals; Blood; Dietary Fats; Fasting; Genetic Therapy; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Male; Muscle, Skeletal; Rats; Rats, Wistar; Triglycerides

Zinc has an antihyperglycemic effect. Zinc can also influence the production of leptin, a satiety factor that reduces appetite and blood sugar level. In this study, we investigated the effect of zinc supplementation on food intake and circulating leptin and glucose concentrations in streptozotocin-induced diabetic mice. Male diabetic mice received zinc supplementation (20 ppm) from drinking water for two weeks. The results showed that zinc treatment did not affect body weight gain, body fat content or food intake in these diabetic mice. However, zinc supplementation markedly ameliorated the hyperglycemia of diabetic mice. After zinc treatment, serum leptin concentrations tended to increase in the diabetic mice. This study suggests that zinc is a mediator of leptin production.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dietary Supplements; Hyperglycemia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Triglycerides; Tumor Necrosis Factor-alpha; Zinc

Orexins (hypocretins) are lateral hypothalamic neuropeptides implicated in regulating feeding and the sleep-wake cycle. To study their possible relevance to obesity and diabetes, we measured hypothalamic prepro-orexin mRNA levels in obese, normoglycemic Zucker fatty (fa/fa) and in hyperglycemic, non-obese Zucker diabetic fatty (ZDF) rats. Hypothalamic prepro-orexin mRNA concentrations in Zucker fatty rats were 31% lower than those in lean controls (0. 69+/-0.06 vs. 1.00+/-0.10 arbitrary units, P<0.05), but did not differ between ZDF diabetic rats and non-diabetic controls. Treatment of ZDF diabetic rats with rosiglitazone (1 or 3 mg/kg body weight daily for 13 weeks) normalized plasma glucose and significantly reduced plasma insulin, while leptin levels were 67% higher than in untreated ZDF rats (20.2+/-0.5 vs. 12.1+/-2.5, P<0. 001). Rosiglitazone treatment markedly enhanced weight gain compared with untreated ZDF rats (final weight 732+/-13 g vs. 409+/-13 g, P<0. 001) even though they were restricted to the same food intake. Rosiglitazone-treated ZDF rats had significantly lower hypothalamic prepro-orexin mRNA levels (0.68+/-0.07 arbitrary units) than both non-diabetic lean controls (1.00+/-0.10, P=0.02) and untreated diabetics (1.03+/-0.14, P=0.03). Our data suggest that prepro-orexin gene expression may be suppressed by substantial weight gain. Obesity-related signals that might mediate this effect have not been identified, but plasma leptin, insulin and glucose are not obviously involved.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gene Expression Regulation; Hyperglycemia; Hypoglycemic Agents; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptides; Obesity; Orexins; Protein Precursors; Rats; Rats, Zucker; RNA, Messenger; Rosiglitazone; Thiazoles; Thiazolidinediones; Thinness; Transcription, Genetic

Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor gamma (PPARgamma), which is expressed primarily in adipose tissues. To elucidate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (< 2,500 micron2) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000 micron2) by approximately 50%. In fact, the percentage of apoptotic nuclei was approximately 2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue than control. Concomitantly, troglitazone normalized the expression levels of TNF-alpha which were elevated by 2- and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARgamma. The increased number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF-alpha and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance.

Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; Blood Glucose; Blotting, Northern; Body Weight; Chromans; DNA; DNA, Complementary; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Mesentery; Polymerase Chain Reaction; Proteins; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Retroperitoneal Space; RNA; RNA, Messenger; Thiazoles; Thiazolidinediones; Transcription Factors; Triglycerides; Troglitazone; Tumor Necrosis Factor-alpha

