exenatide and Body-Weight

This study aimed to perform a network meta-analysis to objectively evaluate the efficacy and safety of 10 Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in combination with metformin that is approved for use worldwide in patients with type 2 diabetes and to provide evidence-based support and reference for the selection of clinical treatment.. Three databases (PubMed, Embase, and Cochrane Library) were searched from their respective inception until September 30, 2022. Only randomized controlled trials comparing the efficacy and safety of GLP-1RAs for treating type 2 diabetes (T2D) were included. The 10 GLP-1RAs are exenatide (including exenatide twice daily and once weekly), liraglutide, lixisenatide, dulaglutide, PEX168, semaglutide (subcutaneous and oral semaglutide), tirzepatide and albiglutide.. 34 RCTs with 10 GLP-1RAs and 12993 patients were included in the Network Meta-Analysis (NMA). According to the NMA, tirzepatide 15 mg, semaglutide 1.0 mg, PEX168-200μg, oral semaglutide 14 and dulaglutide 1.5 mg reduced HbA1c by -2.23%, -1.57%, -1.12%, -1.10%, -1.09% and body weight by -11.33 kg, -5.99 kg, +0.40 kg, -3.95 kg, -1.87 kg, respectively. There was no significant difference in the rate of adverse events for tirzepatide 15 mg, oral-semaglutide 14 mg, and semaglutide 1.0 mg. PEX168-200μg, tirzepatide 15mg, and oral semaglutide 14mg had Surface Under the Cumulative Ranking (SUCRA) values greater than placebo, and only tirzepatide 15mg and oral semaglutide 14mg were significantly different from placebo in the rate of serious adverse events. All GLP-1RA did not lead to increased incidence of hypoglycemia. Albiglutide 30mg and semaglutide 1.0mg significantly differed from placebo in Adverse Event (AE) withdrawal. Finally, the sensitivity analysis and publication bias analysis results indicate that the study results are reliable.. This study's results showed that GLP-1RAs were effective in lowering HbA1c and reducing body weight without increased incidence of hypoglycemic reactions. In addition, this study may provide reference and evidence-based medical evidence for clinicians to select GLP-1RAs in patients with T2D and high body mass index (BMI). Based on the NMA results, tirzepatide 15mg and semaglutide 1.0mg may be preferred.

Topics: Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Metformin

GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).. To summarize current knowledge about GLP-1 receptor agonist.

Topics: Animals; Blood Glucose; Body Weight; Cardiovascular System; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemia; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Neurodegenerative Diseases; Peptides; Psoriasis; Recombinant Fusion Proteins

Fatty liver is associated with obesity, type 2 diabetes, hyperlipidemia, hypertension, and metabolic syndrome. While there are no approved drugs for the treatment of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis, strategies to ameliorate fatty liver often target these related diseases. We sought to determine if any medications approved by the US Food and Drug Administration to treat diabetes are helpful in reducing weight and improving steatohepatitis in patients with NAFLD.. We conducted a systematic review of published and unpublished studies evaluating the comparative effectiveness and harms of diabetes medications for the treatment of NAFLD. We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials through 3rd quarter, 2019 using terms for included drugs and indications.. We screened 1591 citations and included 18 trials of diabetes drugs to treat NAFLD. Studies of metformin found no difference from placebo in steatosis, fibrosis, NAFLD activity score, or resolution of NASH. While weight and glucose control were improved with metformin, it did not substantially impact liver disease. Studies of pioglitazone in NASH patients found benefits in liver function, liver fat, and NASH resolution, though significant increases in weight may be cause for concern. Evidence for other thiazolinediones was more limited and had somewhat mixed results, but findings were generally consistent with those for pioglitazone: liver fat and function and glucose measures improved, but weight also increased. We found some evidence that liraglutide improves liver fat, liver function, and HbA1c and is effective at resolving NASH and reducing weight. Exenatide performed less well but also resulted in significant reductions in liver fat and weight.. Consistent with existing clinical practice guidelines, which recommend lifestyle intervention and treatment for comorbidities related to fatty liver disease as first-line treatment, trial evidence supports the efficacy of some diabetes drugs (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with some diabetes drugs may warrant caution. Larger trials are needed to better characterize the efficacy and harms of diabetes pharmacotherapy in these patients.

Topics: Blood Glucose; Body Weight; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Pioglitazone; Randomized Controlled Trials as Topic; Rosiglitazone

To evaluate if glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce antipsychotic-associated body weight gain in patients with schizophrenia, when compared to controls.. We systematically searched PubMed/EMBASE/PsycINFO/Cochrane using the search terms '(antipsychotic and GLP-1RA)'. Individual participant data from studies randomizing patients to GLP-1RA or control were meta-analysed. The primary outcome was difference in body weight between GLP-1RA and control; secondary outcomes included cardio-metabolic variables and adverse drug reactions (ADRs). Multiple linear regression was conducted including sex, age, psychosis severity, metabolic variable, ADRs, and GLP-1RA agent.. Three studies (exenatide once-weekly = 2; liraglutide once-daily = 1) provided participant-level data (n = 164, age = 40.0 ± 11.1 years, body weight = 105.8 ± 20.8 kg). After 16.2 ± 4.0 weeks of treatment, body weight loss was 3.71 kg (95% CI = 2.44-4.99 kg) greater for GLP-1RA versus control (p < 0.001), number-needed-to-treat ≥5% body weight loss = 3.8 (95% CI = 2.6-7.2). Waist circumference, body mass index, HbA1c, fasting glucose and visceral adiposity were each significantly lower with GLP-1RA. Sex, age, psychosis severity, nausea, any ADR, and GLP-1RA agent did not significantly impact outcomes. Body weight loss with GLP-1RAs was greater for clozapine/olanzapine-treated patients (n = 141) than other antipsychotics (n = 27) (4.70 kg, 95% CI = 3.13-6.27 vs. 1.5 kg, 95% CI = -1.47-4.47) (p < 0.001). Nausea was more common with GLP-1RAs than control (53.6% vs. 27.5%, p = 0.002, number-needed-to-harm = 3.8).. GLP-1RAs are effective and tolerable for antipsychotic-associated body weight gain, particularly clozapine/olanzapine-treated patients. With few included patients, further studies are required before making routine use recommendations for GLP-1RAs.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Body Weight; Cardiovascular Diseases; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Metabolic Diseases; Middle Aged; Obesity; Risk Factors; Schizophrenia; Weight Gain; Young Adult

Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D). Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit-risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide. Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide

Topics: Animals; Body Weight; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hyperglycemia; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Male; Obesity; Peptides; Recombinant Fusion Proteins

The majority of patients with type 2 diabetes also have obesity. Obesity increases the risk of developing diabetes and is associated with worsened glycemic control and increased morbidity and mortality in individuals with diabetes. Sustained weight loss is associated with improved glycemic control, potential for diabetes remission, and decreased medical expenditures.. Herein, the impact of commonly utilized, non-insulin, glucose-lowering drugs on body weight in patients with type 2 diabetes is discussed. The weight change magnitudes, mechanisms, and any within-class differences are also explored.. The weight impact of diabetes medications should be considered when designing treatment regimens, especially in patients who are overweight or have obesity. Lifestyle modification is paramount for optimal diabetes management. Therapeutic regimens should ideally be designed to maximize weight loss and at least minimize or avoid weight gain. Future glucose-lowering medications should continue to offer improvement in cardiovascular risk factors, including weight, in order to be accepted into the armamentarium of diabetes therapy. Therapeutic regimens should be designed to help patients with diabetes and obesity achieve both glycemic and weight goals. Management of these disease states is expected to become increasingly integrated.

Topics: Benzhydryl Compounds; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucosides; Humans; Hypoglycemic Agents; Metformin; Peptides; Sodium-Glucose Transporter 1; Venoms

This article provides an overview of the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of type 2 diabetes mellitus (T2DM). GLP-1 RAs stimulate pancreatic GLP-1 receptors, which increases insulin secretion, delays gastric emptying, and increases satiety. As a class, GLP-1 RAs lower A1c levels and have been associated with reductions in weight and blood pressure and reduced fluctuations in glucose levels, and they have a low risk of hypoglycemia. Exenatide extended release (ER) and dulaglutide monotherapy have shown similar or superior reductions in A1c and weight compared with various oral antidiabetic drugs (OADs). Semaglutide has been shown to reduce both A1c and body weight compared with placebo and, in head-to-head studies versus both exenatide ER and dulaglutide, showed greater reductions in A1c and body weight. Once-weekly GLP-1 RAs have also been evaluated as add-on therapy in the continuum of care for the treatment of T2DM in combination with a variety of background medications, including 1 or more OADs (metformin, sulfonylureas, and/or thiazolidinediones), basal insulin, and prandial insulin. Gastrointestinal adverse events (e.g., nausea, vomiting, and diarrhea) are the most common side effects with once-weekly GLP-1 RAs. Rates of hypoglycemia, and especially major/severe hypoglycemia, are low with once-weekly GLP-1 RAs but, as expected, are higher when used in combination with sulfonylureas or insulin. These once-weekly GLP-1 RAs provide a safe and effective treatment option for patients with T2DM and may offer improved convenience and possibly greater adherence compared with daily GLP-1 RAs.. This supplement was funded by Novo Nordisk. Handelsman reports research grants from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Grifols, Janssen, Lexicon, Merck, Novo Nordisk, Regeneron, and Sanofi; speaker fees from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck, Novo Nordisk, Regeneron, and Sanofi; and has served in advisory capacity to Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Intarcia, Janssen, Lilly, Merck, Merck-Pfizer, Novo Nordisk, Regeneron, and Sanofi. Cannon reports speaker fees and owns stock in Novo Nordisk. Shannon reports consultant and speaker fees from Novo Nordisk and Boehringer Ingelheim-Lilly Alliance. Schneider reports advisory board fees from Intarcia, Lilly, and Novo Nordisk. Wyne has nothing to disclose.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycemic Index; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins; Treatment Outcome

To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM).. Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared.. Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight.. Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fasting; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Peptides; Treatment Outcome; Venoms

A meta-analysis was conducted to assess the clinical efficacy and safety of dulaglutide in patients with type 2 diabetes mellitus (T2DM). Medline, Embase, Cochrane Library and www. clinicaltrials. gov (up to February 15(th), 2015) were searched. Randomized controlled trials comparing dulaglutide to other drugs for T2DM were collected. Twelve RCTs were included, and the overall bias was low. As the monotherapy, compared with control (placebo, metformin and liraglutide), dulaglutide resulted in a significant reduction in HbA1c (WMD, -0.68%; 95% CI, -0.95 to -0.40), FPG (WMD, -0.90 mmol/L; 95% CI, -1.28 to -0.52), a similar risk of hypoglycemia (7.8% vs. 10.6%), less body weight loss (WMD, 0.51 kg; 95% CI, 0.27 to 0.75). As an add-on intervention with oral antihyperglycemic medication (OAM) and insulin, compared with control (placebo, sitagliptin, exenatide, liraglutide and glargine), dulaglutide lowered HbA1c (WMD, -0.51%; 95% CI, -0.68 to -0.35) and body weight significantly (WMD, -1.30 kg, 95% CI, -1.85 to -1.02) notably, and elicited a similar reduction in FPG (WMD, -0.19 mmol/L; 95% CI, -1.20 to 0.82), an similar incidence of hypoglycemia (24.5% vs. 24.5%). This meta-analysis revealed the use of dulaglutide as a monotherapy or an add-on to OAM and lispro appeared to be effective and safe for adults with T2DM.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Insulin Glargine; Liraglutide; Metformin; Patient Safety; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sitagliptin Phosphate; Treatment Outcome; Venoms

Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level ("autotitration") after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective (~50 pg/mL) and steady-state (~300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses.. This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed.. Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA1c, FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not.. Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is increasingly used in obese or overweight patients with diabetes. However, its safety profile and effects on weight loss in non-diabetic obese or overweight population remain unclear. We aimed to evaluate efficacy and safety of exenatide in obese or overweight participants without diabetes.. We searched up to January 2016 in MEDLINE (Ovid SP), EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (CENTRAL), some Chinese databases and ClinicalTrials.gov for randomized controlled trials (RCTs) investigating exenatide in obese or overweight participants without diabetes. The primary outcomes included body weight and body mass index (BMI). We pooled data to calculate the mean differences (MDs) with their 95% confidence intervals (CIs). We assessed overall evidence quality of BMI reduction and weight loss according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.. Six randomized controlled trials involving 362 patients were included in the meta- analysis. The follow-up duration ranged from 12 to 24weeks. Compared with control group, a larger body weight loss (MD: -4.47kg; 95% CI: -6.67 to -2.27; P<0.0001), regardless of dosage and population, was achieved by the obese or overweight patients in exenatide group. Exenatide also elicited a greater reduction in. -0.86kg/m(2); 95% CI: -1.39 to -0.33; P=0.001) and waist circumferences (MD: -1.78cm; 95% CI: -3.13 to -0.44; P=0.009) compared with the control. No significant benefits were showed in exenatide group in terms of blood pressure and lipid profiles. Gastrointestinal adverse events were mostly common during the treatment of exenatide.. Exenatide could significantly reduce body weight in obese or overweight participants without diabetes, and might be a safe alternative GLP-1 receptor agonist for weight control in such patients. Larger randomized trials with longer follow-up duration are required to confirm the effectiveness and safety of exenatide.

Topics: Body Weight; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Obesity; Overweight; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

This review examines the use of exenatide twice daily in managing changes in markers of cardiovascular risk in patients with type 2 diabetes.. Type 2 diabetes is a progressive metabolic disorder, which results from defects in insulin secretion and/or insulin action leading to chronic hyperglycaemia and associated cardiovascular complications. Despite the use of diet, exercise, oral antihyperglycaemic agents and insulin, the progressive nature of the condition means that the levels of the preventive and treatment measures would have to be increased and/or new therapies have to be developed in order to address the long term impact of type 2 diabetes. The advent of exenatide, a glucagon-like peptide-1 receptor agonist provides a useful basis for managing type 2 diabetes and related cardiovascular complications without the side effects of regular diabetes therapies. However, exenatide twice daily is often used in combination with other therapies, although the mechanism of exenatide in managing diabetes and and associated cardiovascular risks and complications remain complex and still evolving.. A range of databases including EBSCOhost online research database were used to access articles based on PICO (Population, Interventions, Comparative Interventions, Outcomes) framework and Boolean operators.. Eleven randomised controlled studies which met the inclusion criteria were selected for this review. Nine of the eleven studies showed significant decrease in body weight among participants in the exenatide group compared with placebo or control group while the other two studies did not report statistically significant differences in body weight. In adition, all the studies showed statistically significant decrease in glycated haemoglobin (HbA1c) in the exenatide group compared to controls except in one study. In the present review, the seven studies, which looked at the effect of exenatide twice daily on lipid profile, did not find any significant difference between the exenatide group and the control group except for High density lipoprotein-cholesterol in two of the studies. However, statistically significant decrease was observed between exenatide group and controls with respect to blood pressure (systolic and/or diastolic) in these studies.. It would appear that exenatide is more effective in reducing body weight in patients with type 2 diabetes when used in combination with metformin than when used alone or in combination with thiazolidinedione. The findings of this review would suggest that exenatide twice daily may be useful in managing cardiovascular risks and complications by reducing body weight, HbA1c and blood pressure.

Topics: Biomarkers; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptides; Risk Factors; Thiazolidinediones; Venoms

Type 2 diabetes mellitus is a progressive disease that requires pharmacologic treatment to prevent microvascular and macrovascular complications. As the disease progresses, most patients require combination therapy to achieve glucose control targets. Exenatide once weekly (EQW) is a glucagon-like peptide-1 receptor agonist approved in the United States in 2012 for use as a second-line agent to treat Type 2 diabetes mellitus. EQW has shown reductions in HbA1c and weight without causing an increased risk of hypoglycemia. This review will summarize the current clinical trial, observational study, and pharmacoeconomic analyses evaluating EQW and its impact on HbA1c and weight.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Progression; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Peptides; Venoms

Type 2 diabetes (T2D) imparts an increased risk of adverse health outcomes in patients unable to achieve glycemic control. Patient education and individualization of treatment are important for effective management of T2D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of injectable glucose-lowering agents that lower A1C with added benefits of weight loss and improved cardiovascular risk markers. This review discusses the role of GLP-1RAs currently approved in the United States (exenatide, liraglutide, albiglutide, dulaglutide) for T2D management and characterizes the efficacy and safety profiles of individual GLP-1RAs.. GLP-1RAs are recommended as a preferred add-on agent to existing metformin monotherapy, as first-line therapy if metformin is contraindicated or poorly tolerated, and for use in combination with other oral glucose-lowering agents or basal insulin. Shorter-acting GLP-1RAs (exenatide and liraglutide) offer improved coverage of postprandial hyperglycemia, while longer-acting GLP-1RA formulations (exenatide extended-release, dulaglutide, and albiglutide) further improve fasting plasma glucose, which can result in additional A1C lowering. Reductions in body weight and blood pressure appear similar among individual agents, and small increases in heart rate are of unknown clinical relevance. Gastrointestinal adverse events abate over time with continued treatment and are less frequent with longer-acting GLP-1RAs. Hypoglycemia incidence is low but increased when GLP-1RAs are used with insulin secretagogues or insulin. GLP-1RAs target multiple pathophysiologic mechanisms in patients with T2D and improve glycemic control, although there are some differences within this drug class that may be relevant in clinical practice. Therefore, selection of the most appropriate treatment for individual patients is important.

Topics: Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Metformin; Peptides; Recombinant Fusion Proteins; Risk Factors; Venoms

To compare the HbA1c-lowering efficacy of glucagon-like peptide-1 (GLP-1) analogues between Asians and non-Asians with type 2 diabetes.. We searched randomized controlled trials from MEDLINE, EMBASE, LILACS, CENTRAL and ClinicalTrials.gov. Studies described in English were included if the treatment duration was 12 weeks or more, information about ethnicity and baseline HbA1c values were available and a GLP-1 analogue was compared with a placebo. For the ethnic comparison, we divided the studies into Asian-dominant studies (≥ 50% Asian participants) and non-Asian-dominant studies (<50% Asian participants).. Among the 837 searched studies, 15 trials were included for the meta-analysis. The weighted mean difference of HbA1c with GLP-1 analogues was -1.16% [95% confidence interval (CI) -1.48, -0.85] in the Asian-dominant studies and -0.83% (95% CI -0.97, -0.70) in the non-Asian-dominant studies. The between-group difference was -0.32% (95% CI -0.64, -0.01; p = 0.04). The relative risk (RR) with 95% CIs for achieving the target HbA1c ≤ 7.0% tended to be greater in the Asian-dominant studies [RR 5.7 (3.8, 8.7)] than in the non-Asian-dominant studies [RR 2.8 (2.4, 3.3)]. Body weight changes were similar between the two groups. Hypoglycaemia tended to be more common in Asian-dominant studies (RR 2.8 [2.3, 3.5]) than in non-Asian-dominant studies (RR 1.5 [1.2, 1.8]), but severe hypoglycaemia was very rare in both groups.. GLP-1 analogues lower HbA1c more in Asian-dominant studies than in non-Asian-dominant studies. Further studies are warranted to explore the potential mechanisms of the ethnic difference.

Topics: Asian People; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Treatment Outcome; Venoms

Type 2 diabetes mellitus is a pandemic, with millions of new diagnoses made each year. In the United States, > 90% of patients with type 2 diabetes mellitus are cared for by primary care physicians who bear the primary responsibility of diagnosing and treating this disease. Building an optimal treatment regimen for a patient from the many choices available depends on many factors, including the ability of a given therapy to safely and effectively lower blood glucose levels, and potential benefits on body weight, cardiovascular risk factors, and hypoglycemia risk. With these considerations at the forefront, this article provides an overview of exenatide once weekly (EQW), a recently available antidiabetes therapy in the glucagon-like peptide-1 receptor agonist class designed to provide continuous glycemic control with once-weekly dosing. We discuss the clinical trials that have demonstrated the ability of EQW to effectively lower blood glucose levels and body weight with a minimal risk of hypoglycemia. In addition, we examine other issues likely to be relevant in a primary care setting, including safety and tolerability profiles, pharmacology and dosing, ease of use, recommended place in treatment, and patient perceptions of EQW.

Topics: Blood Glucose; Body Weight; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Peptides; Primary Health Care; Risk Factors; Venoms

Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1-2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Exenatide; Fasting; Female; Glucagon-Like Peptide 1; Half-Life; Humans; Hypoglycemic Agents; Liraglutide; Male; Peptides; Postprandial Period; Treatment Outcome; Venoms

Recent investigations in finding new drugs in the treatment of diabetes have led to the discovery of several pathological pathways involved in diabetes. Exenatide a drug with incretin mimetic activity was studied in several in vivo and in vitro as well as human studies. It has shown promising results in controlling metabolic indices in type-2 diabetes and was approved by FDA but still there is an active safety alert on it. In this study we aimed to meta-analyze all placebo-controlled clinical trials on the efficacy or tolerability of exenatide in type 2 diabetes. The literature search provided 1016 articles while only 14 articles were eligible to be included in the meta-analysis with a total of 2583 patients enrolled in the study. According to the wide variation in design of various studies, the study duration of 16 weeks and less or more and dose (5 μg bid versus 10 μg bid) were considered and analyzed. The results of this meta-analysis show that exenatide decreases fasting plasma glucose and HbA1C significantly regardless of dose and study duration. The effect of exenatide on weight reduction was more prominent at the dose of 10 μg bid regardless of the study duration, however at the dose of 5 μg bid, significant results were observed after drug administration for more than 16 weeks. Exenatide usage decreased serum triglycerides indifferent to dose and study duration while its effect on cholesterol was not prominent. Along with these impacts, exenatide changed LDL and HDL cholesterol at the lower dose. The hemodynamic effect of exenatide was observed as significant decrements in systolic and diastolic blood pressure at the higher dose. The risk of nausea, vomiting and hypoglycemia was significant and indifferent to dose while headache and nasopharyngaitis were seen more at lower dose. It is concluded that exenatide can be considered as a good hypoglycemic agent in type-2 diabetic patients with benefits on lipid profile and blood pressure with partially questionable tolerability.

