glucagon-like-peptide-1 and Metabolic-Syndrome

A review of publications devoted to the analysis of genetic polymorphisms of the gene encoding the glucagon-like peptide type 1 receptor and some other genes directly and indirectly involved in the implementation of its physiological action is presented. The aim of the study: to search for information on genes polymorphism that can affect the effectiveness of glucagon-like peptide type 1 agonists. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was based on PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic source eLIBRARY.RU from 1993 to 2022. The several genes polymorphisms (. Представлен обзор публикаций, посвященных анализу генетических полиморфизмов гена, кодирующего рецептор глюкагоноподобного пептида 1-го типа (ГПП-1), и некоторых других генов, участвующих в реализации его физиологического действия. Цель – выявить информацию о генах, полиморфизм которых может оказывать влияние на эффективность агонистов ГПП-1. Обзор проводился в соответствии с рекомендациями PRISMA 2020, поиск публикаций осуществлялся по базам данных PubMed (включая Medline), Web of Science, а также российским научным электронным библиотекам eLIBRARY.RU с 1993 по 2022 г. Описан полиморфизм нескольких генов (

Topics: Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metabolic Syndrome; Peptides; Venoms

The introduction of sodium glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus treatment has shown an unexpectedly significant improvement in heart disease outcome trials. Although they have very different modes of action, a portion of the salutary cardiovascular disease improvement may be related to their impact on diabetic dyslipidemia. As discussed in this focused review, the sodium glucose transporter-2 inhibitors as a class show a mild increase in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, while triglycerides (TG) decrease inconsistently. In particular, the rise in LDL appears to be related to the less atherogenic, large buoyant LDL particles. The glucagon-like peptide-1 receptor agonists show more of an impact on weight loss and improvement in the underlying low HDL and high TG dyslipidemia. The effect of sodium glucose transporter-2 inhibitors and glucagon-like peptide 1 receptor agonists when used in combination remains largely unknown. Also unexplored is difference in effect of these medications among various ethnicities and metabolic syndrome.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metabolic Syndrome; Sodium-Glucose Transporter 2 Inhibitors; Triglycerides

Atrial fibrillation (AF) is the most common clinically significant arrhythmia, and it increases stroke risk. A preventive approach to AF is needed because virtually all treatments such as cardioversion, antiarrhythmic drugs, ablation, and anticoagulation are associated with high cost and carry significant risk. A systematic review was performed to identify effective lifestyle-based strategies for reducing primary and secondary AF. A PubMed search was performed using articles up to March 1, 2021. Search terms included atrial fibrillation, atrial flutter, exercise, diet, metabolic syndrome, type 2 diabetes mellitus, obesity, hypertension, stress, tobacco smoking, alcohol, Mediterranean diet, sodium, and omega-3 fatty acids. Additional articles were identified from the bibliographies of retrieved articles. The control of hypertension, ideally with a renin-angiotensin-aldosterone system inhibitor, is effective for preventing primary AF and recurrence. Obstructive sleep apnea is a common cause of AF, and treating it effectively reduces AF episodes. Alcohol increases the risk of AF in a dose-dependent manner, and abstinence reduces risk of recurrence. Sedentary behavior and chronic high-intensity endurance exercise are both risk factors for AF; however, moderate physical activity is associated with lower risk of AF. Recently, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 agonists have been associated with reduced risk of AF. Among overweight/obese patients, weight loss of ≥10% is associated with reduced AF risk. Lifestyle changes and risk factor modification are highly effective for preventing AF.

Topics: Alcohol Drinking; Atrial Fibrillation; Bariatric Surgery; Diabetes Mellitus, Type 2; Diet Therapy; Diet, Mediterranean; Dietary Fats, Unsaturated; Endurance Training; Exercise; Fatty Acids, Omega-3; Glucagon-Like Peptide 1; Humans; Metabolic Syndrome; Obesity; Overweight; Risk Reduction Behavior; Sedentary Behavior; Sleep Apnea, Obstructive; Smoking; Smoking Cessation; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

Despite plenty of currently available information on metabolic syndrome (MetS) in children and adolescents, there are still uncertainties regarding definition, prevention, management and treatment of MetS in children. The first approach to MetS in children consists of lifestyle interventions (nutritional education, physical activity). These recommendations are often difficult to achieve, especially for adolescents, therefore, there is usually a lack of successful outcomes. A pharmacological intervention in obese children may be needed in some cases, with the aim to improve the effects of these primary prevention interventions. Metformin seems to be safe and presents evident positive effects on insulin sensitivity, but long-term and consistent data are still missing to establish its role in the pediatric population and the possible effectiveness of other emergent treatments such as glucagon-like peptide-1 analogues, dipeptidylpeptidase-4 inhibitors, dual inhibitors of SGLT1 and SGLT2 and weight loss drugs. Bariatric surgery might be helpful in selected cases. The aim of this review is to present the most recent available treatments for the main components of metabolic syndrome, with a focus on insulin resistance. A short mention of management of congenital forms of insulin resistance will be included too.

Topics: Adolescent; Anti-Obesity Agents; Bariatric Surgery; Cardiovascular Diseases; Child; Dipeptidyl-Peptidase IV Inhibitors; Exercise; Forecasting; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Metabolic Syndrome; Metformin; Non-alcoholic Fatty Liver Disease; Nutrition Assessment; Pediatric Obesity; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2 Inhibitors

Diabetes Mellitus (DM) is a leading cause of both Cardiovascular Disease (CVD) and End-stage Renal Disease (ESRD). After 2008, there has been much evidence presented, and recently the guidelines for sugar control have changed to focus on being more disease orientated. GLP-1 Receptor Agonists (GLP-1R) and sodium glucose cotransporter-2 inhibitors are suggested as the first line towards fighting all DM, CVD and ESRD. However, the benefits of GLP-1R in organ transplantation recipients remain very limited. No clinical trials have been designed for this particular population. GLP-1R, a gastrointestinal hormone of the incretin family, possesses antidiabetic, antihypertensive, anti-inflammatory, anti-apoptotic and immunomodulatory actions. There are few drug-drug interactions, with delayed gastric emptying being the major concern. The trough level of tacrolimus may not be significant but should still be closely monitored. There are some reasons which support GLP-1R in recipients seeking glycemic control. Post-transplant DM is due to an impaired β-cell function and glucose-induced glucagon suppression during hyperglycemia, which can be reversed by GLP-1R. GLP-1R infusion tends to relieve immunosuppressant related toxicity. Until now, in some cases, glycemic control and body weight reduction can be anticipated with GLP-1R. Additional renal benefits have also been reported. Side effects of hypoglycemia and gastrointestinal discomfort were rarely reported. In conclusion, GLP-1R could be implemented for recipients while closely monitoring their tacrolimus levels and any potential side effects. Any added benefits, in addition to sugar level control, still require more well-designed studies to prove their existence.

Topics: Diabetes Mellitus; Diabetic Nephropathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Transplantation; Metabolic Syndrome

Capsaicin, the major active constituent of chilli, is an agonist on transient receptor potential vanilloid channel 1 (TRPV1). TRPV1 is present on many metabolically active tissues, making it a potentially relevant target for metabolic interventions. Insulin resistance and obesity, being the major components of metabolic syndrome, increase the risk for the development of cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. In vitro and pre-clinical studies have established the effectiveness of low-dose dietary capsaicin in attenuating metabolic disorders. These responses of capsaicin are mediated through activation of TRPV1, which can then modulate processes such as browning of adipocytes, and activation of metabolic modulators including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α (PPARα), uncoupling protein 1 (UCP1), and glucagon-like peptide 1 (GLP-1). Modulation of these pathways by capsaicin can increase fat oxidation, improve insulin sensitivity, decrease body fat, and improve heart and liver function. Identifying suitable ways of administering capsaicin at an effective dose would warrant its clinical use through the activation of TRPV1. This review highlights the mechanistic options to improve metabolic syndrome with capsaicin.

Topics: Adipocytes; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Capsaicin; Diabetes Mellitus, Type 2; Diet; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; PPAR alpha; TRPV Cation Channels; Uncoupling Protein 1

Topics: Asthma; Glucagon-Like Peptide 1; Humans; Metabolic Syndrome; Obesity

Patients with type 1 diabetes mellitus (T1DM) traditionally had a low body mass index and microangiopathic complications were common. The Diabetes Control and Complications Trial, published in 1993, demonstrated that therapy aimed at maintaining HbA1c levels as close to normal as feasible reduced the incidence of microangiopathy. Since then, the use of intensive insulin therapy to optimise metabolic control became generalised, with two main side effects: a higher rate of severe hypoglycaemia and increased weight gain. Approximately 50% of patients with T1DM are currently obese or overweight, which reduces or nullifies the benefits of good metabolic control, and which has other negative consequences; therefore, strategies to achieve weight control in patients with T1DM are necessary. At present, treatment with GLP-1 and SGLT-2 inhibitors has yielded promising short-term results that need to be confirmed in studies with larger numbers of patients and long-term follow-up. It is possible that, in coming years, the applicability of bariatric surgery in obese patients with T1DM will be similar to that of the general population or T2DM.

Topics: Adolescent; Adult; Bariatric Surgery; Body Mass Index; Depression; Diabetes Complications; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hirsutism; Humans; Hypoglycemic Agents; Hypogonadism; Insulin; Life Style; Male; Metabolic Syndrome; Obesity; Osteoporosis; Overweight; Polycystic Ovary Syndrome; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Weight Gain

Topics: Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Male; Metabolic Syndrome; Osteocalcin

Topics: Anti-Obesity Agents; Appetite; Appetite Depressants; Benzazepines; Benzoxazines; Bupropion; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Discovery; Energy Metabolism; Enzyme Inhibitors; Fructose; Glucagon-Like Peptide 1; Humans; Hypothalamus; Lactones; Lipase; Liraglutide; Metabolic Syndrome; Naltrexone; Obesity; Orlistat; Phentermine; Topiramate

Psoriasis is a chronic inflammatory skin disease with a global prevalence of 2-3%. In recent years it has been established that patients with psoriasis carry an increased risk of type 2 diabetes, but the underlying pathophysiological mechanisms remain unclear. The association is most likely due to a combination of shared genes, immunoinflammatory mechanisms and a number of diabetes risk factors in patients with psoriasis. The current review summarises the evidence in the field and calls for attention on diabetes risk assessment, preventive measures and treatment in patients with psoriasis.

Topics: Alcohol Drinking; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucocorticoids; Humans; Incretins; Metabolic Syndrome; Obesity; Psoriasis; Risk Factors; Smoking

The rising rate of overweight/obesity among the ever-growing ageing population is imposing massive and rapidly changing burdens of ill health. The observation that the BMI value associated with the lowest relative mortality is slightly higher in older than in younger adults, mainly through its reduced impact on coronary heart disease, has often been misinterpreted that obesity is not as harmful in the elderly, who suffer a large range of disabling consequences of obesity. All medical consequences of obesity are multi-factorial and most alleviated by modest, achievable weight loss (5-10 kg) with an evidence-based maintenance strategy. But severe obesity, e.g. BMI >40 may demand greater weight loss e.g. >15 kg to reverse type 2 diabetes. Since relatively reduced physical activity and reduced muscle mass (sarcopenic obesity) are common in the elderly, combining exercise and modest calorie restriction optimally reduces fat mass and preserves muscle mass - age presents no obstacle and reducing polypharmacy is a valuable outcome. The currently licensed drug orlistat has no age-related hazards and is effective in a low fat diet, but the risks from bariatric surgery begin to outweigh benefits above age 60. For the growing numbers of obese elderly with diabetes, the glucagon-like peptide-1 (GLP-1) receptor analogue liraglutide appears a safe way to promote and maintain substantial weight loss. Obesity and sarcopenia should be prevented from younger age and during life-transitions including retiral to improve future health outcomes and quality of life, with a focus on those in "obese families".