Chicken is characterized by a relative insulin resistance and a physiological hyperglycemia (2g/L) and is also subjected to fattening. Fat deposits in chicken, as in mammals, are regulated by environmental and genetic factors. In mammals, leptin, an adipose cell-specific secreted protein has been characterized that is encoded by ob gene. Leptin regulates satiety through hypothalamic specific receptors, energy balance, energy efficiency and contributes to adaptation to starvation. The leptin gene has been characterized in various mammalian species, and the cloning and sequencing of the chicken leptin gene (ob gene) are reported. Using RT-PCR and primers flanking the coding region of the leptin gene selected from known mammalian sequences, we have successfully amplified a 600-bp fragment from chicken liver and adipose tissue total ARNs. The amplified fragment exhibits a similar size to that of the coding region of the mammalian leptin gene. The sequences of the coding region of chicken liver and adipose tissue are identical and presented 97%, 96% and 83% similarity to the mouse, rat and human sequences, respectively. Finally, this is the first report showing that leptin gene expression in chicken is not exclusively localized in adipose tissue but is also expressed in liver. The expression of leptin in liver may be associated with a key role of this organ in avian species in controlling lipogenesis.

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Chickens; Cloning, Molecular; Consensus Sequence; Evolution, Molecular; Humans; Hyperglycemia; Insulin Resistance; Leptin; Liver; Male; Mammals; Mice; Molecular Sequence Data; Protein Biosynthesis; Proteins; Rats; Sequence Alignment; Sequence Homology, Amino Acid

Withdrawal of testosterone prevents the development of hyperglycaemia in male Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus (NIDDM), but the exact mechanism has not been established. The present studies were undertaken to examine a possible role of testosterone in the development of obesity in young OLETF rats who have not shown marked hyperphagia.. Body weight, food intake and circulating concentrations of metabolic factors including immunoreactive leptin (IRL) were measured at five weeks of age in young male OLETF rats and their lean controls, Long-Evans-Tokushima-Otsuka (LETO) rats. At six weeks of age, both LETO and OLETF rats were bilaterally orchiectomized (Orchx) and half of each group implanted with a silastic tube containing testosterone. After a three week observation period, all animals were killed and circulating concentrations of metabolic factors and the ob gene expression in retroperitoneal white adipose tissues were measured.. Body weight and 24h food intake were already increased in OLETF rats at five weeks of age. Serum testosterone concentrations were significantly lower in OLETF rats than in LETO rats. Expression of the ob gene was significantly decreased in the retroperitoneal white adipose tissue of OLETF rats, and their serum IRL concentrations were lower. Food intake and body weight gain for three weeks after the operation were significantly lower in the Orchx group of OLETF rats than in the sham-operated group. Hyperglycaemia, accompanied by hyperinsulinaemia, was attenuated by orchiectomy in OLETF rats. Circulating IRL concentrations were significantly higher in OLETF rats than in LETO rats and decreased by orchiectomy. Testosterone supplement reversed all of the changes caused by orchiectomy in OLETF rats. In contrast, the changes, which were observed after orchiectomy in OLETF rats, were not obvious in LETO rats.. The present data indicate that testosterone plays a role in the development of obesity and NIDDM in young OLETF rats, but that changes of leptin production in white adipose tissue may not be important in the development of obesity in young OLETF rats.

Topics: Animals; Base Sequence; Blood Glucose; Cohort Studies; Corticosterone; Diabetes Mellitus, Type 2; Disease Models, Animal; DNA Primers; Drug Implants; Eating; Estradiol; Follicle Stimulating Hormone; Hyperglycemia; Insulin; Leptin; Luteinizing Hormone; Male; Obesity; Orchiectomy; Polymerase Chain Reaction; Protein Biosynthesis; Proteins; Rats; RNA, Messenger; Testosterone; Weight Gain

This study aimed to elucidate possible age-related changes in islet blood perfusion in lean and obese C57BL/6 mice. Obese mice aged 1 mo were hyperglycemic and hyperinsulinemic and had an increased islet blood flow compared with age-matched lean mice. This augmented blood flow could be abolished by pretreatment with leptin. The islet blood perfusion was, in contrast to this, markedly decreased in obese 6- to 7-mo-old animals compared with age-matched lean mice. Reversal of hyperglycemia, but not hyperinsulinemia, in these obese mice with phlorizin normalized the islet blood flow. Spontaneous reversal of hyperglycemia, but not hyperinsulinemia, was seen in the 12-mo-old obese mice. Islet blood perfusion in obese mice at this age did not differ compared with lean mice. It is suggested that the initial increase in islet blood flow in obese mice is due to the leptin deficiency. The subsequent decrease in islet blood perfusion is probably caused by the chronic hyperglycemia. The described islet blood flow changes may be of importance for impairment of islet function in obese-hyperglycemic mice.

