exenatide and Metabolic-Syndrome

Epidemiological studies have suggested that metabolic programming begins during fetal life and adverse events in utero are a critical factor in the etiology of chronic diseases and overall health. While the underlying molecular mechanisms linking impaired fetal development to these adult diseases are being elucidated, little is known about how we can intervene early in life to diminish the incidence and severity of these long-term diseases. This paper highlights the latest clinical and pharmaceutical studies addressing how dietary intervention in fetal and neonatal life may be able to prevent aspects of the metabolic syndrome associated with IUGR pregnancies.

Topics: Antioxidants; Ascorbic Acid; Diet Therapy; Dietary Supplements; Exenatide; Fatty Acids, Omega-3; Female; Fetal Growth Retardation; Folic Acid; Humans; Hypoglycemic Agents; Melatonin; Metabolic Syndrome; Micronutrients; Peptides; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Resveratrol; Stilbenes; Venoms

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 aim of this study was to evaluate the effect of exenatide on fat deposition and a metabolic profile in patients with metabolic syndrome.. An uncontrolled, open clinical study was carried out in 10 patients with metabolic syndrome and without pharmacological treatment. Patients received exenatide (5 μg) subcutaneously twice daily for 1 month. Before and after the intervention, metabolic profile and phases of insulin secretion and insulin sensitivity were estimated. To assess insulin secretion and sensitivity, the hyperglycemic-hyperinsulinemic clamp technique was performed. Computed tomography was performed to evaluate both subcutaneous and visceral fat. The Wilcoxon signed-rank test and Mann-Whitney U-test were used for statistical analyses.. Weight, body mass index, waist circumference, and systolic blood pressure were decreased by exenatide. Subcutaneous fat deposition decreased by 4.4% compared to the basal value. There were significant decreases in total cholesterol and low-density lipoprotein cholesterol, as well as an increment in the first phase of insulin secretion after the intervention.. One-month administration of exenatide significantly decreased subcutaneous fat deposition by 4.4%, improving the metabolic profile in patients with metabolic syndrome.

Topics: Adipose Tissue; Adult; Body Fat Distribution; Drug Administration Schedule; Exenatide; Female; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Lipids; Male; Metabolic Syndrome; Metabolome; Peptides; Venoms; Young Adult

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

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

To compare the effect of different hypoglycemic drugs on laboratory and ultrasonographic markers of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes not controlled on metformin alone.. Prospective study of diabetic patients treated with metformin in combination with gliclazide, pioglitazone, sitagliptin, exenatide, or liraglutide. NAFLD was assessed by abdominal ultrasound and NAFLD fibrosis score was calculated at baseline and 6 months.. Fifty-eight patients completed 6 months of follow-up: 15 received gliclazide, 13 pioglitazone, 15 sitagliptin, 7 exenatide, and 8 liraglutide. NAFLD affected 57.8% of patients at baseline, and its ultrasonographic course varied depending on changes in weight (P=.009) and waist circumference (P=.012). The proportions of patients who experienced ultrasonographic improvement in the different treatment groups were: 33.3% with gliclazide, 37.5% with pioglitazone, 45.5% with sitagliptin, 80% with exenatide, and 33% with liraglutide (P=.28).. Qualitative ultrasonographic NAFLD improvement in diabetic patients treated with metformin in combination with other hypoglycemic drugs is associated to change over time in weight and waist circumference. Long-term clinical trials are needed to assess whether incretin therapies result in better liver outcomes than other hypoglycemic therapies.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Lipids; Liraglutide; Liver Function Tests; Male; Metabolic Syndrome; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Pilot Projects; Pioglitazone; Prospective Studies; Sitagliptin Phosphate; Thiazolidinediones; Venoms; Waist Circumference

Metabolic syndrome (MetS) doubles the risk of adverse cardiovascular events. Glucagon-like peptide 1 (GLP-1) receptor agonists induce weight loss, increase insulin secretion, and improve glucose tolerance. Studies in healthy animals suggest cardioprotective properties of GLP-1 receptor agonists, perhaps partially mediated by improved sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) activity. We examined the acute effect of GLP-1 receptor agonists on coronary smooth muscle cells (CSM) enzymatically isolated from lean, healthy Ossabaw miniature swine. Intracellular Ca(2+) handling was interrogated with fura-2. The GLP-1 receptor agonist exenatide activated SERCA but did not alter other Ca(2+) transporters. Further, we tested the hypothesis that chronic, in vivo treatment with GLP-1 receptor agonist AC3174 would attenuate coronary artery disease (CAD) in swine with MetS. MetS was induced in 20 swine by 6 months' feeding of a hypercaloric, atherogenic diet. Swine were then randomized (n = 10/group) into placebo or AC3174 treatment groups and continued the diet for an additional 6 months. AC3174 treatment attenuated weight gain, increased insulin secretion, and improved glucose tolerance. Intravascular ultrasound and histology showed no effect of AC3174 on CAD. MetS abolished SERCA activation by GLP-1 receptor agonists. We conclude that MetS confers vascular resistance to GLP-1 receptor agonists, partially through impaired cellular signaling steps involving SERCA.