Topics: Adult; Aged; Bariatric Surgery; Body Composition; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Europe; Glucagon-Like Peptide 1; Humans; Life Style; Liraglutide; Male; Metabolic Syndrome; Middle Aged; Morbidity; Obesity; Prevalence; Quality of Life; Sarcopenia; Waist Circumference; Weight Loss

In this article, we review the results that can be expected after significant weight loss in patients with type 2 diabetes mellitus. We provide consensus-based documentation supported by the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation on the importance of physical exercise, metabolic-bariatric surgery, and drug therapy. Lastly, we report the results of studies published in the last few years on glucagon-like peptide-1 analogs and the new family of oral drugs known as gliflozins, specifically studies published on dapagliflozin.

Topics: Bariatric Surgery; Benzhydryl Compounds; Causality; Comorbidity; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Disease Management; Evidence-Based Medicine; Exercise Therapy; Glucagon-Like Peptide 1; Glucosides; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Metabolic Syndrome; Obesity; Practice Guidelines as Topic; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

Regulatory role of the brain in energy expenditure, appetite, glucose metabolism, and central effects of insulin has been prominently studied. Certain neurons in the hypothalamus increase or decrease appetite via orexigenes and anorexigenes, regulating energy balance and food intake. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and beta- and alpha cells, and it regulates induction/inhibition of glucose output from the liver. Incretines, produced in intestine and in certain brain cells (brain-gut hormones), link to special receptors in the hypothalamus. Central role of insulin has been proved both in animals and in humans. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose metabolism. Central glucose sensing, via "glucose-excited" and "glucose-inhibited" cells have outstanding role. Former are active in hyperglycaemia, latter in hypoglycaemia, via influencing beta- and alpha cells, independently of traditional metabolic pathways. Evidence of brain insulin resistance needs centrally acting drugs, paradigm changes in therapy and prevention of metabolic syndrome, diabetes, cardiovascular and oncological diseases.

Topics: Animals; Appetite Depressants; Appetite Regulation; Blood Glucose; Brain; Ceramides; Cognition; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypothalamus; Incretins; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Metabolic Syndrome; Neuropeptides; Non-alcoholic Fatty Liver Disease; Oligopeptides; Orexins; Pyrrolidonecarboxylic Acid

Topics: Animals; Diabetic Nephropathies; Drug Design; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Insulin Resistance; Metabolic Syndrome; Mice; Molecular Targeted Therapy; PPAR gamma; Rats; Thiazolidines

The prevalence of type 2 diabetes mellitus, which is directly associated with overweight/obesity and increased cardiovascular disease risk, is projected to continue to increase during the next few decades. Traditionally, treatment has focused primarily on glycemic control, but accumulating evidence suggests that the clinical management of patients with type 2 diabetes requires a more comprehensive approach to minimize associated morbidity and mortality. Because the majority (80%-90%) of patients with type 2 diabetes are overweight or obese, effective glucose control and weight loss are the cornerstones of initial management. Both effective glucose control and therapy to reduce cardiovascular risk factors, including overweight/obesity, are needed to prevent the complications of type 2 diabetes. Most conventional antidiabetes agents, including sulfonylureas, thiazolidinediones, and insulin, improve glycemic control but are associated with weight gain or, as with metformin, are weight-neutral or weight-sparing. The incretin-based therapies, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 inhibitors, have been shown to be safe and effective in lowering glucose while eliciting favorable effects on weight (ie, weight-reducing and weight-neutral, respectively). The effects of these agents on other parameters of cardiovascular risk are also being studied. Advances in GLP-1 receptor agonist therapy include development of agents with longer durations of activity allowing for more convenient dosing of therapies for patients with type 2 diabetes, which should lead to better patient compliance, adherence, and overall clinical outcomes.

Topics: Algorithms; Caloric Restriction; Cardiovascular Diseases; Comorbidity; Delayed-Action Preparations; Diabetes Complications; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Metabolic Syndrome; Obesity; Peptides; Prevalence; Receptors, Glucagon; Risk Factors; Risk Reduction Behavior; Venoms

The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

Topics: Adipokines; Adrenal Glands; Adult; Androgens; Cushing Syndrome; Diabetes Mellitus, Type 2; Endocrine System; Estrogens; Fatty Liver; Female; Glucagon-Like Peptide 1; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypothalamus; Hypothyroidism; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Obesity; Pancreas; Pituitary Gland; Polycystic Ovary Syndrome; Postmenopause; Thyroid Gland

Prevention and treatment of type 2 diabetes mellitus (T2DM) and the metabolic syndrome represent a major clinical challenge, because effective strategies such as fat restriction and exercise are difficult to implement into diabetes treatment. Based on the increasing knowledge on the pathogenesis of T2DM, new therapeutic approaches are currently under investigation. Potential targets of new therapeutic approaches include: (i) Inhibition of hepatic glucose production, (ii) stimulation of glucose-dependent insulin secretion, (iii) enhancement of insulin signal transduction, and (iv) reduction of body fat mass. Agonists of glucagon-like-peptide 1 (GLP-1) and antagonists of dipeptidylpeptidase IV, which inactivates GLP-1, stimulate glucose-dependent insulin secretion, improve hyperglycemia and are already tested in clinical trials. In humans, glucagon antagonists and an amylin analogue reduce glucagon-dependent glucose production. The glucose-lowering effect of current modulators of lipid oxidation is not pronounced and their use could be limited by side effects. In addition to clinically approved thiazolidendiones, new agonists of the peroxisome proliferator activator receptor gamma (PPAR gamma) as well as combined PPAR alpha/gamma agonists are developed at present. The direct modulation of insulin signal transduction is still limited to experimental studies.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Forecasting; Glucagon; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Glycogen Synthase Kinase 3; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Lipid Peroxidation; Metabolic Syndrome; Mice; Oxazines; Peptide Fragments; Phenylpropionates; Protein Precursors; Rats; Receptor, Insulin; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Signal Transduction; Thiazolidinediones; Transcription Factors

Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic. In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of. A single dose of. NTR-NL6630.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Clostridiales; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide 1; Glycemic Control; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Transcriptome

Several biological markers have been identified as risk factors for cardiovascular disease and are associated with increased risk of metabolic syndrome (MetS). This study provides a factual information on promising biomarkers that are associated with MetS and can aid in early detection and management of MetS in young adults of Western Algeria. We studied a total of one hundred subjects aged between thirty and forty years with MetS, in which anthropometric measurements, insulin resistance, C peptide and HbA1c, lipid profile, circulating adipokines and glucagon-like peptide-1 were measured by suitable methods, in comparison to two groups of control. MetS is closely linked to altered glucose homeostasis, the plasma insulin/glucose ratio; i.e., the insulinogenic index helps to estimate the level of insulin secretion and also for assessing β-cell function. The correlation between homeostasis model assessment insulin resistance index (HOMA-IR) and HbA1c, body mass index or plasma triglycerides yielded positive and significant values. Biomarkers with a known and predictable association with MetS can provide a means to detect those at risk and intervene as needed. This could significantly decrease the burden complications impose on patients and the healthcare system.

Topics: Adipokines; Adult; Algeria; Biomarkers; C-Peptide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Secretion; Male; Metabolic Syndrome; Models, Biological

The risk of cardiovascular diseases and type 2 diabetes mellitus are increased in subjects with metabolic syndrome (MetS), and hydrolyzed fish protein may have favorable effects on metabolic health. Here, we investigated the effect of 8 weeks supplementation with 4 g of cod protein hydrolysate (CPH) on glucose metabolism, lipid profile and body composition in individuals with MetS in a double-blind, randomized intervention study with a parallel-group design. Subjects received a daily supplement of CPH (

Topics: Animals; Blood Glucose; Body Composition; Dietary Supplements; Double-Blind Method; Fasting; Female; Fish Proteins, Dietary; Gadiformes; Glucagon-Like Peptide 1; Humans; Insulin; Lipid Metabolism; Lipids; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Protein Hydrolysates

A multifunctional diet (MFD) was previously shown to reduce blood lipids, CRP and blood pressure in a 4-week intervention under weight-maintenance conditions. Here, MFD effects were evaluated in an 8-week intervention with no restriction for weight changes.. Healthy subjects consumed MFD (23 subjects) or a control diet (CD) devoid of the functional components (24 subjects) in a "free-living" randomized controlled experiment. MFD included several functional concepts: low-glycemic-impact meals, antioxidant-rich foods, oily fish, viscous dietary fibers, soybean and whole barley kernel products, almonds and plant stanols. Measured outcomes were fasting blood values of lipids, glucose, insulin, GGT, CRP, HbA1c, PAI-1, GLP-1, GLP-2, body weight, blood pressure and breath hydrogen.. At baseline, participants were 51-72 years old, with BMI between 25 and 34 and fasting glycemia  ≤ 6.1 mmol/L. Consumption of both diets resulted in similar weight loss after 8 weeks (-4 %; P  <  0.001). Compared to baseline, consumption of MFD reduced total serum cholesterol (-26 %; P  <  0.0001), LDL cholesterol (-35 %; P  <  0.0001), triglycerides (-16 %; P  < 0.05), LDL/HDL (-27 %; P  <  0.0001) and ApoB/ApoA1 (-15 %; P  <  0.0001). There were important net differences between diets, which remained significant after adjustment for body weight. Reduced systolic blood pressure, circulating GGT, HbA1c and insulin concentrations were observed with both MFD and CD with no difference between diets. The Reynolds cardiovascular risk score was decreased by 36 % (P  <  0.0001) with MFD. MFD increased breath hydrogen levels (120 %; P  <  0.05).. Consumption of MFD decreased blood lipids and improved several other aspects of the cardiometabolic risk profile. This effect was not dependent on weight loss.

Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Cross-Over Studies; Diet; Female; gamma-Glutamyltransferase; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Plasminogen Activator Inhibitor 1; Risk Factors; Waist Circumference

The role of the different factors associated with fatty liver is still poorly defined. We evaluated the relationships between liver fat content (LF) and metabolic, inflammatory and nutritional factors in a homogeneous cohort of individuals at high cardio-metabolic risk.. In 70 individuals with high waist circumference and at least one more criterion for metabolic syndrome enrolled in a nutritional intervention study, LF was evaluated at baseline by hepatic/renal echo intensity ratio (H/R), together with dietary habits (7-day dietary record), insulin sensitivity and β-cell function (fasting and OGTT-derived indices), fasting and postprandial plasma GLP-1 and lipoproteins, and plasma inflammatory markers. H/R correlated positively with fasting and OGTT plasma glucose and insulin concentrations, HOMA-IR and β-cell function, and IL-4, IL-17, IFN-γ, TNF-α, FGF and GCSF plasma concentrations (p < 0.05 for all), and negatively with insulin sensitivity (OGIS), dietary, polyphenols and fiber (p < 0.05 for all). By multiple stepwise regression analysis, the best predictors of H/R were OGIS (β = -0.352 p = 0.001), postprandial GLP-1 (β = -0.344; p = 0.001), HDL-cholesterol (β = -0.323; p = 0.002) and IFN-γ (β = 0.205; p = 0.036).. A comprehensive evaluation of factors associated with liver fat, in a homogeneous population at high cardio-metabolic risk, indicated a pathogenic combination of the same pathways underlying the atherosclerotic process, namely whole body insulin sensitivity and inflammation. The higher predictive value of postprandial variables suggests that liver fat is essentially a postprandial phenomenon, with a relevant role possibly played by GLP-1.. NCT01154478.