Topics: Aging; Animals; Arginine; Blood Glucose; Body Weight; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Pancreas; Perfusion; Phlorhizin; Proteins; Receptors, Leptin; Receptors, Neuropeptide Y; Regional Blood Flow

Leptin, the product of the ob gene, has been reported to regulate feeding behavior and energy metabolism. Plasma leptin concentration was strongly correlated with body fat content in humans. It is well known that increased body fat content is accompanied by insulin insensitivity. In order to study the relationship between serum leptin level and metabolic variables, we performed caloric restriction on Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of noninsulin dependent diabetes mellitus. The male OLETF rats were allocated at random to three groups: 100% group, and 85% and 70% groups (which consumed 85% and 70% of the amount of food consumed by the 100% group, respectively). A significant correlation between serum leptin level and the body fat content, body weight, triglyceride, and fasting plasma glucose was observed. Using a partial correlation analysis to control for body fat content, however, the correlation between serum leptin and these variables disappeared. No significant changes in serum leptin levels were observed before and after a 1 h hyperinsulinemic euglycemic clamp test. In conclusion, serum leptin was significantly correlated with body fat content rather than fasting plasma glucose, serum insulin and insulin sensitivity. This suggests that circulating leptin per se may not result in hyperinsulinemia and insulin insensitivity in the OLETF rat.

Topics: Animals; Body Constitution; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Intake; Fats; Food; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Male; Obesity; Proteins; Radioimmunoassay; Rats; Rats, Inbred Strains

We asked whether the likelihood for mice of the C57BL/6J strain to develop glucose intolerance when fed a high-fat diet is related to the increase in circulating levels of leptin or free fatty acids (FFA). We therefore administered a high-fat diet (58% fat) or a control diet (11% fat) for 1.5 years. NMRI mice were used as a more glucose-tolerant control group. After a high-fat diet, the area under the glucose curve following an intraperitoneal glucose challenge (1 g/kg) increased more markedly in C57BL/6J mice (by 42+/-8%) than in NMRI mice (by 21+/-3%, P = 0.007). Plasma levels of insulin, leptin and FFA increased in both strains of mice, whereas plasma glucose levels were elevated after the high-fat diet only in C57BL/6J mice. The slope of the relationship between body weight and plasma leptin was higher in C57BL/6J mice than in NMRI mice. suggesting leptin insensitivity. Circulating leptin correlated to circulating insulin in both strains of mice, whereas plasma FFA correlated to plasma insulin in NMRI mice but not in C57BL/6J mice. These correlations remained significant after adjustment for body weight. The results show that elevated leptin and FFA levels evolve after high-fat feeding in mice, in conjunction with evolvement of glucose intolerance and hyperglycemia.

Topics: Animals; Body Weight; Dietary Fats; Fatty Acids, Nonesterified; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Proteins

1. We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxa zolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. 2. JTT-501 (10-100 mg kg(-1) day(-1)) was administered orally to Zucker fatty rats for 7-21 days. In the high-fat fed rat model, JTT-501 (100 mg kg(-1) day(-1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. 3. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. 4. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.

Topics: Animals; Blood Glucose; Disease Models, Animal; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Resistance; Isoxazoles; Leptin; Lipids; Male; Obesity; Oxidation-Reduction; Phosphorylation; Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Insulin; Triglycerides

In rodents, leptin and the incretin glucagon-like peptide-1 (7-36) amide (GLP-1) affect feeding at least in part via interaction with hypothalamic neuropeptide Y (NPY), suggesting that cross talk may exist between GLP-1 and the ob gene product. Besides insulin, acute hyperglycemia has recently been shown to induce ob gene expression. To address the question of whether leptin plasma levels in humans are affected by GLP-1 infusion and/or hyperglycemia, eight healthy volunteers were studied during euglycemia and hyperglycemic clamping with or without GLP-1 administration while insulin levels were kept constant by somatostatin infusion. Under all conditions, leptin plasma levels remained unchanged, demonstrating that in humans leptin plasma concentrations are affected neither by short-term peripheral GLP-1 infusion nor by hyperglycemia, which suggests that postprandial GLP-1 release and hyperglycemia do not modulate secretion of the ob gene product.