Topics: Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Peptides; Placebos; Randomized Controlled Trials as Topic; Systole; Venoms

During recent years, two strategies of incretin-based therapy [glucagon-like peptide-1 (GLP-1) receptor agonism and dipeptidyl peptidase-4 (DPP-4) inhibition] have entered the market for pharmacological management of type 2 diabetes. A main indication for this therapy is as add-on to on-going metformin therapy in subjects with type 2 diabetes who have insufficient glycaemic control with metformin alone. The aim of this study was to compare improvements in glycaemic control and changes in body weight, as well as adverse events, in comparable studies with incretin-based therapy as add-on to metformin.. Studies having a duration of 16-30 weeks were identified from PubMed.. A total of 27 study groups in 21 studies fulfilled the criteria of examining incretin-based therapy as add-on to metformin at clinically recommended doses in patients with type 2 diabetes for 16-30 weeks; 7 of these used a short-acting GLP-1 receptor agonist (exenatide BID), 7 used longer acting GLP-1 receptor agonists (liraglutide or exenatide LAR), whereas 14 studies examined DPP-4 inhibitors. In all studies, incretin-based therapy reduced HbA1c concentrations. The reduction in HbA1c was significantly greater in study groups with long-acting GLP-1 receptor agonists than with the other two groups (both p < 0.001), whereas there were no differences between exenatide BID and DPP-4 inhibitors. Across all study groups, there was a negative linear correlation between baseline HbA1c and change in HbA1c (r = -0.70; p < 0.001). Fasting glucose also fell significantly more in study groups given liraglutide or exenatide LAR than in those given exenatide BID or DPP-4 inhibitors (both p < 0.001). Furthermore, body weight was reduced by a similar extent in the two groups with GLP-1 receptor agonists and was not significantly altered in the groups with DPP-4 inhibitors. Lipids, blood pressure and heart rate were not reported consistently, which did not allow general conclusions. Adverse events were rare, apart from increased incidence of nausea and vomiting with GLP-1 receptor agonists.. Incretin-based therapy efficiently improves glycaemia when added to metformin in patients with type 2 diabetes, and within 16-30 weeks there is a more pronounced reduction in HbA1c with long-acting GLP-1 receptor agonists (liraglutide and exenatide LAR) than with exenatide BID and DPP-4 inhibitors, although the magnitude of the effect is dependent on the baseline values. Both strategies appear to be associated with a very low risk of adverse events, including hypoglycaemia. Finally, the injectable GLP-1 receptor agonists also reduce body weight (whereas the DPP-4 inhibitors are weight neutral) but are also associated with a greater incidence of gastrointestinal side effects and a tendency to increase heart rate.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms

Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for "exenatide," "liraglutide," "albiglutide," "semaglutide," and "lixisenatide" was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients) and 7 (2,416 patients) trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of -1.0 [-1.3; -0.6] kg/m(2). Considering the average BMI at baseline (32.4 kg/m(2)) these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction.

Topics: Blood Glucose; Body Mass Index; Body Weight; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Liraglutide; Obesity; Peptides; Placebos; Quality Control; Randomized Controlled Trials as Topic; Receptors, Glucagon; Time Factors; Venoms

Exenatide is a glucagon-like peptide-1 receptor agonist shown to improve glycaemic control in patients with type 2 diabetes (T2DM). Intermittent exenatide exposure is achieved with the twice-daily formulation (ExBID), while the once-weekly formulation (ExQW) provides continuous exenatide exposure. This integrated, retrospective analysis compared safety and tolerability of ExQW vs. ExBID in patients with T2DM.. Data were pooled from two open-label, randomized, comparator-controlled, trials directly comparing ExQW (N = 277) to ExBID (N = 268). Between-group differences in adverse event (AE) and hypoglycaemia incidences were calculated. Incidence over time and duration of selected AEs (nausea, vomiting, and injection-site-related AEs) were also summarized.. The most common AEs were nausea, diarrhoea, injection-site pruritus, and vomiting. Nausea and vomiting occurred less frequently with ExQW vs. ExBID, peaking at initiation (ExQW) or at initiation and dose escalation (ExBID), and decreasing over time. Few patients discontinued because of gastrointestinal-related AEs. Injection-site AEs were more common with ExQW but decreased over time in both groups. No major hypoglycaemia occurred; minor hypoglycaemia occurred with low incidence in patients not using concomitant sulphonylurea, with no difference between ExQW and ExBID. Serious AEs and discontinuations because of AEs were reported with similar frequency in both groups.. Both exenatide formulations were generally safe and well-tolerated, with ExQW associated with less nausea and vomiting but more injection-site AEs. Continuous vs. intermittent exposure did not impact the overall tolerability profile of exenatide, with no evidence of prolonged duration or worsened intensities of AEs with continuous exposure.

Topics: Aged; Blood Glucose; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Nausea; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Retrospective Studies; Treatment Outcome; Venoms; Vomiting

To evaluate the potential role of exenatide for weight loss in overweight or obese adults without diabetes.. PubMed (1946-August 2012) and EMBASE (1974-August 2012) were used to conduct a literature search utilizing the terms exenatide, weight loss, obesity, and overweight. Additional references were identified by bibliographic review of relevant articles.. Studies assessing the use of exenatide in adult subjects without type 2 diabetes or polycystic ovary syndrome and reporting effects on body weight were included.. Five studies were identified that reported use of exenatide in nondiabetic adults and included weight change as an outcomes measure. In all 5 of these studies, subjects taking exenatide experienced statistically significant weight loss, which ranged from 2.0 ± 2.8 to 5.1 ± 0.5 kg. Two of the trials were randomized, placebo-controlled studies; 1 trial was a randomized, open-label investigation; 1 study had a prospective, open-label cohort design; and the remaining study was a chart review. Adverse events experienced with exenatide were primarily gastrointestinal in nature, although each trial reported the drug to be well tolerated.. Obesity continues to be a national epidemic, while choices for effective pharmacologic treatments are extremely limited. Exenatide appears to have promising effects on weight in overweight or obese adults without type 2 diabetes. Further investigations with large, placebo-controlled trials assessing long-term weight loss as a primary outcome are warranted.

Topics: Adult; Anti-Obesity Agents; Body Weight; Clinical Trials as Topic; Exenatide; Humans; Obesity; Overweight; Peptides; Venoms; Weight Loss

The management of type 2 diabetes mellitus and, in particular, blood glucose levels can be complex and challenging for physicians and patients. Many patients are frustrated with the agents currently available because they have associated limitations of weight gain, hypoglycemia, and tolerability issues. Advantages of glucagon-like peptide-1 (GLP-1) agonists include their efficacy in lowering blood glucose levels, their lack of association with weight gain, and their indirect association with weight loss. Patients likely to benefit from GLP-1 agonist therapy are those in the early stages of the disease and those in need of sufficient benefit from an agent with good efficacy. Setting appropriate expectations for patients is important, as well as explaining the significance of glucose control and reminding patients that this is the main goal of therapy. Patients (and physicians) who have concerns about hypoglycemia can be reassured that GLP-1 agonists work only in the presence of hyperglycemia. Longer-acting GLP-1 agonists are dosed less frequently, appear to be associated with less nausea, and may be associated with better rates of adherence than shorter-acting agents. When initiating therapy with GLP-1 agonists, doses should be gradually escalated to minimize gastrointestinal adverse effects. The dose of a sulfonylurea may need to be lowered if a GLP-1 agonist is added. A review of possible adverse effects, contraindications, dosing and administration techniques, and expected benefits of therapy is provided in the present article to optimize success rates with this new class of agents.

Topics: Algorithms; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Treatment Outcome; Venoms

Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family: in the presence of elevated blood glucose, it stimulates insulin secretion and inhibits glucagon production. In addition, GLP-1 slows gastric emptying. GLP-1 secretion has also been reported to potentially affect patients with type 2 diabetes (T2DM) compared with non-diabetics and, as enzymatic inactivation by dipeptidyl peptidase-4 (DPP-4) shortens the GLP-1 half-life to a few minutes, GLP-1 receptor agonists such as exenatide twice daily (BID) and liraglutide have been developed, and have become part of the management of patients with T2DM. This review focuses on the potential beneficial effects of these compounds beyond those associated with improvements in blood glucose control and weight loss, including changes in the cardiovascular and central nervous systems.. This was a state-of-the-art review of the literature to evaluate the relationships between GLP-1, GLP-1 receptor agonists, weight and the cardiovascular system.. GLP-1 receptor agonists improve glucose control and do not significantly increase the risk of hypoglycaemia. Also, this new class of antidiabetic drugs was shown to favour weight loss. Mechanisms may involve central action, direct action by reduction of food intake and probably indirect action through slowing of gastric emptying. The relative importance of each activity remains unclear. Weight loss may improve cardiovascular outcomes in patients with T2DM, although GLP-1 receptor agonists may have other direct and indirect effects on the cardiovascular system. Reductions in myocardial infarct size and improvements in cardiac function have been seen in animal models. Beneficial changes in cardiac function were also demonstrated in patients with myocardial infarcts or heart failure. Indirect effects could involve a reduction in blood pressure and potential effects on oxidation. However, the mechanisms involved in the pleiotropic effects of GLP-1 receptor agonists have yet to be completely elucidated and require further study.. These compounds may play an important role in the treatment of patients with T2DM as their potential effects go beyond glucose-lowering (weight loss, potential improvement of cardiovascular risk factors). However, to better understand their place in the management of T2DM, further experimental and clinical prospective studies are required.