Topics: Adaptive Immunity; Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diet Records; Feeding Behavior; Female; Glucagon-Like Peptide 1; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Interferon-gamma; Italy; Liver; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Nutritional Status; Postprandial Period; Regression Analysis; Risk Assessment; Risk Factors; Time Factors

Bile acids (BAs) are increasingly recognised as metabolic regulators, potentially improving insulin sensitivity following bariatric surgery. However, physiological relevance of such observations remains unknown. Hence, we analysed serum BA composition and associated gut-derived hormone levels following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 non-smoking men (45-55 yr) with MetS were randomised to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control arm. Before and after a 6 months intervention period clinical and laboratory parameters, body composition, serum BA profile, FGF-19, and GLP-1 concentrations were determined in fasting blood samples. 30 participants in the control and 33 participants in the treatment arm completed the study and were included in the data analysis. In participants of the treatment arm lifestyle-induced weight loss resulted in markedly improved insulin sensitivity. Serum levels of BA species and total GLP-1 decreased, while FGF-19 remained stable. Serum BA composition changed towards an increased 12α-hydroxylated/non-12α-hydroxylated ratio. None of these parameters changed in participants of the control arm. Our results demonstrate that improved metabolic control by lifestyle modifications lowers serum levels of BAs and GLP-1 and changes serum BA composition towards an increased 12α/non-12α ratio (ICTRP Trial Number: U1111-1158-3672).

Topics: Bile Acids and Salts; Blood Glucose; Body Mass Index; Body Weight; Fasting; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Prospective Studies; Weight Loss

Several studies emphasise that arabinoxylan and β-glucan have more beneficial effects on glucose metabolism than low-dietary fibre (DF) meals. Less attention has been paid to the effects of concentrated DF compared with whole grain. We compared the effects of DF and whole grain on glucose, hormone responses and appetite in subjects with the metabolic syndrome (MetS).. Fifteen subjects with MetS participated in this acute, randomised, cross-over intervention study. The test breads provided 50 g of digestible carbohydrate: wheat bread with concentrated arabinoxylan (AX) or β-glucan (BG), rye bread with kernels (RK) and wheat bread (WB) as control. Blood samples were drawn for 270 min to determine glucose, insulin, glucagon-like peptide-1, glucose-dependent insulinotropic peptide (GIP) and ghrelin. Appetite score was addressed every 30 min. Ad libitum energy intake (EI) was measured 270 min after test meals.. Compared with WB, BG and RK induced lower initial glycaemic responses (P<0.001), whereas AX only reduced the glucose peak value (P<0.001). RK reduced insulin (P<0.001) and GIP responses (P<0.001) compared with the other breads. BG lowered insulin responses more than AX (P<0.001). AX, BG and RK increased satiety feeling (P<0.001) more than WB, but did not differ significantly in terms of subsequent EI (P=0.089).. BG and RK had beneficial impact on the glucose response, whereas AX had only effect on the postprandial glucose peak. The impact of the AX bread was influenced by higher protein content. Whether the metabolic effects of the breads are still present to mixed meals remains to be tested.

Topics: Aged; Appetite; Area Under Curve; beta-Glucans; Blood Glucose; Bread; Cross-Over Studies; Dietary Fiber; Energy Intake; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Satiation; Secale; Triticum; Xylans

Prospective studies have shown an inverse relationship between whole grain consumption and the risk of type 2 diabetes, where short chain fatty acids (SCFA) may be involved. Our objective was to determine the effect of isolated arabinoxylan alone or in combination with whole grain rye kernels on postprandial glucose, insulin, free fatty acids (FFA), gut hormones, SCFA and appetite in subjects with the metabolic syndrome (MetS).. Fifteen subjects with MetS participated in this acute, randomised, cross-over study. The test meals each providing 50 g of digestible carbohydrate were as follows: semolina porridge added concentrated arabinoxylan (AX), rye kernels (RK) or concentrated arabinoxylan combined with rye kernels (AXRK) and semolina porridge as control (SE). A standard lunch was served 4 h after the test meals. Blood samples were drawn during a 6-h period, and appetite scores and breath hydrogen were assessed every 30 min.. The AXRK meal reduced the acute glucose (P=0.005) and insulin responses (P<0.001) and the feeling of hunger (P=0.005; 0-360 min) compared with the control meal. The AX and AXRK meals increased butyrate and acetate concentrations after 6 h. No significant differences were found for the second meal responses of glucose, insulin, FFA, glucagon-like peptide-1 or ghrelin.. Our results indicate a stimulatory effect of arabinoxylan on butyrate and acetate production, however, with no detectable effect on the second meal glucose response. It remains to be tested in a long-term study if a beneficial effect on the glucose response of the isolated arabinoxylan will be related to the SCFA production.

Topics: Aged; Appetite; Blood Glucose; Breath Tests; Cross-Over Studies; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Fatty Acids, Volatile; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin; Male; Meals; Metabolic Syndrome; Middle Aged; Postprandial Period; Secale; Triticum; Xylans

Until recently, very few intervention studies have investigated the effects of whole-grain cereals on postprandial glucose, insulin and lipid metabolism, and the existing studies have provided mixed results. The objective of this study was to evaluate the effects of a 12-week intervention with either a whole-grain-based or a refined cereal-based diet on postprandial glucose, insulin and lipid metabolism in individuals with metabolic syndrome.. Sixty-one men and women age range 40-65 years, with the metabolic syndrome were recruited to participate in this study using a parallel group design. After a 4-week run-in period, participants were randomly assigned to a 12-week diet based on whole-grain products (whole-grain group) or refined cereal products (control group). Blood samples were taken at the beginning and end of the intervention, both fasting and 3 h after a lunch, to measure biochemical parameters. Generalized linear model (GLM) was used for between-group comparisons. Overall, 26 participants in the control group and 28 in the whole-grain group completed the dietary intervention. Drop-outs (five in the control and two in the whole-grain group) did not affect randomization. After 12 weeks, postprandial insulin and triglyceride responses (evaluated as average change 2 and 3 h after the meal, respectively) decreased by 29% and 43%, respectively, in the whole-grain group compared to the run-in period. Postprandial insulin and triglyceride responses were significantly lower at the end of the intervention in the whole-grain group compared to the control group (p = 0.04 and p = 0.05; respectively) whereas there was no change in postprandial response of glucose and other parameters evaluated.. A twelve week whole-grain cereal-based diet, compared to refined cereals, reduced postprandial insulin and triglycerides responses. This finding may have implications for type 2 diabetes risk and cardiovascular disease.

Topics: Adult; Aged; Apolipoproteins A; Apolipoproteins B; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diet; Edible Grain; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Glycemic Index; Humans; Insulin; Linear Models; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Nutrition Assessment; Patient Compliance; Postprandial Period; Triglycerides

The role of gastrointestinal (GI) hormones in the pathophysiology of obesity is unclear, although they are involved in the regulation of satiation and glucose metabolism. To (i) examine glucagon-like peptide 1 (GLP-1), amylin, ghrelin, and glucagon responses to a meal in obese adolescents and to (ii) test which GI peptides are associated with insulin resistance are presented.. A total of 16 obese (body mass index (BMI) ≥ 97th percentile for age and gender) and 14 control (BMI between 25th and 75th percentiles) adolescents were included. Subjects were instructed to eat a test meal (490 kcal). Plasma samples were collected for hormone and glucose analysis.. Obese adolescents were insulin resistant as expressed by the Homeostasis Model Assessment (HOMA) index and had significantly increased fasting glucagon and amylin levels compared to the control group (P = 0.003 and 0.044, respectively). In response to the meal, the increase in GLP-1 levels was reduced in obese adolescents (P < 0.001). In contrast, amylin secretion was significantly increased in the obese population compared to the control group (P < 0.005).. Obese adolescents have increased fasting glucagon and amylin levels and attenuated post-prandial GLP-1 concentrations compared with the control group. These factors could contribute to the metabolic syndrome.

Topics: Adolescent; Body Mass Index; Child; Female; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Male; Meals; Metabolic Syndrome; Pediatric Obesity; Postprandial Period; Satiation

Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS.. Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5).. In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both).. In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.

Topics: Acetylcholine; Glucagon-Like Peptide 1; Glucose; Humans; Hyperinsulinism; Metabolic Syndrome; Nitroprusside; Oxidative Stress; Vasodilation

We hypothesize that type 2 diabetic patients with different phenotypes may show different response to incretin-based therapies. Therefore, we tested whether the presence of metabolic syndrome (MS) influences glycemic response to these drugs. We prospectively followed 211 patients, treated with the GLP-1 analog exenatide (n = 102) or a DPP-4 inhibitor (n = 109) for at least 4 months. Treatment was decided on clinical grounds. We collected baseline data (age, sex, BMI, waist, systolic and diastolic blood pressure, lipid profile, data on diabetic complications and concomitant treatment) and HbA1c at subsequent visits. Patients were divided into groups according to the presence/absence of MS. Compared to patients on exenatide, patients on DPP-4 inhibitors were older and had lower BMI, waist, diastolic blood pressure, fasting plasma glucose, and HbA1c. At means of baseline values, HbA1c reduction was similar in patients treated with exenatide or DPP-4 inhibitors. Patients on exenatide showed significantly higher HbA1c reduction if they had MS (-1.55 ± 0.22%; n = 88) than if they had not (-0.34 ± 0.18%; P = 0.002). Conversely, patients on DPP-4 inhibitors showed significantly lower HbA1c reduction if they had MS (-0.60 ± 0.12%; n = 73) than if they had not (-1.50 ± 0.24%; P < 0.001). Type of MS definition (ATP-III, IDF or WHO) poorly influenced these trends. The interaction between type of therapy (exenatide vs. DPP-4 inhibitors) and MS remained significant after adjusting for age, baseline HbA1c, BMI, and concomitant medications. In conclusion, the presence of MS appears to modify the response to incretin-based therapies. Given the non-randomized nature of this study, these data need to be replicated.

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Metabolic Syndrome; Middle Aged; Nitriles; Peptides; Prognosis; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms; Vildagliptin

Survivors of pediatric hematopoietic stem cell transplantation (HSCT) have increased risk of developing metabolic syndrome (MetS), but the mechanisms are poorly understood.. We aimed to test the hypothesis that insufficient secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) plays a pathogenetic role in HSCT survivors with MetS.. This cross-sectional cohort study, conducted at the Danish national referral center for HSCT, studied 42 male HSCT survivors (median age 28.9 years) for a median 21.2 years from HSCT, along with 15 age- and sex-matched healthy controls. Main outcome measures were glucose metabolism and incretin hormones (by oral glucose tolerance test [OGTT]) and MetS criteria. The hypothesis was formulated before data collection.. GLP-1, GIP, and glucagon during an OGTT were similar in patients and controls, with no overall difference between survivors with (24%) and without MetS. However, fasting glucagon was significantly higher in patients with hypertriglyceridemia (mean difference [MD]: 6.1 pmol/L; 95% CI, 1.5-10.8; P = 0.01), and correlated with HDL (MD: 4.7 mmol/L; 95% CI, -0.6 to 9.9; P = 0.08), android-gynoid ratio (correlation coefficient [r] = 0.6, P = 0.0001) and waist-hip ratio (r = 0.5, P = 0.002). A similar pattern was seen for GIP, correlating positively with triglyceride (MD: 60%; 95% CI, 44-82; P = 0.002). GIP levels were significantly increased in patients treated with total body irradiation (TBI) (MD: 165%; 95% CI, 118-230; P = 0.004), which was found to be a significant risk factor for MetS.. This study demonstrates an altered production of incretin hormones in HSCT survivors previously treated with TBI, developing dyslipidemia and abdominal adiposity.