Topics: Adult; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Leptin; Male; Osmolar Concentration; Peptide Fragments; Protein Precursors; Proteins

New Zealand Obese (NZO) mice exhibit a polygenic syndrome of hyperphagia, obesity, hyperinsulinemia, and hyperglycemia similar to that observed in young diabetes mutant mice on the C57BLKS/J background (C57BLKS/J-Lepr(db)/Lepr(db)). Here we show that in NZO this syndrome is accompanied by a marked elevation of the leptin protein in adipose tissue and serum. The promoter region and the complementary DNA of the ob gene of NZO mice, including its 5'-untranslated region, are identical with the wild-type sequence (C57BL, BALB/c), except that the transcription start is located 5 bp upstream of the reported site. In contrast to C57BLKS/J+/+ and C57BL/6J-Lep(ob)/Lep(ob) mice, NZO mice failed to respond to recombinant leptin (7.2 microg/g) with a reduction of food intake. Leptin receptor messenger RNA as detected by PCR appears as abundant in hypothalamic tissue of NZO mice as in tissue from lean mice. Ten nucleotide polymorphisms are found in the complementary DNA of the leptin receptor, resulting in two conservative substitutions (V541I and V651I) in the extracellular part of the receptor and one nonconservative substitution (T1044I) in the intracellular domain between the presumed Jak and STAT binding boxes. However, these mutations are also present in the related lean New Zealand Black strain (body fat at 9 weeks: New Zealand Black, 6.2 +/- 1.3%; NZO, 17.0 +/- 1.7%). Thus, the polymorphic leptin receptor seems to play only a minor, if any, role in the obesity and hyperleptinemia of the NZO mouse. It is suggested that the main defect in NZO is located distal from the leptin receptor or at the level of leptin transport into the central nervous system.

Topics: Adipose Tissue; Animals; Base Sequence; Blotting, Northern; Body Weight; Carrier Proteins; Disease Models, Animal; DNA, Complementary; Eating; Hyperglycemia; Hyperinsulinism; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Precipitin Tests; Promoter Regions, Genetic; Proteins; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; RNA, Messenger

It has previously been demonstrated that plasma leptin correlates to body fat content. It has also been demonstrated that in subjects with normal glucose tolerance, circulating leptin correlates to circulating insulin and to insulin secretion and that these relations are independent of body fat. However, whether leptin also covaries with other islet hormones is not known. We therefore studied the relation between plasma levels of leptin and glucagon secretion and circulating pancreatic polypeptide (PP) in healthy humans. Arginine was injected intravenously (5 g) at fasting and at 14 and 28 mmol/L, glucose in 71 postmenopausal women with normal glucose tolerance. In a multivariate analysis controlling for the influence of the body mass index, we found that circulating leptin correlated significantly to fasting insulin (r = .38, P = .002), and to circulating insulin at 14 mmol/L glucose levels (r = .29, P = .0019) and 28 mmol/L glucose (r = .32, P = .009), as well as to the insulin response to arginine at all three glucose levels (r > .30, P < .013). Circulating leptin, independently of the body mass index, also correlated to fasting glucagon (r = .31, P = .012) and to the glucagon response to arginine at all three glucose levels (r > .28, P < .038). In contrast, circulating leptin did not correlate to plasma glucagon at 14 or 28 mmol/L glucose or to plasma levels of PP. We conclude that circulating leptin correlates to the secretory capacity of both glucagon and insulin but not to the reduction of plasma glucagon during hyperglycemia or to PP in a large group of postmenopausal women. This suggests that islet function is related to circulating leptin in humans.