Topics: Body Weight; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Receptors, Glucagon; Venoms

Exenatide (exendin-4) is a 39-amino acid peptide belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class that has been demonstrated to improve glycemic control in patients with type 2 diabetes mellitus. Exenatide can be injected twice daily (ExBID) before meals or once weekly (ExQW) when encompassed within dissolvable poly-(D,L-lactide-co-glycolide) microspheres. The primary difference between these formulations is the plasma concentration of exenatide over time, with the long-acting form providing continuous delivery. Clinical trials have examined the similarities and differences in the efficacy and safety/tolerability outcomes of these formulations. In 2 clinical studies spanning 24 and 30 weeks, significant (P < 0.05) reductions from baseline were observed in fasting plasma glucose (ExBID, -12 and -25 mg/dL; ExQW, -35 and -41 mg/dL), postprandial glucose (ExBID, -124 mg/dL; ExQW, -95 mg/dL), and glycated hemoglobin (HbA1c) (ExBID, -0.9% and -1.5%; ExQW, -1.6% and -1.9%). Reductions in body weight from baseline were significant and similar with both treatments (ExBID, -1.4 and -3.6 kg; ExQW, -2.3 and -3.7 kg). Reductions in systolic blood pressure from baseline were observed with both formulations, particularly in patients who were hypertensive at baseline. Beneficial improvements in lipid profiles were small and fluctuated in significance. Patients reported greater treatment satisfaction with ExQW compared with ExBID dosing. Gastrointestinal adverse events were commonly observed with both formulations but were less frequent with ExQW. These events were of mild-to-moderate intensity and rarely led to discontinuation. Real-world data for ExBID demonstrated decreases in HbA1c, fasting plasma glucose, and body weight that were consistent with clinical trial results. Cases of pancreatitis or renal impairment have been reported in patients treated with ExBID, although no causal relationship with treatment has been shown. This review describes the similarities and differences between exenatide delivered as a twice-daily or as a once-weekly injection to provide a better understanding of the clinical effects and potential clinical uses of each.

Topics: Blood Glucose; Body Weight; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Microspheres; Patient Preference; Peptides; Risk Factors; Venoms

Obesity is associated with an increased risk of developing type 2 diabetes and cardiovascular disease. Pharmacological treatments of diabetes are mostly associated with weight gain, an undesirable event due to the fact that an increase in adiposity, especially visceral, is associated with reduced insulin sensitivity, worse cardiovascular risk profile and decreased adherence to treatment. Analogues of glucagon-like peptide-1 (GLP-1) represent a new therapeutic option for type 2 diabetes, which offer the advantage of combining beneficial effects on metabolic control with a significant reduction in body weight. In this review, we discuss data of preclinical studies and clinical trials that evaluated the effects of liraglutide and exenatide, the two analogues of GLP-1 currently available in Italy, on body weight.

Topics: Appetite; Body Mass Index; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Liraglutide; Models, Animal; Obesity; Peptides; Treatment Outcome; Venoms

Type 2 diabetes mellitus is a chronic debilitating disease characterized by insulin resistance and progressive pancreatic dysfunction. Concomitant with declining pancreatic function and decreasing insulin production, there is a progressive increase in blood glucose levels. Hyperglycemia plays a major role in the development of the microvascular and macrovascular complications of diabetes. Traditional agents used for the treatment of type 2 diabetes are able to improve glycemia, but their use is often limited by treatment-associated side effects, including hypoglycemia, weight gain, and edema. Moreover, these agents do not have any sustained effect on beta-cell mass or function. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both exenatide (the first dipeptidyl peptidase-4-resistant glucagonlike peptide-1 receptor agonist approved by the US Food and Drug Administration [FDA]), and liraglutide (a long-acting incretin mimetic), improve beta-cell function and glycemia with minimal hypoglycemia. Both agents have trophic effects on beta-cell mass in animal studies. The use of these agents is also associated with reduced body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic function, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

Topics: Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Endothelium, Vascular; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Liraglutide; Liver; Peptides; Receptors, Glucagon; Venoms

To describe the efficacy and safety of the glucagon-like peptide 1 (GLP-1) analogues exenatide and liraglutide, and the dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin and sitagliptin, registered in the Netherlands for treatment of type 2 diabetes mellitus (DM2).. Literature study.. The Medline database was searched up to and including August 2009 for systematic reviews and randomised trials with a minimum duration of 12 weeks in patients with DM2. Two authors independently selected the studies based on the title, abstract and, if necessary, the full text.. In addition to 1 systematic review on GLP-1 analogues and 1 review on DPP-4 inhibitors, 10 studies on DPP-4 inhibitors and 16 studies on GLP-1 analogues were included. According to these studies, the DPP-4 inhibitors sitagliptin and vildagliptin gave a mean HbA1c reduction of 0.7% and 0.6% respectively. GLP-1 analogues led to a mean HbA1c reduction of 1%, which is comparable to insulin therapy. Sitagliptin was associated with a slight increase in the number of upper respiratory tract infections. In a large number of patients, GLP-1 analogues were associated with gastrointestinal complaints. DPP-4 inhibitors were associated with a small weight gain, compared with weight loss in patients treated with GLP-1 analogues. Data on microvascular and macrovascular complications, as well as data on mortality, are not yet available in either group.. GLP-1 analogues regulate blood glucose levels as effectively as the current glucose-lowering agents; DPP-4 inhibitors are less effective. GLP-1 analogues lead to a clear weight reduction while DPP-4 inhibitors cause slight weight gain. Data on efficacy and safety in the longer term are not yet available.

Topics: Adamantane; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms; Vildagliptin

In May 2008, the National Institute for Health and Clinical Excellence (NICE) issued an updated guideline [clinical guideline (CG) 66] for the management of all aspects of type 2 diabetes. This report aims to provide information on new drug developments to support a 'new drugs update' to the 2008 guideline.. To review the newer agents available for blood glucose control in type 2 diabetes from four classes: the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones.. The following databases were searched: MEDLINE (1990-April 2008), EMBASE (1990-April 2008), the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000-April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers' websites.. Data extraction was carried out by one person, and checked by a second. Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (RevMan) software. Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE CG 66. The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycaemic control, reflected by glycated haemoglobin (HbA1c) level, hypoglycaemic episodes, changes in weight, adverse events, quality of life and costs. Modelling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model.. Exenatide improved glycaemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycaemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycaemic control but had modest advantages in terms of hypoglycaemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycaemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in our meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) -0.70 to -0.38] and hypoglycaemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between 386 pounds and 460 pounds. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around 437 pounds and 482 pounds, respectively. Exenatide was more expensive, with an annual cost of around 830 pounds. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with a NPH-based regimen having an annual cost of around 468 pounds for the representative patient, whereas the glargine and detemir regimens were more expensive, at around 634 pounds and 716 pounds, respectively. Comparisons of sitagliptin and rosiglitazone, and of vidagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around 1800 pounds. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between 2700 pounds and 2600 pounds.. The UKPDS Outcomes Model does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycaemic events and the fear of severe hypoglycaemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios.. Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.

Topics: Adamantane; Body Weight; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Nitriles; Peptides; Pyrazines; Pyrrolidines; Quality of Life; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; State Medicine; Thiazolidinediones; Triazoles; United Kingdom; Venoms; Vildagliptin

To review the differences between the human glucagon-like peptide-1 (GLP-1) molecule and the analogue liraglutide, and to summarise key data from the liraglutide preclinical study programme showing the therapeutic promise of this new agent.. Liraglutide is a full agonist of the GLP-1 receptor and shares 97% of its amino acid sequence identity with human GLP-1. Unlike human GLP-1, however, liraglutide binds reversibly to serum albumin, and thus has increased resistance to enzymatic degradation and a longer half-life. In preclinical studies, liraglutide demonstrated good glycaemic control, mediated by the glucose-dependent stimulation of insulin and suppression of glucagon secretion and by delayed gastric emptying. Liraglutide also had positive effects on body weight, beta-cell preservation and mass, and cardiac function.. The therapeutic promise of liraglutide is evident from preclinical data. Liraglutide showed the potential to provide good glycaemic control without increasing the risk of hypoglycaemia and, as with exenatide, but not dipeptidyl peptidase-4 inhibitors, to mediate weight loss. Although these benefits have subsequently been studied clinically, beta-cell mass can be directly studied only in animal models. In common with other incretin-based therapies, liraglutide showed the potential to modulate the progressive loss of beta-cell function that drives the continuing deterioration in glycaemic control in patients with type 2 diabetes. Body weight was lowered by a mechanism involving mainly lowered energy intake, but also potentially altered food preference and maintained energy expenditure despite weight loss.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Mice; Mice, Obese; Peptides; Rats; Rats, Zucker; Receptors, Glucagon; Swine; Swine, Miniature; Venoms

To provide insight into clinical experience with liraglutide by reviewing four case studies of patients initiating liraglutide treatment.. Liraglutide treatment was associated with clinically relevant reductions in glycated haemoglobin (HbA(1c.) ) levels. In two of three cases for which HbA(1c) information was available, patients achieved an HbA(1c) of 6.5% at 9-month follow-up and 6.1% at 12-month follow-up. In the third case, the HbA(1c) level was 7.5% at 18-month follow-up. Individuals treated with liraglutide also experienced clinically relevant weight reductions of 4-10%. Other non-glycaemic benefits of liraglutide treatment included reductions in blood pressure. There were no reported incidences of hypoglycaemia. Gastrointestinal adverse side effects were most commonly reported, including nausea, vomiting and dyspepsia; however, symptoms generally subsided during the first month of treatment. In one patient who had prolonged nausea with exenatide over 2 years, a treatment switch to liraglutide resulted in resolution of the nausea symptoms.. Liraglutide treatment was associated with reductions in HbA(1c) levels as well as benefits beyond glycaemic control, such as weight loss and systolic blood pressure reductions. No hypoglycaemic episode was reported. Transient gastrointestinal adverse side effects were most commonly reported.

Topics: Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Drug Substitution; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Medical Records; Monitoring, Physiologic; Peptides; Venoms; Vomiting

Glucagon-like peptide-1 (GLP-1) analogues-based therapies are a new option for type 2 diabetes treatment that hold the promise of overcoming the major limitations of traditional treatments, including the increased risk for hypoglycemia and weight gain. Herein, we review the data from clinical trials that have assessed the mechanism of action, the efficacy, and safety of exenatide and liraglutide, two analogues already available for therapy. The data of these trials showed that exenatide and liraglutide induced an improvement in glycemic control comparable with type 2 diabetes traditional treatments, as insulin, thiazolidinediones and sulfonylurea. GLP-1 analogues-based therapy was also associated with progressive weight reduction and a very low risk for hypoglycemia.

Topics: Blood Glucose; Body Weight; Clinical Trials as Topic; Exenatide; Glucagon-Like Peptide 1; Humans; Liraglutide; Peptides; Venoms

Insulin administration is the primary therapy for type 1 diabetes mellitus (T1DM). Current available insulin therapies do not successfully enable children with T1DM to reach glycemic goals without side effects such as hypoglycemia and weight gain. Pramlintide is a synthetic analog of human amylin that acts in conjunction with insulin to delay gastric emptying and inhibit the release of glucagon and is indicated for use in patients with type 1 and type 2 diabetes. Recent studies in adult patients have examined the role of glucagon-like peptide 1 (GLP-1) and agents that bind to its receptor in type 1 diabetes. It is hypothesized that a major component of the glycemic effect is attributable to the known action of GLP-1 to delay gastric emptying and to inhibit glucagon secretion. Further studies with the use of amylin analogs and long-acting GLP-1 agonists as congeners with insulin in T1DM are indicated in children. In recent years, our better understanding of the pathophysiology of diabetes has led to the development of new therapies for diabetes. This article reviews the potential use of these newer pharmacologic agents as adjunctive therapy in T1DM in children and adolescents.