Topics: Adult; Blood Glucose; Child; Cross-Sectional Studies; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Hematopoietic Stem Cell Transplantation; Humans; Incretins; Insulin; Male; Metabolic Syndrome; Survivors

Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global adult population and can progress to end-stage liver disease with life-threatening complications; however, no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNCs) are a very versatile platform, easy to produce, and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being extensively studied in clinical trials in the context of NAFLD. Our nanosystem provides with increased levels of GLP-1, triggered by the nanocarrier itself, and by the plasmatic absorption of the encapsulated synthetic analog (exenatide). Our goal in this study was to demonstrate a better outcome and a greater impact on the metabolic syndrome and liver disease progression associated with NAFLD with our nanosystem than with the subcutaneous injection of the GLP-1 analog alone. To that end, we studied the effect of chronic administration (one month) of our nanocarriers in two mouse models of early NASH: a genetic model (foz/foz mice fed a high fat diet (HFD)) and a dietary model (C57BL/6J mice fed with a western diet plus fructose (WDF)). Our strategy had a positive impact in promoting the normalization of glucose homeostasis and insulin resistance in both models, mitigating the progression of the disease. In the liver, diverging results were observed between the models, with the foz/foz mice presenting a better outcome. Although a complete resolution of NASH was not achieved in either model, the oral administration of the nanosystem was more efficient at preventing the progression of the disease into more severe states than the subcutaneous injection. We thus confirmed our hypothesis that the oral administration of our formulation has a stronger effect on alleviating the metabolic syndrome associated with NAFLD than the subcutaneous injection of the peptide.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Glucagon-Like Peptide 1; Lipids; Liver; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Nanocapsules; Non-alcoholic Fatty Liver Disease

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, is a risk factor for endothelial dysfunction, a common pathophysiological denominator for both atherogenesis and cardiac fibrosis. We aimed to investigate whether the cardioprotective and antifibrotic effects of incretin drugs, exenatide and sitagliptin, may be associated with their ability to affect circulating and cardiac ADMA metabolism. Normal and fructose-fed rats were treated with sitagliptin (5.0/10 mg/kg) or exenatide (5/10 µg/kg) for 4 weeks. The following methods were used: LC-MS/MS, ELISA, Real-Time-PCR, colorimetry, IHC and H&E staining, PCA and OPLS-DA projections. Eight-week fructose feeding resulted in an increase in plasma ADMA and a decrease in NO concentration. Exenatide administration into fructose-fed rats reduced the plasma ADMA level and increased NO level. In the heart of these animals exenatide administration increased NO and PRMT1 level, reduced TGF-ß1, α-SMA levels and COL1A1 expression. In the exenatide treated rats renal DDAH activity positively correlated with plasma NO level and negatively with plasma ADMA level and cardiac α-SMA concentration. Sitagliptin treatment of fructose-fed rats increased plasma NO concentration, reduced circulating SDMA level, increased renal DDAH activity and reduced myocardial DDAH activity. Both drugs attenuated the myocardial immunoexpression of Smad2/3/P and perivascular fibrosis. In the metabolic syndrome condition both sitagliptin and exenatide positively modulated cardiac fibrotic remodeling and circulating level of endogenous NOS inhibitors but had no effects on ADMA levels in the myocardium.

Topics: Amidohydrolases; Animals; Arginine; Biomarkers; Chromatography, Liquid; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fibrosis; Fructose; Glucagon-Like Peptide 1; Hypoglycemic Agents; Metabolic Syndrome; Nitric Oxide; Protease Inhibitors; Rats; Sitagliptin Phosphate; Tandem Mass Spectrometry

Metabolic Syndrome (MetS) represents a common dysmetabolic state in children with obesity. Although data in youth show a role of gut hormones (GH) in the risk of developing MetS, no data are available during the prepubertal age, especially across clusters of MetS.. We characterized components of MetS and changes in GH concentrations in 90 prepubertal children with obesity compared to 30 healthy age- and gender-matched peers. Children with obesity were divided into three groups according to the number of the components of MetS (group 1: 30 obese without components of MetS; group 2: 30 obese with 1 component of MetS; group 3: 30 obese with 2 or more components of MetS). Anthropometric parameters, blood pressure (BP), fasting insulin and glycemia, lipid profile, transaminases, and GH concentration were determined. Differences across the groups were evaluated by the Kruskal-Wallis test and post hoc analysis by Mann-Whitney test.. Fasting glycemia and insulin, HOMA-IR, triglycerides, and BP progressively increased and high-density lipoprotein progressively decreased across the groups of children with obesity compared to controls, showing worse values in group 3. GLP-1 and ghrelin values progressively decreased and obestatin progressively increased. The more components of the MetS were present, the further GH concentrations deviated from standard values.. Components of MetS and GH concentrations are impaired in prepubertal children with obesity compared to controls. The close association between progressive alterations in GH levels and increasing number of components of the MetS might indicate a role of these hormones in the determination of metabolic risk.

Topics: Adolescent; Blood Glucose; Body Mass Index; Child; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Lipoproteins, HDL; Metabolic Syndrome; Obesity; Transaminases; Triglycerides

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat diabetes and obesity and reduce rates of major cardiovascular events, such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R-expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood, and gut. Glp1r expression in bone marrow cells was very low and not further reduced in Glp1rTie2-/- mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2-/- mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2-/- mice, and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression; triglyceride content; and collagen accumulation in high-fat, high-cholesterol diet-fed Glp1rTie2+/+ mice but not Glp1rTie2-/- mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the antiatherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the antiinflammatory actions of semaglutide in the liver.

Topics: Animals; Atherosclerosis; Endothelial Cells; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hematopoietic Stem Cells; Humans; Liver; Male; Metabolic Syndrome; Mice

Glucagon-like peptide GLP-1 and -2 have been shown to regulate immune responses in immune-mediated disorders, including Crohn's disease (CD). Our aim was to investigate post-prandial GLP release and its potential link to chronic inflammation, insulin secretion/sensitivity and body composition changes in CD patients.. Fifteen patients with CD, 15 healthy controls (HC) and 15 patients with metabolic syndrome (MS) were recruited. All patients underwent assessment of body composition by means of bio-impedance followed by a meal tolerance test (MTT). Only one CD patient did not tolerate the MTT and was excluded.. CD is characterized by abnormal fasting and post-prandial GLP levels. Circulating GLP influences subclinical inflammation and glucose metabolism in CD patients, but not their body composition parameters.

Topics: Blood Glucose; Crohn Disease; Glucagon-Like Peptide 1; Humans; Inflammation; Insulin; Metabolic Syndrome; Peptide Fragments

Topics: Animals; Blood Glucose; Body Weight; Down-Regulation; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Resistance; Intestine, Small; Liraglutide; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Pancreas; Quinolones; Rats; Signal Transduction; Thiophenes

Gypenosides, extracts of Gynostemma yixingense, have been traditionally prescribed to improve metabolic syndrome in Asian folk and local traditional medicine hospitals. However, the mechanism of its action remains unclarified. In this work, our results indicated that chronic administration of 2α-OH-protopanoxadiol (GP2), a metabolite of gypenosides in vivo, protected mice from high-fat diet-induced obesity and improved glucose tolerance by improving intestinal L-cell function. Mechanistically, GP2 treatment inhibited the enzymatic activity of bile salt hydrolase and modulated the proportions of the gut microbiota, which led to an increase in the accumulation of tauro-β-muricholic acid (TβMCA) in the intestine. TβMCA induced GLP-1 production and secretion by reducing the transcriptional activity of nuclear receptor farnesoid X receptor (FXR). Transplantation of GP2-remodelled fecal microbiota into antibiotic-treated mice also increased the intestinal TβMCA content and improved intestinal L-cell function. These findings demonstrate that GP2 ameliorates metabolic syndrome at least partly through the intestinal FXR/GLP-1 axis via gut microbiota remodelling and also suggest that GP2 may serve as a promising oral therapeutic agent for metabolic syndrome.

Topics: Animals; Diet, High-Fat; Drug Design; Gastrointestinal Microbiome; Glucagon; Glucagon-Like Peptide 1; Gynostemma; Intestines; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Plant Extracts; RNA-Binding Proteins; RNA, Ribosomal, 16S; Taurocholic Acid

Background Hypothalamic damage may alter glucagon-like peptide-1 (GLP-1) secretion and be involved in the pathogenesis of obesity. We aim to evaluate the metabolic features and the dynamic changes of GLP-1 levels during an oral glucose tolerance test (OGTT) in children with hypothalamic obesity (HO) compared with simple obesity controls. Methods Subjects included eight patients (six females, aged 9-16 years) with hypothalamo-pituitary tumors who later developed obesity and eight controls with simple obesity matched for age, body mass index (BMI), gender and puberty. We assessed the metabolic syndrome features, fat mass, severity of hyperphagia using a standardized questionnaire, and measured glucose, insulin and GLP-1 levels during a standard 75 g OGTT. Results Age, gender distribution, pubertal status and BMI-Z scores were not significantly different. Subjects with HO had higher fasting triglycerides (TG) than controls (128 vs. 94 mg/dL; p=0.05). Four HO subjects and three controls met the criteria for the metabolic syndrome. Fasting and 120 min post-glucose load GLP-1 levels were significantly higher in HO patients than in controls (21.9 vs. 19.7 pg/mL; p=0.025, 22.1 vs. 17.7 pg/mL; p=0.012). Patients with HO had significantly higher hyperphagia scores than in simple obese controls (13 vs. 2.5; p=0.012). Conclusions Patients with HO appear to have more metabolic complications and hyperphagia than controls with simple obesity. Impaired satiety may play an important role in HO. Fasting and glucose-induced serum GLP-1 concentrations seem to be altered in HO patients and could be a part of the pathogenesis of HO.

Topics: Adolescent; Blood Glucose; Body Mass Index; Child; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperphagia; Hypothalamic Diseases; Hypothalamic Neoplasms; Insulin; Male; Metabolic Syndrome; Obesity

The oral glucose test (OGT) is a useful tool for diagnosing insulin dysregulation (ID) and is somewhat repeatable in ponies under consistent management. This study aimed to determine whether the insulin and incretin responses to an OGT in ponies differed after short-term access to fertilised pasture, compared to unfertilised pasture, by using a randomised, repeated measures study design. Sixteen mixed-breed ponies were classified as severely insulin-dysregulated (SD; post-prandial insulin ≥80 μIU/mL) or not severely insulin-dysregulated (NSD; post-prandial insulin < 80 μIU/mL) using an OGT prior to the study. The ponies accessed pasture that was fertilised, or unfertilised, for 5 days (4 h/day, with supplemental hay provided at 0.7% bodyweight), with a 10 day period between phases. An OGT was performed after each phase. Glucose, insulin, active glucagon-like peptide-1 (aGLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured in post-prandial blood samples.. The volume of fertilised pasture was five-fold greater than unfertilised pasture, with % non-structural carbohydrates (NSC) similar between all forages. Consuming fertilised pasture increased (P = 0.018) the serum insulin response to an OGT, compared to grazing unfertilised pasture. A limitation of the study was that pasture intake was unable to be quantified. Insulin responses were greater in SD, compared to NSD, ponies (P < 0.001) and remained well above the test cut-off at all times. A subset of ponies, initially screened as NSD, became (more) insulin-dysregulated after pasture access. Further, aGLP-1 was a significant predictor of insulin concentration in this cohort.. Whereas some insulin-dysregulated ponies were comparatively resistant to dietary intervention, others showed markedly different OGT responses following subtle changes in their forage-based diet. This implies that mild/early ID might be unmasked by dietary change, and that dietary management is important in these ponies. However, dietary management alone may not be adequate for all cases of ID.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Cross-Over Studies; Diet; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Horse Diseases; Horses; Hyperinsulinism; Incretins; Insulin; Metabolic Syndrome; Peptide Fragments; Queensland; Random Allocation

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the

Topics: Amidohydrolases; Amino Acid Substitution; Animals; Blood Glucose; Disease Models, Animal; Eating; Ethanolamines; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Injections, Intravenous; Insulin; Islets of Langerhans; Male; Metabolic Syndrome; Mice; Mice, Transgenic; Middle Aged; Oleic Acids; Postprandial Period; Receptors, G-Protein-Coupled; Taurine

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Disease Models, Animal; Disease Progression; Eating; Enterocytes; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Integrin beta Chains; Intestine, Small; Intraepithelial Lymphocytes; Male; Metabolic Syndrome; Mice

In clinical practice, there are patients with a combination of metabolic syndrome (MS) and chronic obstructive pulmonary disease (COPD). The pathological mechanisms linking MS and COPD are largely unknown. It remains unclear whether the effect of MS (possible obesity) has a major impact on the progression of COPD. This complicates the development of effective approaches for the treatment of patients with a diagnosis of MS and COPD. Experiments were performed on female C57BL/6 mice. Introduction of monosodium glutamate and extract of cigarette smoke was modeled to simulate the combined pathology of lipid disorders and emphysema. Biological effects of glucagon-like peptide 1 (GLP-1) and GLP-1 on endothelial progenitor cells (EPC) in vitro and in vivo were evaluated. Histological, immunohistochemical methods, biochemical methods, cytometric analysis of markers identifying EPC were used in the study. The CD31⁺ endothelial cells in vitro evaluation was produced by Flow Cytometry and Image Processing of each well with a Cytation™ 3. GLP-1 reduces the area of emphysema and increases the number of CD31⁺ endothelial cells in the lungs of mice in conditions of dyslipidemia and damage to alveolar tissue of cigarette smoke extract. The regenerative effects of GLP-1 are caused by a decrease in inflammation, a positive effect on lipid metabolism and glucose metabolism. EPC are proposed as pathogenetic and diagnostic markers of endothelial disorders in combination of MS with COPD. Based on GLP-1, it is proposed to create a drug to stimulate the regeneration of endothelium damaged in MS and COPD.