Topics: Arginine; Blood Glucose; Body Mass Index; Dose-Response Relationship, Drug; Female; Glucagon; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Injections, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Middle Aged; Multivariate Analysis; Pancreatic Polypeptide; Postmenopause; Proteins; Sex Characteristics; White People

Expression of the obese (ob) gene is up-regulated in the adipose tissue in several obese rodent models. To study the regulation of the ob gene expression during the development of obesity, we examined the ob gene expression in genetically obese-hyperglycemic Wistar fatty (fa/fa) rats at several stages of obesity. The ob mRNA levels in the adipose tissue from Wistar fatty rats was unequivocally augmented and continued to rise in the process of obesity. Furthermore, the ob gene expression in this obese model was much more rapidly enhanced in the mesenteric fat than in the subcutaneous fat. Moreover, the ob gene expression was more greatly augmented in the mesenteric fat than the lipoprotein lipase gene expression. These results suggest the presence of obesity-linked and region-specific regulation of the ob gene expression.

Topics: Adipose Tissue; Age Factors; Animals; Body Weight; Disease Models, Animal; Gene Expression; Hyperglycemia; Leptin; Lipoprotein Lipase; Male; Obesity; Proteins; Rats; Rats, Wistar; RNA, Messenger; Tissue Distribution

The acute effects of hyperglycemia and hyperinsulinemia on plasma leptin levels were determined in 42 highly trained women athletes (18-69 yr) and 14 sedentary control women (18-50 yr, body mass index < 25 kg/m2), using the glucose clamp technique. The relationships of body composition, physical fitness, age, and plasma leptin levels were examined in all participants. In addition, the effect of weight loss and aerobic exercise and plasma leptin levels were examined in 4 Newly diagnosed untreated noninsulin-dependent diabetes mellitus patients. The time course of plasma leptin levels changed little from basal during hyperglycemic (approximately 10 mmol/L) or hyperinsulinemic-euglycemic (400-3000 pmol/L) clamp studies in either athletes, controls, or noninsulin-dependent diabetes mellitus patients. A strong correlation between plasma leptin levels and fasting insulin was present (r = 0.60, P < 0.001). Plasma leptin and percent fat were higher in controls than athletes (12.6 vs. 4.0 ng/mL and 33.2 vs. 20.8%; both P < 0.001). The relationships between percent fat (dual-energy x-ray absorptiometry) or intraabdominal adipose tissue (computed tomography) and leptin for the entire group were highly significant (r = 0.70, r = 0.52; P < 0.001). When percent fat was controlled, the relationship between fasting insulin and leptin remained (P < 0.002). There was not a significant association between age and plasma leptin levels in a univariate analysis in this population. However, after adjustment for percent fat, a significant inverse relationship between age and leptin appeared (P < 0.05). The weight loss and aerobic exercise program resulted in an average 6 +/- 0.8 kg wt loss. Leptin levels decreased > 28% in each patient (P < 0.01). In conclusion, neither acute hyperglycemia or hyperinsulinemia affects plasma leptin levels. Percent fat is the strongest predictor of leptin levels, even in lean, highly trained women athletes.

Topics: Adipose Tissue; Adolescent; Adult; Age Factors; Aged; Diabetes Mellitus, Type 2; Exercise; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hyperinsulinism; Leptin; Middle Aged; Peptide Fragments; Protein Precursors; Proteins; Weight Loss

Expression of the obese (ob) gene is augmented in the adipose tissue in several rodent models of genetic obesity. In the present study, we examined the ob gene expression in a rodent model of acquired obesity obtained by pure overfeeding of normal rats. Male Sprague-Dawley rats at 8 weeks of age were fed standard diet or high-fat diet. Rats fed high-fat diet developed moderate degree of obesity, hyperglycemia, and hyperlipidemia as compared with rats fed standard diet. Northern blot analysis revealed that the ob gene is expressed abundantly in the adipose tissue obtained from the epididymal, mesenteric, subcutaneous, retroperitoneal, and interscapular fat pads in rats fed standard diet. Expression of the ob gene was augmented in all the adipose tissue examined in rats fed high-fat diet. The present study demonstrates that the ob gene expression is augmented in the adipose tissue in diet-induced obesity, thereby suggesting the pathophysiologic roles of the ob gene in acquired obesity.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Dietary Fats; Gene Expression; Hyperglycemia; Hyperlipidemias; Leptin; Male; Obesity; Organ Size; Protein Biosynthesis; Proteins; Rats; Rats, Sprague-Dawley