Topics: Amyloid; Blood Glucose; Body Weight; Child; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Pancreas; Peptides; Treatment Outcome; Venoms

Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying.. In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c

Topics: Blood Glucose; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Fasting; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Tight diabetes control sometimes comes with a price: weight gain and hypoglycemia. Two of the three major recent trials that looked at the relationship between intensive diabetes control and cardiovascular events reported significant weight gain among the intensively treated groups. There is a growing concern that the weight gain induced by most diabetes medications diminishes their clinical benefits. On the other hand, there is a claim that treating diabetes with medications that are weight neutral or induces weight loss or less weight gain while minimizing those that increase body weight may emerge as the future direction for treating overweight and obese patients with diabetes. This review clarifies the weight effect of each of the currently available diabetes medications, and explains the mechanism of action behind this effect. Despite the great variability among reviewed clinical trials, the currently available evidence is quite sufficient to demonstrate the change in body weight in association with most of the currently available medications. This review also provides some guidelines on using diabetes medications during weight management programs.

Topics: Abdominal Fat; Benzamides; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Exenatide; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Metformin; Obesity; Peptides; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazolidinediones; Venoms; Weight Gain; Weight Loss

The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM.

Topics: Adamantane; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Nitriles; Peptides; Postprandial Period; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.. To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.. Review of Phase III clinical trials based on Medline search published up to April 2008.. The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.. Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.

Topics: Adamantane; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nausea; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Vomiting

To review data from clinical trials of incretin mimetics in patients with type 2 diabetes.. Incretin mimetics are a new class of antidiabetic medication that mimic the actions of the hormone glucagon-like peptide-1. They exhibit several properties, including glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and induction of satiety, which result in improvements in glycemic control with weight loss in patients with type 2 diabetes. Recent 2-year data with exenatide, the only commercially available incretin mimetic, have demonstrated long-term sustained reductions in hemoglobin A1c with progressive weight loss. Glycemic and weight benefits were also recently reported in a 15-week study assessing once-weekly administration of long-acting release exenatide, a formulation currently in phase 3 of clinical development. Once-daily administration of liraglutide, also in phase 3 of development, has recently been shown to improve glycemic and weigh control as monotherapy, and in combination with metformin. The most common side effects of incretin mimetics are gastrointestinal in nature, particularly nausea.. The ability of incretin mimetics to improve glycemic control and reduce body weight is a unique property that fills an important void in the treatment of patients with type 2 diabetes.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Molecular Mimicry; Peptides; Venoms

Glucagon-like peptide-1 (GLP-1)-based therapy is a novel treatment for type 2 diabetes. It is executed either by GLP-1 mimetics or by dipeptidyl peptidase-IV inhibitors. In type 2 diabetes, the two strategies reduce hemoglobin A(1c) by 0.6% to 1.1% from baseline levels of 7.7% to 8.5%. They are efficient both in monotherapy and in combination with metformin or thiazolidinediones. Both treatments are well tolerated with low risk of hypoglycemia.

Topics: Adamantane; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Islets of Langerhans; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Obesity is a chronic metabolic disorder that affects one third of American adults. Modest weight losses of just 5% to 10% of body weight, which are achievable with lifestyle modification and pharmacotherapy, can lead to remarkable improvements in many obesity-associated co-morbidities, including dyslipidemia, hypertension, and type 2 diabetes. In this review, the indications for pharmacotherapy and the goals of treatment are discussed, and current and future pharmacologic approaches to the treatment of obesity are examined. Current pharmacologic therapies for obesity are limited, but recent advances in our understanding of the complex and overlapping endocrine pathways that regulate body weight have led to new opportunities for antiobesity drug development. Important drug targets that are highlighted in this review include adipocyte-derived hormones, hypothalamic neuropeptides, and gastrointestinal hormones.

Topics: Amyloid; Anti-Obesity Agents; Appetite Depressants; Body Weight; Chronic Disease; Comorbidity; Cyclobutanes; Exenatide; Gastrointestinal Hormones; Humans; Islet Amyloid Polypeptide; Lactones; Leptin; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Venoms

Although a number of compounds are currently used to treat Type 2 diabetes mellitus, achieving a sustained glycaemic control over time is often not possible using oral antidiabetics. Endogenous incretins exhibit beneficial effects that could be useful for Type 2 diabetes mellitus treatment, such as stimulating insulin secretion during hyperglycaemia, improving beta-cell mass and function, reducing glucagon secretion, delaying gastric emptying, reducing postprandial hyperglycaemia and diminishing body weight; however, their short half-life makes them unsuitable for treatment. Incretin mimetics such as liraglutide and exenatide were developed to overcome this limitation. This review discusses the effects of these compounds and their potential as a new class of antidiabetic agents.

Topics: Animals; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Type 2; Drugs, Investigational; Exenatide; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Venoms

Interventional studies have demonstrated the impact of hyperglycemia on the development of vascular complications associated with type 2 diabetes, which underscores the importance of safely lowering glucose to as near-normal as possible. Among the current challenges to reducing the risk of vascular disease associated with diabetes is the management of body weight in a predominantly overweight patient population, and in which weight gain is likely with many current therapies. Exenatide is the first in a new class of agents termed incretin mimetics, which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1 (GLP-1). Currently approved in the US as an injectable adjunct to metformin and/or sulfonylurea therapy, exenatide improves glycemic control through multiple mechanisms of action including: glucose-dependent enhancement of insulin secretion that potentially reduces the risk of hypoglycemia compared with insulin secretagogues; restoration of first-phase insulin secretion typically deficient in patients with type 2 diabetes; suppression of inappropriately elevated glucagon secretion to reduce postprandial hepatic output; and slowing the rate of gastric emptying to regulate glucose appearance into the circulation. Clinical trials in patients with type 2 diabetes treated with subcutaneous exenatide twice daily demonstrated sustained improvements in glycemic control, evidenced by reductions in postprandial and fasting glycemia and glycosylated hemoglobin (HbA(1c)) levels. Notably, improvements in glycemic control with exenatide were coupled with progressive reductions in body weight, which represents a distinct therapeutic benefit for patients with type 2 diabetes. Acute effects of exenatide on beta-cell responsiveness along with significant reductions in body weight in patients with type 2 diabetes may have a positive impact on disease progression and potentially decrease the risk of associated long-term complications.

Topics: Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Molecular Mimicry; Obesity; Peptides; Treatment Outcome; Venoms

Topics: Adamantane; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Exenatide; Glucagon-Like Peptide 1; Humans; Liraglutide; Nitriles; Peptides; Protease Inhibitors; Pyrrolidines; Venoms; Vildagliptin

To evaluate the albuminuria-lowering effect of dapagliflozin, exenatide, and the combination of dapagliflozin and exenatide in patients with type 2 diabetes and microalbuminuria or macroalbuminuria.. We enrolled 20 patients, who completed 53 treatment periods in total. Mean percentage change in UACR from baseline was -21.9% (95% CI: -34.8% to -6.4%) during dapagliflozin versus -7.7% (95% CI: -23.5% to 11.2%) during exenatide and -26.0% (95% CI: -38.4% to -11.0%) during dapagliflozin-exenatide treatment. No correlation was observed in albuminuria responses between the different treatments. Numerically greater reductions in systolic blood pressure, body weight and eGFR were observed during dapagliflozin-exenatide treatment compared with dapagliflozin or exenatide alone. Renal blood flow and effective renal plasma flow (ERPF) did not significantly change with either treatment regimen. However, all but four and two patients in the dapagliflozin and dapagliflozin-exenatide groups, respectively, showed reductions in ERPF. The filtration fraction did not change during treatment with dapagliflozin or exenatide, and decreased during dapagliflozin-exenatide treatment (-1.6% [95% CI: -3.2% to -0.01%]; P = .048).. In participants with type 2 diabetes and albuminuria, treatment with dapagliflozin, exenatide and dapagliflozin-exenatide reduced albuminuria, with a numerically larger reduction in the combined dapagliflozin-exenatide treatment group.

Topics: Albuminuria; Benzhydryl Compounds; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glomerular Filtration Rate; Humans

We studied the effect of the GLP-1RA exenatide on skin microvascular function in patients with T2DM and CAD.. Thirty-five patients with T2DM, CAD, and HbA1C 42-86 mmol/mol were randomized to treatment with exenatide or conventional non-GLP-1-based therapy for 12 weeks. Skin microvascular function was examined in the forearm by LDF and iontophoretic application of acetyl choline and SNP, and by PORH at baseline and after 12 weeks. Blood samples for fasting plasma glucose, HbA1C, and lipid profile were collected.. At 12 weeks, patients on exenatide showed reductions in HbA1C (from 63.5 ± 13 to 60.7 ± 14 mmol/mol, p = .065), body weight (from 92.6 ± 16 to 89 ± 16 kg, p < .001), and systolic blood pressure (from 141 ± 13 to 134 ± 16 mm Hg, p < .05) as compared to the conventionally treated group. There were no significant changes in skin microvascular function between or within the two groups at follow-up.. Three months' daily treatment with the GLP-1RA exenatide in T2DM patients with CAD showed no significant effects on skin microvascular function or blood glucose control, while this study confirms a reduction in body weight and blood pressure by exenatide, as compared to conventional antidiabetic drug treatment.

Topics: Blood Glucose; Body Weight; Coronary Artery Disease; Diabetes Mellitus, Type 2; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Peptides; Venoms

Brown adipose tissue (BAT) improves energy metabolism by combusting glucose and lipids into heat. Agonism of the glucagon-like peptide-1 receptor (GLP-1R) within the central nervous system activates BAT in mice. Moreover, in patients with type 2 diabetes, GLP-1R agonism lowers body weight and improves glucose and lipid levels, possibly involving BAT activation. Interestingly, people from South Asian descent are prone to develop cardiometabolic disease. We studied the effect of GLP-1R agonism on BAT in humans, specifically in South Asians and Europids without obesity or type 2 diabetes.. We show for the first time that GLP-1R agonism increases [. Clinicaltrials.gov NCT03002675.