Topics: Animals; Cigarette Smoking; Disease Models, Animal; Disease Progression; Endothelial Progenitor Cells; Flow Cytometry; Glucagon-Like Peptide 1; Glucose; Humans; Lipid Metabolism; Lung; Metabolic Syndrome; Mice; Platelet Endothelial Cell Adhesion Molecule-1; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Sodium Glutamate

Type 2 diabetes (T2DM) associated with non-alcoholic fatty liver disease (NAFLD) increases cardiovascular risk. Complex and subtle connections are established between hepatic dysfunction and adipose tissue hyperactivity. This relationship is mediated by insulin resistance, dyslipidemia and inflammation. Recently incretins have been involved in this connection including GLP-1 (glucagon-like peptide-1). The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipocytokines profile (leptin, adiponectin, resistin, TNFα and IL-6) in diabetic subjects with or without NAFLD. The study was undertaken on 320 adult subjects divided into four groups: NAFLD, DT2, NAFLD+DT2 and control. In all subjects, the metabolic syndrome clusters was investigated according to the NCEP/ATPIII criteria. Insulin resistance was evaluated by the Homa-IR model. The metabolic parameters were determined on Cobas® automated biochemical analysis. The adipocytokines are determined by immunoassay method on Elisa human reader - Biotek ELX 800. The NAFLD has been confirmed by abdominal ultrasound and by histology. Feeding and fasting plasma GLP-1 was assessed by Elisa method. The data revealed that insulin resistance (Homa-IR) is present in all groups. Homa-IR is negatively associated with plasma GLP-1 depletion in the NAFLD, DT2 and NAFLD+DT2 groups. Adiponectin levels are decreased in all groups as for GLP-1. At the opposite, leptin, resistin, TNFα and IL-6 levels show an inverse correlation with GLP-1. This study suggests that plasma GLP-1 can be considered as a transition and evolution biomarker between NAFLD and T2D. GLP-1 accurately reflects metabolic and inflammatory status, both in subjects with NAFLD only or with T2D only, before the diabetes - steatosis stage.

Topics: Adipokines; Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Liver; Male; Metabolic Networks and Pathways; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease

This study examined the effect of pre-germinated brown rice extract (PGBRE), containing no dietary fibers, but γ-oryzanol, γ-aminobutyric acid (GABA), flavonoids, and anthocyanidin, on high-fat-diet (HFD)-induced metabolic syndrome. C57BL/6 mice were divided into five groups: regular diet, HFD, HFD with oral PGBRE 30, 300, or 600 mg/kg per day for 18 weeks. In the HFD group, higher body and liver weight gain, hyperglycemia, HbA1c, and insulin; higher TG, TC, LDL-C, non-HDL, atherosclerosis index, lower HDL, adiponectin in blood; higher TG in the liver; higher TG, bile acid in feces; and lower protein levels of AMP-activated protein kinase, insulin receptor, insulin receptor substrate-1, insulin receptor substrate-2, peroxisome proliferator-activated receptor-γ, phosphatidylinositol-3-kinase, Akt/PKB, glucose transporter-1, glucose transporter-4, glucokinase in the skeletal muscle; lower glucagon-like peptide 1 (GLP-1) in the intestine; higher sterol regulatory element-binding protein-1 (SREBP-1), stearoyl-CoA desaturase 1 (SCD-1), fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9 (PCSK9), and lower PPAR-α, low-density lipoprotein receptor, cholesterol-7α-hydroxylase in the liver; higher SREBP-1, SCD-1, FAS, and lower PPAR-α, adiponectin in the adipose tissue were found. In HFD + PGBRE groups, the above biochemical parameters were improved. PRACTICAL APPLICATIONS: According to the results, we suggested that dietary fibers played a minor role in this study. Extract of PGBR, excluding dietary fiber, showed beneficial activity to ameliorate metabolic syndrome. γ-oryzanol, GABA, flavonoids, and anthocyanidin in PGBRE can inhibit HFD-induced metabolic syndrome and we demonstrated clearly its action mechanisms. This is the first report to examine the relation between PGBRE, GLP-1, and PCSK9. Taken together, PGBRE can potentially be used to develop a good supplement to control metabolic syndrome.

Topics: Animals; Diet, High-Fat; Female; Germination; Glucagon-Like Peptide 1; Humans; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Oryza; Plant Extracts; PPAR gamma; Proprotein Convertase 9; Sterol Regulatory Element Binding Protein 1

Metabolic syndrome increases the risk of cardiovascular disease. Recently glucagon-like peptide 1 (GLP-1) agonists proved to be effective in preventing cardiovascular disease (CVD) in patients with type 2 diabetes. We investigated the association of blood incretin levels with metabolic syndrome in patients with type 2 diabetes.. This is a cross-sectional study involving 334 people with type 2 diabetes. Intact GLP-1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 min after ingestion of a standard mixed meal. Metabolic syndrome was diagnosed based on the criteria of the International Diabetes Federation.. Two hundred twenty-five (69%) of the subjects have metabolic syndrome. The fasting iGLP-1 level was no different between groups. Thirty-min postprandial iGLP-1 was non-significantly lower in the subjects who had metabolic syndrome. Incremental iGLP-1 (ΔiGLP-1, the difference between 30-min postmeal and fasting iGLP-1 levels) was significantly lower in those with metabolic syndrome. There were no significant differences in fasting iGIP, postprandial iGIP, and ΔiGIP between groups. The ΔiGLP-1, but not ΔiGIP levels decreased significantly as the number of metabolic syndrome components increased. In hierarchical logistic regression analysis, the ΔiGLP-1 level was found to be a significant contributor to metabolic syndrome even after adjusting for other covariates.. Taken together, the iGLP-1 increment in the 30 min after meal ingestion is inversely associated with metabolic syndrome in patients with type 2 diabetes. This suggests that postmeal iGLP-1 increment could be useful in assessing cardiovascular risk in type 2 diabetes.

Topics: Aged; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Risk

The contribution of gut-derived factors to the mechanisms linking obesity and metabolic disease remains under-investigated. The aim of the current study was to examine the associations between glucagon and enteroendocrine signaling and type 2 diabetes (T2D) using a derived risk score approach. To compare the relative importance of the enteroendocrine system, associations between adipokine measures and T2D were also investigated.. A total of 130 individuals with T2D and 161 individuals without T2D were included in the study. Circulating concentrations of enteroendocrine (glucagon, ghrelin, glucagon-like peptide-1, and gastric inhibitory peptide) and adipokine mediators (adiponectin, leptin, resistin, visfatin, and adipsin) were measured. Standard scores (Z-scores) were determined for each measure and enteroendocrine risk scores (ERS) and adipokine risk scores (ARS) calculated based on summation of the component measures. Associations between both the ERS and ARS and T2D status were assessed using logistic regression models.. The ERS was significantly associated with T2D status in an adjusted model (odds ratio: 1.36; 95% confidence interval [CI]: 1.08-1.72; P = 0.009). Associations between the ARS and T2D status were not independent of age, sex, and body mass index (odds ratio: 1.21; 95%CI: 0.99-1.47; P = 0.06). Quantification of risk across ERS tertiles revealed that individuals with an ERS in the upper tertile were 10 times more likely (CI: 3.23-32.73; P < 0.001) to have T2D.. These data support an association between enteroendocrine signaling and T2D. Use of the ERS as a potential tool for classifying individuals with metabolic syndrome as high or low risk for T2D development is being considered.

Topics: Adipokines; Adolescent; Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Male; Metabolic Syndrome; Middle Aged; Phenotype; Risk Assessment; Young Adult

In this study, gamma-aminobutyric acid (GABA) enriched rice bran (ERB) was supplemented to obese rats to investigate the attenuation of metabolic syndromes induced by high-fat diet. ERB-containing diet stimulated butyrate and propionate production by promoting Anaerostipes, Anaerostipes sp., and associated synthesizing enzymes. This altered short-chain fatty acid (SCFA) distribution further enhanced circulatory levels of leptin and glucagon-like peptide-1, controlling food intake by downregulating orexigenic factors. Together with the enhanced fatty acid β-oxidation highlighted by Prkaa2, Ppara, and Scd1 expression via AMPK signaling pathway and nonalcoholic fatty liver disease pathway, energy expenditure was positively modulated. Serum lipid compositions showed ERB supplement exhibited a more efficient effect on lowering serum sphingolipids, which was closely associated with the status of insulin resistance. Consistently, genes of Ppp2r3b and Prkcg, involved in the function of ceramides in blocking insulin action, were also downregulated following ERB intervention. Enriched GABA and phenolic acids were supposed to be responsible for the health-beneficial effects.

Topics: Adipose Tissue; Animals; Ceramides; Diet; Diet, High-Fat; DNA; Energy Metabolism; Fatty Acids, Volatile; Food, Fortified; gamma-Aminobutyric Acid; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Insulin Resistance; Leptin; Liver; Male; Metabolic Syndrome; Obesity; Oryza; Rats; Rats, Sprague-Dawley; Seeds; Sphingolipids

Grape seed proanthocyanidin extract (GSPE) modulates several parameters involved in metabolic syndrome. GSPE is a mixture of compounds, some which are rapidly absorbed, while others remain in the lumen where they might have effects that are translated to the whole organism. Our aim was to decipher if the 8-day treatment of GSPE, previously shown to reduce food intake, induces changes in the microbiota and enterohormone secretion. The ratio of Firmicutes : Bacteroidetes was lower in the microbiota of GSPE-treated rats compared to controls, and differences in several taxonomic families and genera were observed. Such modulation led to a reduction in cecal butyrate content. GSPE also increased plasma glucagon-like-peptide-1 (GLP-1). Gallic acid did not induce major changes in the microbiota profile nor in GLP-1 secretion. Correlations between several microbiota taxa and plasma triacylglycerol, adiposity, and enterohormones were observed. Modulation of microbiota may be one of the mechanism by which GSPE impacts metabolic health.

Topics: Adiposity; Animals; Bacteria; Butyrates; Female; Gallic Acid; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Grape Seed Extract; Humans; Metabolic Syndrome; Proanthocyanidins; Rats; Rats, Wistar

Obesity and insulin resistance are associated with an increased risk of colorectal adenoma (CRA). Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis through its amplification of insulin secretion in response to oral nutrients; however, its role in human CRA remains unknown. We investigated oral glucose-mediated GLP-1 secretion in patients with adenoma.. We performed a case-control study of 15 nondiabetic patients with pathologically diagnosed CRA and 10 age-matched healthy controls without adenoma. Plasma concentrations of active GLP-1 were measured during a 75 g oral glucose tolerance test.. Mean waist circumference (WC), homeostasis model assessment of insulin resistance (HOMA-IR) values, the total areas under the curve (AUC) of glucose and insulin were significantly higher in patients with CRA than in controls. The total AUC of GLP-1 (p = 0.01) was lower in patients with CRA than in controls. Moreover, the total AUC of GLP-1 showed a negative correlation with WC, total AUC of glucose, and HOMA-IR. Multiple linear regression analyses revealed that the total AUC of GLP-1 was independently correlated with the number and maximum size of CRAs.. GLP-1 could actively participate in the development of CRA in humans, particularly in patients with metabolic syndrome.