Topics: Animals; Blood Glucose; Calcium; Coronary Artery Disease; Coronary Vessels; Diet, Atherogenic; Exenatide; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Secretion; Metabolic Syndrome; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Peptides; Random Allocation; Receptors, Glucagon; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Swine; Ultrasonography; Venoms; Weight Loss

The aim of the present study was to test the effect of sitagliptin and exendin-4 upon metabolic alterations, β-cell mass decrease and hepatic steatosis induced by F (fructose) in rats. Normal adult male Wistar rats received a standard commercial diet without (C) or with 10% (w/v) F in the drinking water (F) for 3 weeks; animals from each group were randomly divided into three subgroups: untreated (C and F) and simultaneously receiving either sitagliptin (CS and FS; 115.2 mg/day per rat) or exendin-4 (CE and FE; 0.35 nmol/kg of body weight, intraperitoneally). Water and food intake, oral glucose tolerance, plasma glucose, triacylglycerol (triglyceride), insulin and fructosamine concentration, HOMA-IR [HOMA (homoeostasis model assessment) for insulin resistance], HOMA-β (HOMA for β-cell function) and liver triacylglycerol content were measured. Pancreas immunomorphometric analyses were also performed. IGT (impaired glucose tolerance), plasma triacylglycerol, fructosamine and insulin levels, HOMA-IR and HOMA-β indexes, and liver triacylglycerol content were significantly higher in F rats. Islet β-cell mass was significantly lower in these rats, due to an increase in the percentage of apoptosis. The administration of exendin-4 and sitagliptin to F animals prevented the development of all the metabolic disturbances and the changes in β-cell mass and fatty liver. Thus these compounds, useful in treating Type 2 diabetes, would also prevent/delay the progression of early metabolic and tissue markers of this disease.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Diet; Dipeptidyl-Peptidase IV Inhibitors; Drinking; Drug Evaluation, Preclinical; Eating; Exenatide; Fatty Liver; Fructose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Metabolic Syndrome; Peptides; Pyrazines; Rats; Rats, Wistar; Sitagliptin Phosphate; Triazoles; Venoms

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

Type 2 diabetes mellitus (T2DM) with the presence of metabolic syndrome (MetS) carries increased risk for cardiovascular disease. Adjunctive exenatide treatment in patients with T2DM is associated with improvements in glycemic control coupled with progressive weight reduction. We evaluated exenatide use on glycosylated hemoglobin A1c (HbA(1c)) and cardiometabolic risk factors in patients with T2DM and MetS in a single clinical practice setting.. A retrospective analysis of clinical data extracted from the records of 176 adult patients with T2DM and MetS (106 women, 70 men) who received exenatide along with existing therapeutic regimes from 2005 to 2007 was performed. HbA(1c), lipid profiles, blood pressure, and anthropometric measures were evaluated at baseline and after 16 (+/-4) weeks of exenatide therapy.. Mean HbA(1c) was significantly reduced from baseline in 16 weeks (P < 0.001), with 68% of patients achieving HbA(1c) <7%. Total, high-density lipoprotein-, and low-density lipoprotein-cholesterol levels decreased significantly. This decline was not attributable to changes in lipid-lowering agents. Significant reductions were also noted in body mass index, mean body weight, and abdominal girth (AG) with the addition of exenatide. Additional analyses showed 76% of subjects lost weight. Lessening of AG was much more pronounced in female compared with male subjects with diabetes (P < 0.032). No consistent changes in blood pressure were observed.. We found that addition of exenatide to an existing treatment regimen in patients with T2DM and MetS resulted in significant reductions in HbA(1c) along with decline in lipids, AG, and body weight. This indicates improvement in these patients' metabolic profiles.

Topics: Adult; Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Exenatide; Female; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Male; Metabolic Syndrome; Peptides; Retrospective Studies; Sulfonylurea Compounds; Venoms

To evaluate the effect of exenatide therapy on cardiometabolic risk factors and anthropometric parameters in patients with metabolic syndrome.. From June 2005 to June 2007, we performed a retrospective analysis of data extracted from the records of adult patients with metabolic syndrome being treated with exenatide. Diagnosis of any type of diabetes mellitus was exclusionary. Patients were initiated on exenatide therapy, 5 mcg, 1 hour before their morning and evening meals for the first month and were instructed to titrate up to 10 mcg. Cardiometabolic risk factors (total cholesterol, high-density lipoprotein cholesterol, triglycerides, calculated low-density lipoprotein cholesterol, and blood pressure) and anthropometric parameters (absolute body weight, body mass index, and abdominal girth) were measured at baseline and at 16 +/- 4 weeks after initiating exenatide therapy. Data collected also included age, sex, metabolic syndrome diagnosis, and other concomitant medication used in the management of endocrine disorders.. The study population consisted of 299 patients (259 women, 40 men) with an age range of 18 to 74 years. Exenatide treatment was associated with significant reductions in mean body weight (P<.001) and body mass index (P<.001). Weight loss in 76.6% of patients was concomitant with a significant reduction in mean abdominal girth (P<.001). Further analysis revealed significant decreases in mean triglycerides (P<.001), total cholesterol (P<.01), and both systolic (P<.01) and diastolic blood pressure (P<.03). Approximately 60.2% of patients used metformin concomitantly, and half either decreased or discontinued metformin therapy.. This is the first report examining the effect of exenatide on patients with metabolic syndrome. We observed a significant improvement in cardiometabolic risk factors and anthropometric parameters as a result of exenatide over the treatment interval.

Topics: Adolescent; Adult; Aged; Blood Pressure; Body Mass Index; Body Weight; Cholesterol; Cholesterol, HDL; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Metabolic Syndrome; Middle Aged; Peptides; Retrospective Studies; Triglycerides; Venoms; Young Adult

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