Topics: Adipose Tissue, Brown; Adult; Body Composition; Body Weight; Energy Metabolism; Exenatide; Fluorodeoxyglucose F18; Humans; Male; Oxidation-Reduction; Oxidative Phosphorylation; Positron Emission Tomography Computed Tomography; Rest; Young Adult

The weight-reducing effect of exenatide has been proved, but too much weight loss in normal-weight patients may concern physicians. This study evaluated the effects of exenatide monotherapy on glycemic control and weight change in normal-weight, overweight, and obese patients with newly diagnosed type 2 diabetes (T2D).. In this multicenter prospective study, 29 normal-weight, 54 overweight, and 27 obese newly diagnosed and drug-naïve patients with T2D were treated with exenatide for 48 weeks. The primary efficacy endpoint was the effect of baseline body mass index (BMI) on glycemic control, measured as the change in HbA1c from baseline to Week 48 compared among different BMI groups. Other endpoints included comparisons of the effects of exenatide on fasting plasma glucose (FPG), postprandial plasma glucose (PPG), body weight, and other metabolic indices.. After 48-week treatment, the estimated mean changes in HbA1c in normal-weight, overweight, and obese patients were -1.9%, -1.8%, and -1.5%, respectively (P = 0.290 among groups after adjustment for baseline values). There were similar declines in FPG and 0.5- and 2-hour PPG among groups. There were non-significant trends from normal-weight to overweight to obese patients for increased weight reduction (decreases of 2.2, 3.9, and 4.0 kg, respectively; P = 0.104) and changes in waist circumference (decreases of 2.2, 3.2, and 5.6 cm, respectively; P = 0.078).. Baseline BMI had no effect on glycemic control, weight change, or other metabolic indices with exenatide monotherapy. Normal-weight patients with T2D would benefit from exenatide as much as overweight or obese patients on glucose control, without increased risk of excess weight loss.. 背景: 艾塞那肽减重的作用已被研究证实，但医生可能会担心正常体重的患者接受艾塞那肽治疗后体重过度下降。本研究将评估艾塞那肽对正常体重、超重和肥胖的初诊2型糖尿病患者血糖控制和体重改变的影响。 方法: 在这项多中心、前瞻性临床研究中纳入了初诊且未接受过药物治疗的2型糖尿病患者，他们接受了艾塞那肽治疗48周，其中正常体重组29人，超重组54人，肥胖组27人。主要终点为基线体重指数(body mass index，BMI)对于不同BMI组患者血糖控制的影响。采用各组48周治疗后糖化血红蛋白(HbA1c)与基线HbA1c的变化值作为评估指标。其他终点包括艾塞那肽对于各组患者空腹血糖、餐后血糖、体重和其他代谢指标的影响。 结果: 经过48周的治疗，正常体重、超重和肥胖组患者的HbA1c平均下降了1.9%、1.8%和1.5%(校正了基线HbA1c水平后，组间比较P值为0.290)。各组间空腹血糖、餐后半小时血糖和餐后2小时血糖的下降情况相近。体重下降幅度和腰围下降幅度从正常体重、超重到肥胖组呈现逐渐增加的趋势，但没有达到统计学差异(体重下降分别为2.2公斤、3.9公斤和4.0公斤，P = 0.104；腰围下降分别为2.2厘米、3.2厘米和5.6厘米，P = 0.078)。 结论: 基线BMI对接受艾塞那肽单药治疗的初诊2型糖尿病患者的血糖控制、体重变化和其他代谢指标没有明显影响。正常体重的2型糖尿病患者接受艾塞那肽治疗可获得与超重、肥胖患者一样的血糖控制疗效，并且没有增加体重过度降低的风险。.

Topics: Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Overweight; Prognosis; Prospective Studies

To investigate the glycemic efficacy, effects on cardiovascular risk factors, and safety of exenatide once weekly (QW) in patients with type 2 diabetes over 7 years in the DURATION-1 study.. Patients were initially randomized to exenatide QW 2 mg or exenatide twice daily for 30 weeks, after which they received open-label, open-ended treatment with exenatide QW 2 mg for up to 7 years. Efficacy analyses included changes from baseline in glycated hemoglobin (HbA. Of 295 patients in the intention-to-treat population, 122 (41%) completed 7 years of treatment. Patients in the 7-year completer population showed sustained glycemic improvements from baseline (7-year least-squares mean [LSM] change in HbA. Treatment with exenatide QW for 7 years was associated with sustained improvements in glycemic control and several cardiovascular risk factors.

Topics: Adult; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Risk Factors; Time Factors

This post hoc analysis assessed the effects on cardiovascular risk factors of body weight, systolic blood pressure (SBP) and triglycerides after 28 weeks' treatment with exenatide once weekly plus dapagliflozin, as compared with exenatide once weekly or dapagliflozin, in patient subpopulations from the DURATION-8 trial of patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. Subgroups of patients were stratified according to their baseline body weight, SBP and triglyceride levels. Body weight, SBP and triglyceride levels were reduced across most respective subgroups, with no significant subgroup-by-treatment interactions. For each treatment, weight loss was numerically greater as baseline body mass index increased. SBP reductions were greater among patients with SBP ≥140 vs <140 mm Hg for exenatide once weekly plus dapagliflozin and exenatide once weekly. Reductions in triglyceride levels were greater among patients with baseline triglycerides <1.69 vs ≥1.69 mmol/L for each treatment. The combination of exenatide once weekly plus dapagliflozin reduced cardiovascular risk factors across baseline subgroups for each variable to a greater extent than did either individual drug; the greatest effects were observed in the high baseline subgroups for body weight and SBP.

Topics: Anti-Obesity Agents; Benzhydryl Compounds; Blood Pressure; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Sodium-Glucose Transporter 2 Inhibitors; Triglycerides

Topics: Administration, Oral; Adult; Aged; Benzhydryl Compounds; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Metformin; Middle Aged; Sodium-Glucose Transport Proteins

The efficacy and safety of semaglutide vs comparators in non-elderly (<65 years) and elderly (≥65 years) patients with type 2 diabetes (T2D) across the SUSTAIN 1-5 trials were evaluated. Patients were randomized to once-weekly subcutaneous semaglutide (0.5 or 1.0 mg) vs placebo, sitagliptin, exenatide or insulin. The primary objective was change in HbA1c and secondary objectives were changes in body weight and safety. Mean HbA1c decreased from baseline by 1.2%-1.5% and 1.5%-1.9% vs 0%-0.9% (non-elderly, n = 3045) and by 1.3%-1.5% and 1.2%-1.8% vs 0.2%-1.0% (elderly, n = 854) with semaglutide 0.5 and 1.0 mg vs comparators. Similar reductions from baseline in mean body weight with semaglutide occurred in both age groups. Similar proportions of patients experienced adverse events; premature treatment discontinuations were higher in elderly vs non-elderly patients. No increased risk of severe or blood glucose-confirmed hypoglycaemia was seen with semaglutide vs comparators between age groups. Semaglutide had a comparable efficacy and safety profile in non-elderly and elderly patients across the SUSTAIN 1-5 trials, making it an effective treatment option for elderly patients with T2D.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Sitagliptin Phosphate; Treatment Outcome

To examine the efficacy and safety of combination therapy with exenatide plus pioglitazone vs basal/bolus insulin in patients with poorly controlled type 2 diabetes mellitus (T2DM) with very high hemoglobin A1c (HbA1c) (>10%) receiving sulfonylurea plus metformin and with a long duration of disease.. Participants (n = 101) in the Qatar Study with very poor glycemic control (HbA1c >10%) and a long duration of diabetes (10.9 years) receiving maximum/near-maximum doses of sulfonylurea plus metformin were randomly assigned to receive pioglitazone plus weekly exenatide (combination therapy), or basal plus prandial insulin (insulin therapy), to maintain HbA1c <7.0%.. Baseline HbA1c was 11.5% ± 0.2% and 11.2% ± 0.2% (P = not significant) in combination therapy and insulin therapy groups, respectively. At 6 months, combination therapy caused a robust decrease in HbA1c to 6.7% ± 0.1% (∆ = -4.8%) compared with 7.4% ± 0.1% (∆ = -3.8%) in subjects receiving insulin therapy. Combination therapy was effective in lowering the HbA1c independent of sex, ethnicity, or body mass index. Subjects in the insulin therapy group experienced significantly greater weight gain and a 2.5-fold higher rate of hypoglycemia compared with patients receiving combination therapy.. Exenatide/pioglitazone combination therapy is an effective and safe therapeutic option in patients with poorly controlled T2DM receiving metformin plus sulfonylurea with very high HbA1c (>10%).

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptides; Pioglitazone; Thiazolidinediones; Treatment Outcome; Venoms

Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS.. The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS.. Ten overweight and obese subjects with PWS (13-25 years) were recruited for a 6-month open-label, non-randomized, longitudinal study conducted at Children's Hospital Los Angeles. Exenatide was given using standard diabetes dosing without dietary modifications. Weight, body mass index (BMI), truncal fat, appetite and plasma acylated ghrelin were measured over 6 months. Mixed meal tolerance tests were performed at 0 and 6 months.. Appetite scores significantly decreased from baseline (32.2 ± 8.7) after 1, 3 and 6 moths of treatment (27.5 ± 8.8, 25.4 ± 9.3, and 25.4 ± 7.2 respectively; p = 0.004). Hemoglobin A1c decreased significantly after treatment, but weight, BMI z-score and adiposity did not. There was no significant change in ghrelin.. This is the first longitudinal investigation of the effects of exenatide in subjects with PWS. It was effective in decreasing appetite, without change in weight or BMI in the short term. Larger, controlled, longer-term trials in patients with PWS are needed to confirm the efficacy and safety of exenatide and to evaluate whether its use might induce weight loss when given in conjunction with behavioural modification.

Topics: Adolescent; Adult; Appetite; Body Mass Index; Body Weight; Exenatide; Female; Ghrelin; Humans; Hyperphagia; Incretins; Longitudinal Studies; Male; Obesity; Peptides; Prader-Willi Syndrome; Venoms; Young Adult

To explore the effects of dual therapy with dapagliflozin and exenatide on body weight, body composition, glycaemic variables and systolic blood pressure (SBP) in obese adults without diabetes.. In this single-centre, double-blind trial, we randomized 50 obese adults without diabetes (aged 18-70 years; body mass index 30-45 kg/m. Of 25 dapagliflozin/exenatide- and 25 placebo-treated participants, 23 (92.0%) and 20 (80.0%) completed 24 weeks of treatment, respectively. At baseline, the mean participant age was 52 years, 61% were female, the mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks, for dapagliflozin/exenatide versus placebo: the difference in body weight change was -4.13 kg (95% confidence interval -6.44, -1.81; P < .001), which was mostly attributable to adipose tissue reduction without lean tissue change; 36.0% versus 4.2% of participants achieved ≥5% body weight loss, respectively; and prediabetes was less frequent with active treatment (34.8% vs 85.0%, respectively; P < .01). The difference in SBP change for dapagliflozin/exenatide versus placebo was -6.7 mm Hg. As expected, nausea and injection-site reactions were more frequent with dapagliflozin/exenatide than with placebo. Only two and three participants, respectively, discontinued because of adverse events.. Compared with placebo, dapagliflozin/exenatide dual therapy reduced body weight, frequency of prediabetes and SBP over 24 weeks and was well tolerated in obese adults without diabetes.

Topics: Adipose Tissue; Adult; Aged; Benzhydryl Compounds; Blood Glucose; Blood Pressure; Body Composition; Body Weight; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glucose Intolerance; Glucosides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Magnetic Resonance Imaging; Male; Middle Aged; Nausea; Obesity; Peptides; Prediabetic State; Treatment Outcome; Venoms; Weight Loss

Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D. Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis.. Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment.. Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia.