Topics: Adenoma; Adult; Aged; Blood Glucose; Case-Control Studies; Colonoscopy; Colorectal Neoplasms; Comorbidity; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Metabolic Syndrome; Middle Aged

Glucagon-Like Peptide-1 (GLP-1) is hydrolyzed by Dipeptidyl-Peptidase 4 (DPP4), and several studies suggest that both GLP-1 and DPP4 inhibitors have potentially beneficial effects on cardiovascular risks. The objective of this study was to analyze the differences between plasma GLP-1 and DPP4 activity in male and female patients with metabolic syndrome, and its relationship with physiological and metabolic parameters. The study included 25 apparently healthy Controls (C) and 21 Metabolic Syndrome patients (MS). Anthropometric indices, cardiovascular risk-score, and Mediterranean Diet Adherence (AMeDit) were evaluated. Fasting glucose, glycosylated hemoglobin (HbA1c), and insulin were measured. Insulin, GLP-1, and plasma DPP4 were determined within the first 30-min postprandial period. Body-Mass-Index was significantly higher, and AMeDit was significantly lower, but only in MS women. However, fasting glucose, HbA1c, and postprandial insulin were significantly higher in MS men, but not in MS women. Postprandial GLP-1 levels were lower in C men than in C women. Interestingly, in comparison with controls, we found significant lower levels of plasma DPP4 in MS-women only. Moreover, negative lineal regressions were established between DPP4 activity with waist-to-hip ratio and cardiovascular risk-score, and positive lineal regression with AMeDit. These results indicate gender differences in the behavior of GLP-1 and DPP4 activity in MS, which could be relevant for its treatment with GLP-1 analogues and DPP4 inhibitors.

Topics: Diet; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Humans; Insulin; Male; Metabolic Syndrome; Pilot Projects; Sex Factors

Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY

Topics: Administration, Oral; Animals; Antipsychotic Agents; Aripiprazole; Body Weight; Cytokines; Disease Models, Animal; Ghrelin; Glucagon-Like Peptide 1; Leptin; Male; Metabolic Syndrome; Poly I-C; Random Allocation; Rats, Wistar; Schizophrenia

Incretins stimulated by oral meals are claimed to be protective for the pancreatic beta cells, to increase insulin secretion, to inhibit glucagon release, slow gastric emptying (glucagon-like peptide-1) and suppress appetite. Recently it has however been suggested that glucagon-like peptide-1 (GLP-1) is putative early biomarker of metabolic consequences of the obesity associated proinflammatory state. The study was aimed to compare the release of incretins and some of early markers of inflammation at the fasting and postprandial period induced by functional oral glucose as well as lipid load in healthy controls and patients with metabolic syndrome (MS) to see if functional tests may be helpful in searching for the inflammatory status of patients. Fifty patients with MS and 20 healthy volunteers (C) participated in this study. The 3-hour oral glucose (OGTT) and the 8-hour oral lipid (OLTT) tolerance tests were performed. At fasting leptin and adiponectin, as well as every 30 minutes of OGTT and every 2 hours of OLTT blood concentration of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucose, insulin, triglycerides, free fatty acids, glutathione peroxidase, interleukin-6, sE-selectin, monocyte chemoattractant protein-1 (MCP1) and visfatin were measured. At fasting and during both OGTT and OLTT the level of incretins did not differ between the MS and the C group. Both glucose and lipids reach food activated incretins secretion. Glucose was the main GLP-1 release activator, while the lipid load activated evidently GIP secretion. A significantly larger AUC-GIP after the lipid-rich meal over the carbohydrate meal was observed, while statistically bigger value of AUC-GLP-1 was noticed in OGTT than in OLTT (P < 0.001) within each of the investigated groups. In patients with the highest fasting plasma GIP concentration (3(rd) tertile), IL-6, MCP-1, sE-selectin and visfatin blood levels were increased and correlated with glutathione peroxydase, leptin/adiponectin ratio, higher visfatin and interleukin-6 levels. The fat containing meals stimulate the long-lasting release of incretins, mainly GIP, parallel to the increase of the markers of low grade inflammation associating obesity in metabolic syndrome. The possibility of use of the postprandial (OLTT) GIP release measurement for the low grade inflammation progress in MS patients is suggested.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Cytokines; E-Selectin; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Interleukin-6; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Nicotinamide Phosphoribosyltransferase; Postprandial Period

Metabolic syndrome (MS) is found in approximately% 30-40% of patients with type 1 diabetes mellitus (T1DM). Meal-induced glucagon-like peptide-1 (GLP-1) secretion in T1DM patients with MS is yet to be clarified. The aim of the present study was to analyse the relationship between total fasting GLP-1 concentrations and the meal-induced GLP-1 response with MS prevalence in T1DM patients compared with lean, normal glucose tolerance (NGT), control subjects.. The study included 77 T1DM patients (61% male), 26 (34%) with MS, who had a mean age of 45.08 years, mean body mass index (BMI) of 25.42 kg/m(2) , and median diabetes duration of 21 years. Ten age-, gender, and BMI-matched NGT control subjects were also included in the study. Circulating GLP-1 concentrations ere measured before and 30 min after a meal by ELISA. The difference between the 30-min postprandial and fasting GLP-1 concentration (ΔGLP-1) was calculated by subtracting fasting GLP-1 concentrations from postprandial GLP-1 concentrations.. The NGT group had significantly higher total fasting, postprandial, and meal-induced GLP-1 concentrations than the T1DM groups. The T1DM patients without MS had a higher increase in circulating GLP-1 concentrations compared with the T1DM group with MS. After adjustment for age, gender, disease duration, and meal caloric value, GLP-1 response levels were inversely correlated with MS prevalence in binary logistic regression analysis.. A higher meal-induced GLP-1 response is associated with lower MS prevalence, but whether GLP-1 has a protective role in MS development is yet to be determined. This may provide further insight into the implementation of GLP-1-based therapies in the T1DM population.

Topics: Adult; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diet; Fasting; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Prevalence

Quantification of changes in glucose and lipid concentrations in women with intrahepatic cholestasis of pregnancy (ICP) and uncomplicated pregnancy and study of their influence on fetal growth.. A prospective study comparing metabolic outcomes in cholestastic and uncomplicated singleton pregnancies was undertaken at two university hospitals in the U.K. and U.S. from 2011-2014. A total of 26 women with ICP and 27 control pregnancies with no prior history of gestational diabetes mellitus were recruited from outpatient antenatal services and followed until delivery. Alterations in glucose, incretins, cholesterol, and triglycerides were studied using a continuous glucose monitoring (CGM) system and/or a standard glucose tolerance test (GTT) in conjunction with GLP-1 and a fasting lipid profile. Fetal growth was quantified using adjusted birth centiles.. Maternal blood glucose concentrations were significantly increased in ICP during ambulatory CGM (P < 0.005) and following a GTT (P < 0.005). ICP is characterized by increased fasting triglycerides (P < 0.005) and reduced HDL cholesterol (P < 0.005), similar to changes observed in metabolic syndrome. The offspring of mothers with ICP had significantly larger customized birth weight centiles, adjusted for ethnicity, sex, and gestational age (P < 0.005).. ICP is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. These findings may have implications regarding the future health of affected offspring.

Topics: Adult; Birth Weight; Blood Glucose; Cholestasis, Intrahepatic; Cholesterol; Diabetes, Gestational; Dyslipidemias; Female; Fetal Development; Fetal Macrosomia; Gestational Age; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Lipids; Male; Metabolic Syndrome; Metabolome; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Triglycerides

The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

Topics: AMP-Activated Protein Kinases; Animals; Blood Glucose; Calorimetry, Indirect; Cecum; Dietary Fiber; Fatty Acids, Volatile; Galactans; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Male; Mannans; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Plant Gums; PPAR gamma

A soluble form of CD26/dipeptidyl peptidase-IV (sCD26/DPP-IV) induces DPP-IV enzymatic activity that degrades incretin. We investigated fasting serum levels of sCD26/DPP-IV and active glucagon-like peptide-1 (GLP-1) in Malaysian patients with type 2 diabetes mellitus (T2DM) with and without metabolic syndrome (MetS), as well as the associations between sCD26/DPP-IV levels, MetS, and antidiabetic therapy.. We assessed sCD26/DPP-IV levels, active GLP-1 levels, body mass index (BMI), glucose, insulin, A1c, glucose homeostasis indices, and lipid profiles in 549 Malaysian subjects (including 257 T2DM patients with MetS, 57 T2DM patients without MetS, 71 non-diabetics with MetS, and 164 control subjects without diabetes or metabolic syndrome).. Fasting serum levels of sCD26/DPP-IV were significantly higher in T2DM patients with and without MetS than in normal subjects. Likewise, sCD26/DPP-IV levels were significantly higher in patients with T2DM and MetS than in non-diabetic patients with MetS. However, active GLP-1 levels were significantly lower in T2DM patients both with and without MetS than in normal subjects. In T2DM subjects, sCD26/DPP-IV levels were associated with significantly higher A1c levels, but were significantly lower in patients using monotherapy with metformin. In addition, no significant differences in sCD26/DPP-IV levels were found between diabetic subjects with and without MetS. Furthermore, sCD26/DPP-IV levels were negatively correlated with active GLP-1 levels in T2DM patients both with and without MetS. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-cholesterol (LDL-c) levels.. Serum sCD26/DPP-IV levels increased in T2DM subjects with and without MetS. Active GLP-1 levels decreased in T2DM patients both with and without MetS. In addition, sCD26/DPP-IV levels were associated with Alc levels and negatively correlated with active GLP-1 levels. Moreover, metformin monotherapy was associated with reduced sCD26/DPP-IV levels. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-c.

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Fasting; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Malaysia; Male; Metabolic Syndrome; Metformin; Middle Aged; Solubility

Surgical interventions that prevent nutrient exposure to the duodenum are among the most successful treatments for obesity and diabetes. However, these interventions are highly invasive, irreversible and often carry significant risk. The duodenal-endoluminal sleeve (DES) is a flexible tube that acts as a barrier to nutrient-tissue interaction along the duodenum. We implanted this device in Zucker Diabetic Fatty (ZDF) rats to gain greater understanding of duodenal nutrient exclusion on glucose homeostasis.. ZDF rats were randomised to four groups: Naive, sham ad libitum, sham pair-fed, and DES implanted. Food intake, body weight (BW) and body composition were measured for 28 days postoperatively. Glucose, lipid and bile acid metabolism were evaluated, as well as histological assessment of the upper intestine.. DES implantation induced a sustained decrease in BW throughout the study that was matched by pair-fed sham animals. Decreased BW resulted from loss of fat, but not lean mass. DES rats were also found to be more glucose tolerant than either ad libitum-fed or pair-fed sham controls, suggesting fat mass independent metabolic benefits. DES also reduced circulating triglyceride and glycerol levels while increasing circulating bile acids. Interestingly, DES stimulated a considerable increase in villus length throughout the upper intestine, which may contribute to metabolic improvements.. Our preclinical results validate DES as a promising therapeutic approach to diabetes and obesity, which offers reversibility, low risk, low invasiveness and triple benefits including fat mass loss, glucose and lipid metabolism improvement which mechanistically may involve increased villus growth in the upper gut.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Body Composition; Body Weight; Diabetes Mellitus, Experimental; Duodenum; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycerol; Homeostasis; Ileum; Intestinal Absorption; Jejunum; Male; Metabolic Syndrome; Obesity; Prostheses and Implants; Random Allocation; Rats; Rats, Zucker; Triglycerides

This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans.. Male obese, IR and dyslipidemic E3L.CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11β-hydroxysteroid-dehydrogenase-1 (HSD-1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4-6 weeks. The effects on bw, IR and plasma and liver lipids were assessed.. Rosiglitazone, liraglutide and HSD-1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD-1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high-density lipoprotein (HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin.. We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Apolipoprotein E3; Atorvastatin; Cholesterol Ester Transfer Proteins; Disease Models, Animal; Fenofibrate; Glucagon-Like Peptide 1; Heptanoic Acids; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Liraglutide; Male; Metabolic Syndrome; Mice, Transgenic; Niacin; Non-alcoholic Fatty Liver Disease; Obesity; Pyrroles; Rosiglitazone; Thiazolidinediones

Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading to low-grade inflammatory responses. An increased penetration of the impaired gut membrane by bacterial components is believed to induce this inflammation, possibly involving epigenetic alteration of inflammatory molecules such as Toll-like receptors (TLRs). We evaluated changes of the gut microbiota and epigenetic DNA methylation of TLR2 and TLR4 in three groups of subjects: type 2 diabetics under glucagon-like peptide-1 agonist therapy, obese individuals without established insulin resistance, and a lean control group. Clostridium cluster IV, Clostridium cluster XIVa, lactic acid bacteria, Faecalibacterium prausnitzii and Bacteroidetes abundances were analysed by PCR and 454 high-throughput sequencing. The epigenetic methylation in the regulatory region of TLR4 and TLR2 was analysed using bisulfite conversion and pyrosequencing. We observed a significantly higher ratio of Firmicutes/ Bacteroidetes in type 2 diabetics compared to lean controls and obese. Major differences were shown in lactic acid bacteria, with the highest abundance in type 2 diabetics, followed by obese and lean participants. In comparison, F. prausnitzii was least abundant in type 2 diabetics, and most abundant in lean controls. Methylation analysis of four CpGs in the first exon of TLR4 showed significantly lower methylation in obese individuals, but no significant difference between type 2 diabetics and lean controls. Methylation of seven CpGs in the promoter region of TLR2 was significantly lower in type 2 diabetics compared to obese subjects and lean controls. The methylation levels of both TLRs were significantly correlated with body mass index. Our data suggest that changes in gut microbiota and thus cell wall components are involved in the epigenetic regulation of inflammatory reactions. An improved diet targeted to induce gut microbial balance and in the following even epigenetic changes of pro-inflammatory genes may be effective in the prevention of metabolic syndrome.

Topics: Bacteroidetes; Body Mass Index; Clostridium; Diabetes Mellitus, Type 2; DNA Methylation; Epigenomics; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Inflammation; Inflammation Mediators; Metabolic Syndrome; Microbiota; Obesity; Promoter Regions, Genetic; Toll-Like Receptor 2; Toll-Like Receptor 4

To determine whether fasting plasma Dipeptidyl Peptidase 4 (DPP4) activity and active Glucagon-Like Peptide-1 (GLP-1) were predictive of the onset of metabolic syndrome.. A prospective cohort study was conducted of 2042 adults (863 men and 1,179 women) aged 18-70 years without metabolic syndrome examined in 2007(baseline) and 2011(follow-up). Baseline plasma DPP4 activity was determined as the rate of cleavage of 7-amino-4- methylcoumarin (AMC) from the synthetic substrate H-glycyl-prolyl-AMC and active GLP-1 was determined by enzymoimmunoassay.. During an average of 4 years of follow-up, 131 men (15.2%) and 174 women (14.8%) developed metabolic syndrome. In multiple linear regression analysis, baseline DPP4 activity was an independent predictor of an increase in insulin resistance over a 4-year period (P<0.01). In multivariable-adjusted models, the odds ratio (OR) for incident metabolic syndrome comparing the highest with the lowest quartiles of DPP4 activity and active GLP-1 were 2.82, 0.45 for men and 2.48, 0.36 for women respectively. Furthermore, plasma DPP4 activity significantly improved the area under the ROC curve for predicting new-onset metabolic syndrome based on information from metabolic syndrome components (Both P<0.01).. DPP4 activity is an important predictor of the onset of insulin resistance and metabolic syndrome in apparently healthy Chinese men and women. This finding may have important implications for understanding the aetiology of metabolic syndrome.. #TR-CCH-Chi CTR-CCH-00000361.

Topics: Adult; Asian People; China; Diabetes Mellitus; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Humans; Linear Models; Male; Metabolic Syndrome; Middle Aged; Odds Ratio

Topics: Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Metabolic Syndrome; Metformin; Obesity

Synthetic biology has significantly advanced the design of genetic devices that can reprogram cellular activities and provide novel treatment strategies for future gene- and cell-based therapies. However, many metabolic disorders are functionally linked while developing distinct diseases that are difficult to treat using a classic one-drug-one-disease intervention scheme. For example, hypertension, hyperglycemia, obesity, and dyslipidemia are interdependent pathologies that are collectively known as the metabolic syndrome, the prime epidemic of the 21st century. We have designed a unique therapeutic strategy in which the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin. Therefore, the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements. Based on this designer signaling cascade, it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin, a bifunctional therapeutic peptide hormone that combines the glucagon-like peptide 1 (GLP-1) and leptin via an IgG-Fc linker. In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia. Using a clinically licensed drug to coordinate expression of therapeutic transgenes combines drug- and gene-based therapies for coordinated treatment of functionally related metabolic disorders.

Topics: Animals; Cyclic AMP Response Element-Binding Protein; Dose-Response Relationship, Drug; Drug Design; Gene Expression Regulation; Glucagon-Like Peptide 1; Guanabenz; Leptin; Metabolic Syndrome; Mice; Models, Molecular; Receptors, G-Protein-Coupled; Signal Transduction; Transgenes

Topics: Animals; Diet; Drug Combinations; Drug Therapy, Combination; Estradiol; Glucagon-Like Peptide 1; Humans; Metabolic Syndrome; Mice; Obesity; Weight Loss

Glucagonlike peptide 1 (GLP-1) is the most potent stimulator of glucose-induced insulin secretion. The purpose of the present study was to investigate the relationships of basal circulating GLP-1 and metabolic syndrome in obese patients without cardiovascular disease.. A sample of 202 obese patients was enrolled. Dietary intake, weight, bioimpedance, blood pressure, fasting glucose, insulin, C-reactive protein, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood triglycerides, and GLP-1 levels were measured in all patients. To estimate the prevalence of metabolic syndrome, the definitions of the Adult Treatment Panel III was considered.. Patients were divided at the median of GLP-1 value (8.02 ng/dL): group 1 (n = 101) and group 2 (n = 101). Metabolic syndrome (MS) prevalence was higher in patients with the lowest median group of GLP-1 (52.5% vs 38.6%; P < 0.05). Correlation analysis showed a significant correlation among serum GLP-1 levels and the independent variables; waist-to-hip ratio (r = -0.15; P < 0.05), glucose (r = -0.15; P < 0.05), total cholesterol (r = -0.22; P < 0.05), and low-density lipoprotein cholesterol (r = -0.27; P < 0.05). In the logistic analysis with MS presence/absence as an independent variable, only weight and GLP-1 levels remained in the model. Weight shows an odds ratio of 1.10 (95% confidence interval, 1.06-1.13) by each increase of 1 kg of weight, and GLP-1 levels shows an odds ratio of 0.89 (95% confidence interval, 0.80-0.99) by each increase of 1 ng/dL of GLP-1 levels.. Obese patients with MS had lower mean GLP-1 levels than those without MS. Glucagonlike peptide 1 levels remained as a preventive factor to develop MS.

Topics: Anthropometry; Diet; Female; Glucagon-Like Peptide 1; Humans; Male; Metabolic Syndrome; Middle Aged; Obesity

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucokinase; Humans; Insulin; Insulin-Secreting Cells; Metabolic Syndrome; Receptors, G-Protein-Coupled; Sodium-Glucose Transporter 2 Inhibitors

Pulses are low in energy density, supporting their inclusion in the diet for the management of risk factors of the metabolic syndrome (MetSyn). The aim of the present study was to describe the effects of frequent consumption (five cups/week over 8 weeks) of pulses (yellow peas, chickpeas, navy beans and lentils), compared with counselling to reduce energy intake by 2093 kJ/d (500 kcal/d), on risk factors of the MetSyn in two groups (nineteen and twenty-one subjects, respectively) of overweight or obese (mean BMI 32·8 kg/m2) adults. Body weight, waist circumference, blood pressure, fasting blood parameters and 24 h food intakes were measured at weeks 1, 4 and 8. Blood glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and ghrelin were measured after a 75 g oral glucose load at weeks 1 and 8. At week 8, both groups reported reductions in energy intake, waist circumference, systolic blood pressure, glycosylated Hb (HbA1c) and glucose AUC and homeostasis model of insulin resistance (HOMA-IR) following the glucose load (P < 0·05). However, HDL, fasting C-peptide and insulin AUC responses were dependent on diet (P < 0·05). HDL and C-peptide increased by 4·5 and 12·3 %, respectively, in the pulse group, but decreased by 0·8 and 7·6 %, respectively, in the energy-restricted group. Insulin AUC decreased in both females and males on the energy-restricted diet by 24·2 and 4·8 %, respectively, but on the pulse diet it decreased by 13·9 % in females and increased by 27·3 % in males (P < 0·05). In conclusion, frequent consumption of pulses in an ad libitum diet reduced risk factors of the MetSyn and these effects were equivalent, and in some instances stronger, than counselling for dietary energy reduction.

Topics: Adult; Blood Glucose; C-Peptide; Caloric Restriction; Counseling; Diet; Fabaceae; Female; Glucagon-Like Peptide 1; Humans; Insulin; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Risk Factors; Seeds; Waist Circumference

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1-targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1-estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.

Topics: Analysis of Variance; Animals; Binding, Competitive; Body Composition; Chromatography, High Pressure Liquid; Drug Combinations; Drug Discovery; Estrogens; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Magnetic Resonance Imaging; Male; Mass Spectrometry; MCF-7 Cells; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; Xenograft Model Antitumor Assays

Topics: Animals; Estrogens; Female; Glucagon-Like Peptide 1; Humans; Male; Metabolic Syndrome; Receptors, Estrogen

The metabolic syndrome, a disease arising from the world-wide epidemic of obesity, is manifested as severe insulin resistance, hyperlipidaemia, hepatic steatosis and diabetes. Previously we reported that GLP-1(9-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), suppresses gluconeogenesis in isolated hepatocytes. The aims of this study were to determine the effects of GLP-1(9-36)amide in diet-induced obese mice that model the development of the metabolic syndrome.. Mice rendered obese by feeding a very high fat diet were administered GLP-1(9-36)amide via subcutaneous osmopumps for 8 weeks. Body weight, energy intake, plasma insulin and glucose levels (insulin-resistance), and hepatic steatosis were assessed.. Eight-week infusions of GLP-1(9-36)amide inhibited weight gain, increased energy intake, prevented the development of fasting hyperinsulinaemia and hyperglycaemia, and curtailed the accumulation of liver triglycerides. The peptide had no effects in mice fed a normal chow diet. Notably, energy intake in the obese mice receiving GLP-1(9-36)amide was 20% greater than obese mice receiving vehicle control.. GLP-1(9-36)amide exerts insulin-like actions in the presence of insulin resistance and prevents the development of metabolic syndrome. Curtailment of weight gain in the face of increased caloric intake suggests that GLP-1(9-36)amide increases energy expenditure. These findings suggest the possibility of the use of GLP-1(9-36)amide, or a peptide mimetic derived there from, for the treatment of obesity, insulin resistance and the metabolic syndrome.