Topics: Absorptiometry, Photon; Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Composition; Body Weight; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Incretins; Male; Middle Aged; Obesity; Peptides; Schizophrenia; Treatment Outcome; Venoms; Waist Circumference; Waist-Hip Ratio; Weight Loss; Young Adult

The efficacy and safety of exenatide twice daily (BID) and once weekly (QW) were assessed in Asian versus White patients with type 2 diabetes mellitus (T2DM).. This post-hoc pooled analysis evaluated patients receiving 10μg exenatide BID for 12-30 weeks or 2mg exenatide QW for 24-30 weeks in exenatide clinical development program trials. Race was self-identified.. A total of 4625 patients were included (exenatide BID: Asian, n=787; White, n=2223; exenatide QW: Asian, n=511; White, n=1104). At study end, glycated hemoglobin (HbA1c), fasting glucose (FG), body weight, post-prandial glucose (PPG), and PPG excursions were significantly reduced (all P<0.0001 vs baseline). For exenatide BID, HbA1c reduction was greater in Asians (P<0.0001 vs Whites), whereas HbA1c reduction did not differ by race for exenatide QW. FG reduction did not differ by race for either exenatide formulation. Weight reduction was significantly greater in Whites (P<0.0001 vs Asians), regardless of exenatide formulation. PPG reduction was greater in Asians (P<0.0001 vs Whites) for exenatide BID but did not differ by race for exenatide QW. For exenatide BID, reductions in PPG excursions for all meals were significantly greater in Asians (P<0.0001 vs Whites), whereas only post-breakfast and post-lunch excursions were significantly greater in Asians for exenatide QW (P=0.0009 and P=0.0189 vs Whites, respectively). Common adverse events included nausea, headache, and diarrhea.. Exenatide BID and QW improved glycemic control, including PPG, in Asian and White patients with T2DM. With exenatide BID, Asian patients exhibited significantly greater reductions in HbA1c and PPG than White patients. Both exenatide formulations were well tolerated in both groups.

Topics: Asian People; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Maximum Tolerated Dose; Middle Aged; Peptides; Postprandial Period; Racial Groups; Retrospective Studies; Treatment Outcome; Venoms; White People

A1C is associated with diabetes complications but does not reflect glycemic variability (GV), which may worsen outcomes by inducing inflammation, oxidative stress, and cardiac arrhythmias. We tested whether a glucagon-like peptide 1 agonist-based regimen can reduce GV and cardiometabolic risk markers while maintaining similar A1C levels in people with insulin-requiring type 2 diabetes and high cardiovascular risk.. After run-in on metformin and basal-bolus insulin (BBI), 102 participants continued metformin and basal insulin and were randomized to exenatide dosing before the two largest meals (glucacon-like peptide-1 receptor agonist and insulin [GLIPULIN group]) or continuation of rapid-acting insulin analogs (BBI group). Indices of GV by continuous glucose monitoring (CGM), hypoglycemia, weight, risk markers, and cardiac arrhythmias were assessed. The primary end point was change in glucose coefficients of variation (CV) by CGM from baseline to 26 weeks.. At randomization, the median A1C was 7.3% (57 mmol/mol) for GLIPULIN and 7.4% (56.3 mmol/mol) for BBI, and glucose CVs were 30.3 for BBI and 31.9 for GLIPULIN. At 26 weeks, A1C levels were similar (7.1% [54 mmol/mol] vs. 7.2% [55 mmol/mol]), whereas mean CV improved with GLIPULIN (-2.4 vs. 0.4, P = 0.047). Other GV indices followed similar nonsignificant patterns of improvement with GLIPULIN. There were no differences in hypoglycemic events during CGM or arrhythmias during electrocardiographic monitoring. On-trial changes in body weight (-4.8 kg vs. +0.7 kg, P < 0.001), alanine aminotransferase (P = 0.0002), and serum amyloid A (P = 0.023) favored GLIPULIN.. GLIPULIN reduced GV, weight, and some cardiometabolic risk markers while maintaining equivalent A1C levels versus BBI and might improve clinical outcomes in a larger trial.

Topics: Adult; Aged; Alanine Transaminase; Arrhythmias, Cardiac; Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Short-Acting; Male; Meals; Metformin; Middle Aged; Peptides; Risk Factors; Serum Amyloid A Protein; Venoms

This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QMS) doses of exenatide-containing microspheres in Miglyol referenced against the clinical dose of exenatide once-weekly (QW) microspheres in aqueous solution.. In this phase II, randomized, controlled, single-blind study, 121 adults (∼30/arm) with type 2 diabetes and HbA1c 7.1-11.0% (54-97 mmol/mol) were randomized 1:1:1:1 to subcutaneous exenatide QW 2 mg (self-administered) or exenatide QMS 5, 8, or 11 mg (caregiver-administered) for 20 weeks. The primary end point was change in HbA1c.. At baseline, mean age was 50 years, HbA1c was 8.5% (69 mmol/mol), fasting plasma glucose (FPG) was 184 mg/dL, and body weight was 98 kg. At week 20, mean ± SD HbA1c reductions were -1.54% ± 1.26% with exenatide QW and -1.29% ± 1.07%, -1.31% ± 1.66%, and -1.45% ± 0.93% with exenatide QMS 5, 8, and 11 mg, respectively (evaluable population: n = 110). There were no significant differences in HbA1c reductions among the exenatide QMS doses. FPG reductions were -34 ± 48 mg/dL with exenatide QW and -25 ± 43, -30 ± 52, and -49 ± 49 mg/dL with exenatide QMS 5, 8, and 11 mg, respectively. Weight decreased with all treatments. For exenatide QMS, nausea (16.7-23.3%) and headache (16.7-26.7%) were the most common adverse events. No major or minor hypoglycemia occurred.. All doses of exenatide QMS resulted in efficacy and tolerability profiles consistent with exenatide QW. These results combined with pharmacokinetic and pharmacodynamic modeling could inform dose selection for further development.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Single-Blind Method; Venoms

Socioeconomic changes in Latin American countries have led to an increased prevalence of type 2 diabetes (T2D). We examined the effects of exenatide twice daily (BID) or insulin lispro, each added to insulin glargine, in Latin American patients with T2D.. This was a subgroup analysis of patients from Argentina and Mexico in the 4B study (N=114). Patients with glycated hemoglobin (HbA1c) of 7.0-10.0% (53-86mmol/mol) after 12weeks of intensive basal insulin optimization were randomized to exenatide BID or thrice-daily insulin lispro added to insulin glargine and metformin.. After 30weeks, addition of exenatide BID or insulin lispro resulted in significant (P<0.0001) reductions in HbA1c (exenatide BID: -0.9% [-10mmol/mol]; insulin lispro: -1.2% [-13mmol/mol]). Weight was stable in the exenatide BID group (-0.1kg) and increased significantly (+3.4kg; P<0.0001) with insulin lispro. Major and minor hypoglycemia occurred less frequently (40 vs. 253 events) with exenatide BID compared with insulin lispro. Gastrointestinal adverse events of nausea, diarrhea, and vomiting occurred more frequently with exenatide BID than with insulin lispro.. Both exenatide BID and prandial insulin lispro, each added to basal insulin glargine, were effective at reducing HbA1c in Latin American patients. Treatment with exenatide BID resulted in stable weight but more gastrointestinal adverse events. Treatment with insulin lispro resulted in weight gain and an increased risk of hypoglycemia. These findings support the addition of exenatide BID to insulin glargine as an option for Latin American patients unable to achieve glycemic control on basal insulin alone.

Topics: Adult; Aged; Argentina; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Male; Metformin; Mexico; Middle Aged; Peptides; Retrospective Studies; Treatment Outcome; United States; Venoms

To evaluate the 5-year efficacy and safety of once weekly exenatide.. The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 μg of exenatide twice daily) with an open-ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 μg of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate.. Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, -1.6%; 95% CI, -1.8% to -1.4%; vs -1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (-28.8 mg/dL; 95% CI, -36.2 to -21.5 mg/dL), weight (-3.0 kg; 95% CI, -4.6 to -1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed.. Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes.. clinicaltrials.gov Identifier: NCT00308139.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Treatment Outcome; Venoms

Glycemic variability may contribute to adverse medical outcomes of type 2 diabetes, but prior therapies have had limited success in controlling glycemic fluctuations, and the hypothesis has not been adequately tested.. People with insulin-requiring type 2 diabetes and high cardiovascular risk were enrolled during a run-in period on basal-bolus insulin (BBI), and 102 were randomized to continued BBI or to basal insulin with a prandial GLP-1 receptor agonist (GLIPULIN) group, each seeking to maintain HbA(1c) levels between 6.7% and 7.3% (50-56 mmol/mol) for 6 months. The primary outcome measure was glycemic variability assessed by continuous glucose monitoring; other measures were HbA(1c), weight, circulating markers of inflammation and cardiovascular risk, albuminuria, and electrocardiographic patterns assessed by Holter monitoring.. At randomization, the mean age of the population was 62 years, median duration of diabetes 15 years, mean BMI 34 kg/m(2), and mean HbA(1c) 7.9% (63 mmol/mol). Thirty-three percent had a prior cardiovascular event, 18% had microalbuminuria, and 3% had macroalbuminuria. At baseline, the continuous glucose monitoring coefficient of variation for glucose levels was similar in both groups.. FLAT-SUGAR is a proof-of-concept study testing whether, in a population of individuals with type 2 diabetes and high cardiovascular risk, the GLIPULIN regimen can limit glycemic variability more effectively than BBI, reduce levels of cardiovascular risk markers, and favorably alter albuminuria and electrocardiographic patterns. We successfully randomized a population that has sufficient power to answer the primary question, address several secondary ones, and complete the protocol as designed.

Topics: Albuminuria; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Metformin; Middle Aged; Peptides; Postprandial Period; Risk Factors; Time Factors; Venoms

Preclinical studies suggested that insulin, incretin and thiazolidinediones had effect on regulation of bone metabolism. But clinical evidence is limited. We assessed the effects of these antihyperglycemic agents on bone metabolism in patients with newly diagnosed type 2 diabetes.. The present study was a two-center, randomized, parallel-group clinical trial. Sixty-two newly diagnosed and drug-naïve patients with type 2 diabetes were randomized to exenatide (EXE, n = 20), mixed protamine zinc recombinant human insulin lispro injection (25R; INS, n = 21) or pioglitazone (PIO, n = 21) group for a 24-week treatment. Glycosylated hemoglobin A1c (HbA1c), body weight, body mineral density (BMD) and fasting serum concentration of bone turnover markers including osteocalcin (OC), C-telopeptide of type I collagen (CTX) and tartrate-resistant alkaline phosphatase 5b (TRAcP5b) were assessed at baseline and week 24.. Baseline characteristics were similar among groups. At week 24, HbA1c improved in all patients (EXE:-2.4 ± 0.3 %, INS:-2.4 ± 0.3 %, PIO:-2.0 ± 0.2 %; p > 0.05 among groups). Patients treated with exenatide lost body weight remarkably (-4.7 ± 0.8 kg). In spite of the amelioration of glucose control, no significant improvement of OC, CTX or TRAcP5b was observed at week 24 (EXE: OC -0.619 ± 0.728 ng/ml, CTX 0.147 ± 0.046 ng/ml, TRAcP5b 0.302 ± 0.149 U/L;INS: OC 0.637 ± 0.787 ng/ml, CTX -0.012 ± 0.074 ng/ml, TRAcP5b 0.124 ± 0.395 U/L; PIO: OC -0.150 ± 0.691 ng/ml, CTX 0.073 ± 0.094 ng/ml, TRAcP5b 0.586 ± 0.183 U/L; p > 0.05), as well as BMD measurement, regardless of the treatments.. Twenty-four-week treatment with exenatide, insulin and pioglitazone improved glucose control in patients with newly diagnosed type 2 diabetes, but had no impact on bone turnover markers or BMD.