Topics: Animals; Body Weight; Dietary Fats; Energy Intake; Fatty Liver; Glucagon-Like Peptide 1; Insulin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Receptors, Glucagon; Weight Gain

The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome.. Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight.. GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome.

Topics: Animals; Diabetes Mellitus, Type 2; Dietary Fats; Eating; Fatty Liver; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Peptide Fragments; Triglycerides; Weight Gain

Various digestive tract procedures effectively improve metabolic syndrome, especially the control of type 2 diabetes mellitus. Very good metabolic results have been shown with vertical gastrectomy and entero-omentectomy; however, the metabolic effects of an isolated entero-omentectomy have not been previously studied.. Nine patients with type 2 diabetes mellitus and a body mass index ranging from 29 to 34.8 kg/m² underwent an entero-omentectomy procedure that consisted of an enterectomy of the middle jejunum and exeresis of the major part of the omentum performed through a mini-laparotomy. Glucagon-like peptide-1 and peptide YY were measured preoperatively and three months following the operation. Fasting and postprandial variations in glycemia, insulinemia, triglyceridemia, hemoglobin A1c, and body mass index were determined in the preoperative period and 3, 18 and, 36 months after the operation.. All patients significantly improved the control of their type 2 diabetes mellitus. Postprandial secretion of peptide YY and Glucagon-like peptide-1 were enhanced, whereas hemoglobin A1c, fasting and postprandial glucose, insulin, and triglyceride levels were significantly reduced. Mean body mass index was reduced from 31.1 to 27.3 kg/m². No major surgical or nutritional complications occurred.. Entero-omentectomy is easy and safe to perform. A simple reduction in jejunal extension and visceral fat causes important improvements in the metabolic profile.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Jejunum; Male; Metabolic Syndrome; Middle Aged; Nutritional Status; Omentum; Peptide YY; Postoperative Period; Time Factors; Treatment Outcome

We hypothesized that soy protein (S)-based diets fed during pregnancy and lactation increase food intake and the presence of characteristics of the metabolic syndrome to a lesser extent in female than in male rats. Soy protein- and casein (C)-based American Institute of Nutrition-93G diets were fed to 2 groups (n = 12 per group) of pregnant Wistar rats from day 3 of gestation and throughout lactation. Their effects on characteristics of metabolic syndrome and food intake regulation in female pups maintained for 15 weeks on the C diet were compared. Body weight (BW) and food intake (FI) were measured weekly. Fat pad mass was measured at birth, at weaning, and at week 15. Glucose and insulin tolerance tests were conducted at weeks 8 and 12; and systolic and diastolic blood pressures were measured at weeks 4, 8, and 12. Plasma was collected at weaning and at the end of the studies for glucose, insulin, glucagon-like peptide 1, peptide YY, and ghrelin. Food intake in response to protein preloads was measured at week 7. Feeding the S diet throughout gestation and lactation resulted in higher systolic blood pressure (P < .005), FI (P < .05), and glucagon-like peptide 1 and lower peptide YY at weaning and higher BW during weeks 11 to 15 and fat pad mass at week 15 (all Ps < .05). However, no sign of insulin resistance was found; nor was short-term FI in response to protein preloads affected. In conclusion, S- compared with C-based American Institute of Nutrition-93 G diets consumed throughout gestation and lactation increased BW and FI later and resulted in fewer characteristics of metabolic syndrome in female than in male offspring.

Topics: Adipose Tissue; Animals; Biomarkers; Blood Pressure; Body Weight; Caseins; Diet; Dietary Proteins; Energy Intake; Female; Glucagon-Like Peptide 1; Humans; Lactation; Male; Metabolic Syndrome; Peptide YY; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sex Factors; Soybean Proteins

Topics: Anti-Obesity Agents; Comorbidity; Female; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Male; Metabolic Syndrome; Obesity; Treatment Outcome; Weight Loss

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Ileum; Lipid Metabolism; Metabolic Syndrome; Rats

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.. To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).. Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.. Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Chi-Square Distribution; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Japan; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Obesity, Abdominal; Odds Ratio; Risk Assessment; Risk Factors; Triglycerides; Up-Regulation; Uric Acid; Waist Circumference

The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization including blood biochemistry and glucose homeostasis was examined at 2, 3, 6, and 9 months of age. Furthermore, in 6-month-old HE-fed DIO rats, the anti-obesity effects of liraglutide and sibutramine were examined in a 28-day study. Only HE-fed DIO rats developed visceral obesity, hyperleptinemia, hyperinsulinemia, and dyslipidemia, and showed a worsening of glucose tolerance over time. In line with the hyperlipidemic profile, a severe hepatic fat infiltration was observed in DIO rats at 6 months of age. The effects of liraglutide and sibutramine were tested in 6-month-old DIO rats. Both compounds effectively reduced food intake and body weight in DIO rats. Liraglutide furthermore improved glucose tolerance when compared with sibutramine. Our data highlights the usefulness of a polygenetic animal model for screening of compounds affecting food intake, body weight, and glucose homeostasis. Furthermore, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents.

Topics: Analysis of Variance; Animals; Appetite Depressants; Blood Glucose; Cyclobutanes; Diet; Disease Models, Animal; Eating; Enzyme-Linked Immunosorbent Assay; Feeding Behavior; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Leptin; Liraglutide; Metabolic Syndrome; Obesity; Rats; Rats, Sprague-Dawley

Exenatide is a peptide incretin mimetic that has glucoregulatory actions associated with weight reduction. Previous reports demonstrated acute increases in blood pressure after systemic or intracerebroventricular administration of exenatide or glucagon like peptide 1 (GLP 1) in rats. However, there are limited studies testing the chronic effects of these peptides on arterial pressure and no reports showing the effects of these peptides to reverse hypertension in the context of the metabolic syndrome.. Thus, we examined the response to peripheral exenatide using telemetry in conscious, unrestrained rats under normotensive conditions and in a model of hypertension/metabolic syndrome induced by corticosterone. Rats were implanted with either corticosterone or wax (control) pellets, followed 14 days later by the additional implantation of pumps to deliver exenatide (1 microg/kg per day) or vehicle for 7 days.. The 21-day corticosterone treatment produced hypertriglyceridemia, visceral fat deposition, hyperglycemia, insulin resistance, and an elevation of mean arterial blood pressure (MAP) by 14 +/- 1 mmHg. Exenatide significantly reversed corticosterone-induced increases in blood pressure and this normalization occurred independently from change in body weight. Additionally, exenatide reduced MAP by 5 +/- 3 mmHg in normotensive control rats.. These results are the first demonstration of a durable antihypertensive effect of exenatide in a glucocorticoid-induced model of the metabolic syndrome.

Topics: Animals; Blood Pressure; Body Weight; Corticosterone; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Hypertension; Hypoglycemic Agents; Injections, Intraventricular; Male; Metabolic Syndrome; Peptides; Rats; Rats, Sprague-Dawley; Telemetry; Time Factors; Venoms

The effect of high multivitamin intake during pregnancy on the metabolic phenotype of rat offspring was investigated. Pregnant Wistar rats (n=10 per group) were fed the AIN-93G diet with the recommended vitamin (RV) content or a 10-fold increase [high vitamin (HV) content]. In experiment 1, male and female offspring were followed for 12 wk after weaning; in experiment 2, only males were followed for 28 wk. Body weight (BW) was measured weekly. Every 4 wk, after an overnight fast, food intake over 1 h was measured 30 min after a gavage of glucose or water. An oral glucose tolerance test was performed every 3-5 wk. Postweaning fasting glucose, insulin, ghrelin, glucagon-like peptide-1, and systolic blood pressure were measured. No difference in BW at birth or litter size was observed. Food intake was greater in males born to HV dams (P<0.05), and at 28 wk after weaning, BW was 8% higher (P<0.05) and fat pad mass was 27% higher (P<0.05). Food intake reduction after the glucose preload was nearly twofold less in males born to HV dams at 12 wk after weaning (P<0.05). Fasting glucose, insulin, and ghrelin were 11%, 62%, and 41% higher in males from HV dams at 14 wk after weaning (P<0.05). Blood glucose response was 46% higher at 23 wk after weaning (P<0.01), and systolic blood pressure was 16% higher at 28 wk after weaning (P<0.05). In conclusion, high multivitamin intake during pregnancy programmed the male offspring for the development of the components of metabolic syndrome in adulthood, possibly by its effects on central mechanisms of food intake control.

Topics: Adipose Tissue; Animal Nutritional Physiological Phenomena; Animals; Appetite Regulation; Blood Glucose; Blood Pressure; Body Weight; Dietary Supplements; Eating; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Time Factors; Vitamins

Metabolic syndrome refers to risk factors for cardiovascular disease. Hyperglycemia is a critical component contributing to the predictive power of the syndrome. This study aimed to evaluate the results from the laparoscopic interposition of an ileum segment into the proximal jejunum for the treatment of metabolic syndrome in patients with type 2 diabetes mellitus and a body mass index (BMI) lower than 35.. Laparoscopic procedures were performed for 60 patients (24 women and 36 men) with a mean age of 51.7 +/- 6.4 years (range, 27-66 years) and a mean BMI of 30.1 +/- 2.7 (range, 23.6-34.4). All the patients had a diagnosis of type 2 diabetes mellitus (T2DM) given at least 3 years previously and evidence of stable treatment using oral hypoglycemic agents, insulin, or both for at least 12 months. The mean duration of type 2 diabetes mellitus was 9.6 +/- 4.6 years (range, 3-22 years). Metabolic syndrome was diagnosed for all 60 patients. Arterial hypertension was diagnosed for 70% of the patients (mean number of drugs, 1.6) and hypertriglyceridemia for 70%. High-density lipoprotein was altered in 51.7% of the patients and the abdominal circumference in 68.3%. Two techniques were performed: ileal interposition (II) into the proximal jejunum and sleeve gastrectomy (II-SG) or ileal interposition associated with a diverted sleeve gastrectomy (II-DSG).. The II-SG procedure was performed for 32 patients and the II-DSG procedure for 28 patients. The mean postoperative follow-up period was 7.4 months (range, 3-19 months). The mean BMI was 23.8 +/- 4.1 kg/m(2), and 52 patients (86.7%) achieved adequate glycemic control. Hypertriglyceridemia was normalized for 81.7% of the patients. An high-density lipoprotein level higher than 40 for the men and higher than 50 for the women was achieved by 90.3% of the patients. The abdominal circumference reached was less than 102 cm for the men and 88 cm for the women. Arterial hypertension was controlled in 90.5% of the patients. For the control of metabolic syndrome, II-DSG was the more effective procedure.. Laparoscopic II-SG and II-DSG seem to be promising procedures for the control of the metabolic syndrome and type 2 diabetes mellitus. A longer follow-up period is needed.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Ileum; Insulin; Jejunum; Laparoscopy; Male; Metabolic Syndrome; Middle Aged; Triglycerides

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Metabolic Syndrome; Obesity

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Metabolic Syndrome; Obesity

Topics: Animals; Diabetes Mellitus, Type 2; Dogs; Exenatide; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Metabolic Syndrome; Obesity; Peptides; Venoms

Type 2 diabetic patients pass through a phase of impaired glucose tolerence and/or impaired fasting glucose known as 'prediabetic state'. Prediabetic state form a part of syndrome X, other components being obesity, hypertension, dyslipidaemia, hyperinsulinaemia and insulin resistance. The pathophysiology of prediabetes is similar to type 2 diabetes mellitus, two basic defects are insulin resistance and early beta cell failure. In prediabetes, the rapid oscillations of insulin secretion are lost and amplitude of large pulses are decreased. When insulin is delivered in a pulsatile fashion that mimics the normal rapid oscillation, its hypoglycaemic effects are greater. In prediabetes, the glycaemic excursions after each meal are high and early insulin responses to meals tend to be lower than normal but the second phase of insulin secretion is delayed and prolonged.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Metabolic Syndrome; Prediabetic State