Topics: Adult; Aged; Body Weight; Bone and Bones; Bone Density; Collagen Type I; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Osteocalcin; Peptides; Pioglitazone; Tartrate-Resistant Acid Phosphatase; Thiazolidinediones; Venoms

Exenatide treatment improves glycemia in adults with type 2 diabetes and has been shown to reduce postprandial hyperglycemia in adolescents with type 1 diabetes. We studied the effects of exenatide on glucose homeostasis in adults with long-standing type 1 diabetes.. Fourteen patients with type 1 diabetes participated in a crossover study of 6 months' duration on exenatide (10 μg four times a day) and 6 months off exenatide. We assessed changes in fasting and postprandial blood glucose and changes in insulin sensitivity before and after each study period.. High-dose exenatide therapy reduced postprandial blood glucose but was associated with higher fasting glucose concentrations without net changes in hemoglobin A1c. Exenatide increased insulin sensitivity beyond the effects expected as a result of weight reduction.. Exenatide is a promising adjunctive agent to insulin therapy because of its beneficial effects on postprandial blood glucose and insulin sensitivity in patients with type 1 diabetes.

Topics: Adult; Blood Glucose; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 1; Drug Administration Schedule; Exenatide; Fasting; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Male; Middle Aged; Peptides; Postprandial Period; Venoms

Mealtime insulin is commonly added to manage hyperglycemia in type 2 diabetes when basal insulin is insufficient. However, this complex regimen is associated with weight gain and hypoglycemia. This study compared the efficacy and safety of exenatide twice daily or mealtime insulin lispro in patients inadequately controlled by insulin glargine and metformin despite up-titration.. In this 30-week, open-label, multicenter, randomized, noninferiority trial with 12 weeks prior insulin optimization, 627 patients with insufficient postoptimization glycated hemoglobin A1c (HbA1c) were randomized to exenatide (10-20 µg/day) or thrice-daily mealtime lispro titrated to premeal glucose of 5.6-6.0 mmol/L, both added to insulin glargine (mean 61 units/day at randomization) and metformin (mean 2,000 mg/day).. Randomization HbA1c and fasting glucose (FG) were 8.3% (67 mmol/mol) and 7.1 mmol/L for exenatide and 8.2% (66 mmol/mol) and 7.1 mmol/L for lispro. At 30 weeks postrandomization, mean HbA1c changes were noninferior for exenatide compared with lispro (-1.13 and -1.10%, respectively); treatment differences were -0.04 (95% CI -0.18, 0.11) in per-protocol (n = 510) and -0.03 (95% CI -0.16, 0.11) in intent-to-treat (n = 627) populations. FG was lower with exenatide than lispro (6.5 vs. 7.2 mmol/L; P = 0.002). Weight decreased with exenatide and increased with lispro (-2.5 vs. +2.1 kg; P < 0.001). More patients reported treatment satisfaction and better quality of life with exenatide than lispro, although a larger proportion of patients with exenatide experienced treatment-emergent adverse events. Exenatide resulted in fewer nonnocturnal hypoglycemic episodes but more gastrointestinal adverse events than lispro.. Adding exenatide to titrated glargine with metformin resulted in similar glycemic control as adding lispro and was well tolerated. These findings support exenatide as a noninsulin addition for patients failing basal insulin.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Male; Meals; Metformin; Middle Aged; Peptides; Quality of Life; Receptors, Glucagon; Treatment Outcome; Venoms

Compared to traditional weight loss strategies, the compensatory decrease in energy expenditure in response to body weight loss is markedly attenuated after Roux-en-Y gastric bypass surgery (RYGB). Because basal and postprandial levels of glucagon-like peptide-1 (GLP-1) are increased after RYGB surgery, and because GLP-1 has been shown to increase energy expenditure, we investigated if increased GLP-1 levels are involved in the alterations in energy expenditure after RYGB. Adult male Wistar rats were randomized for RYGB (n=8) or sham surgery (n=17). Part of the sham-operated rats were food restricted and body weight-matched (n=8) to the RYGB animals. The effects of acute subcutaneous administration of the GLP-1 antagonist Exendin (9-39) (Ex-9, 30μg/kg) or the GLP-1 agonist Exendin-4 (Ex-4, 5μg/kg), respectively, on energy expenditure were tested using indirect calorimetry. We found that Ex-9 increased food intake in RYGB, but not in sham-operated rats. Energy expenditure was lower in RYGB and sham-operated body weight-matched rats compared to sham-operated ad libitum fed rats, but significantly higher in RYGB rats compared to sham-operated body weight-matched rats. There was no effect of Ex-9 treatment on energy expenditure in either group of animals. Similarly, Ex-4 decreased food intake more in RYGB than in sham-operated rats, but Ex-4 did not modulate energy expenditure in any surgical group. We conclude that acute modulation of GLP-1 signaling is not directly involved in altered energy expenditure after RYGB surgery in rats.

Topics: Activity Cycles; Animals; Body Weight; Calorimetry; Eating; Energy Metabolism; Exenatide; Food Deprivation; Gastric Bypass; Glucagon-Like Peptide-1 Receptor; Male; Motor Activity; Peptide Fragments; Peptides; Rats; Rats, Wistar; Receptors, Glucagon; Respiration; Time Factors; Venoms

Exenatide, a glucagon-like peptide-1 receptor agonist administered by self-injection, decreases plasma glucose, glycosylated hemoglobin (HbA1c), and weight in patients with type 2 diabetes. ITCA 650 is an investigational new drug that provides continuous subcutaneous delivery of exenatide.. This randomized, open-label, multicenter, 28-day study evaluated the tolerability, pharmacodynamics, and pharmacokinetics of ITCA 650 in patients with type 2 diabetes.. The study enrolled patients with type 2 diabetes who were receiving a stable regimen of diet and exercise alone or a stable dose of metformin monotherapy, thiazolidinedione monotherapy, or metformin plus thiazolidinedione combination therapy. Patients were randomized to receive 10, 20, 40, or 80 μg/d of ITCA 650 placed subcutaneously for 28 days. Plasma glucose, HbA1c, insulin, and weight were measured at regular intervals throughout the study. Exenatide levels and anti-exenatide antibodies were also assessed.. Forty-four patients were randomized to treatment. From baseline to end point, significant (P < 0.05) decreases in fasting plasma glucose levels, 2-hour postprandial glucose levels, and glucose AUC curve were seen in all treatment groups. HbA1c levels also decreased significantly (P < 0.001) in all 4 treatment groups. Weight was significantly (P < 0.05) lowered in the 40- and 80-μg/d groups. Detectable levels of exenatide were noted within 12 to 24 hours of ITCA 650 placement, reached steady state by 24 hours, and then remained relatively steady during a plateau period until device removal on day 29. Exenatide levels declined to undetectable levels within 24 hours after removal of the ITCA 650. The most common adverse events were nausea, decreased appetite, and vomiting; these were transient and mostly mild or moderate in severity. Mild local adverse events related to the healing process were common at the placement site but abated after 1 week. Twelve patients developed anti-exenatide antibodies; however, the pharmacokinetics of ITCA 650 were not altered compared with those who did not develop antibodies.. ITCA 650 provided continuous and controlled subcutaneous delivery of exenatide for 28 days that was generally well tolerated and produced significant reductions in plasma glucose, HbA1c, and weight. Further studies are warranted to characterize the long-term tolerability and efficacy of ITCA 650 for the treatment of patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01798264.

Topics: Blood Glucose; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Male; Middle Aged; Peptides; Receptors, Glucagon; Time Factors; Treatment Outcome; Venoms

To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes.. We conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 μg/day of ITCA 650 or Ex-BID 5 → 10 μg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 μg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24.. HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9-8.0% was -0.98, -0.95, and -0.72% for the 20 and 40 μg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤ 7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (≈ 1.4% from baseline) were achieved with 60 and 80 μg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤ 7% at 24 weeks; respectively. Weight was reduced by 2.8-3.7 kg (P < 0.05) at 24 weeks in all except the 20 → 20 μg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 μg/day relative to Ex-BID; and 60 μg/day had the best profile of tolerability and HbA1c lowering.. ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20 → 60 μg/day regimen was considered the best dose for further examination in phase 3.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Metformin; Middle Aged; Peptides; Venoms; Young Adult

To evaluate the effects of exenatide on some inflammatory markers and to quantify the effect of exenatide on β-cell function.. A randomized, double-blind, placebo-controlled trial.. Seven hospitals in Italy.. A total of 174 white treatment-naive adults with type 2 diabetes and a glycated hemoglobin (HbA(1c)) level higher than 7.5%.. After an open-label run-in period of 8 ± 2 months with metformin, patients were randomized to take exenatide (5 μg twice/day for the first 4 weeks, 10 μg twice/day thereafter) or a placebo volume equivalent for 12 months.. Body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index, homeostasis model assessment β-cell function index (HOMA-β), fasting plasma proinsulin (FPPr), proinsulin-to-fasting plasma insulin ratio (Pr:FPI ratio), C-peptide, glucagon, vaspin, chemerin, and resistin were evaluated at baseline, at randomization, and at 3, 6, 9, and 12 months. Patients also underwent a combined euglycemic, hyperinsulinemic, and hyperglycemic clamp with subsequent arginine stimulation to assess insulin sensitivity and insulin secretion. HbA(1c) was significantly improved with exenatide plus metformin compared with placebo plus metformin. Exenatide plus metformin was also significantly more effective than placebo plus metformin in increasing HOMA-β C-peptide, and all measures of β-cell function after the euglycemic hyperinsulinemic and hyperglycemic clamp. We observed that exenatide plus metformin also reduced resistin compared with placebo plus metformin. No variations in vaspin and chemerin were noted in group-to-group comparisons. We observed a significant correlation between M value increase, an index of insulin sensitivity, and a decrease in inflammatory parameters in the exenatide plus metformin group.. The combination of exenatide plus metformin was more effective than metformin alone in improving glycemic control, β-cell function, and inflammatory parameters.

Topics: Aged; Arginine; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Chimerin Proteins; Diabetes Mellitus, Type 2; Diet; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Exenatide; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Male; Metformin; Middle Aged; Peptides; Resistin; Risk Factors; Serpins; Venoms

Exenatide is a glucagon-like peptide-1 receptor agonist demonstrated to improve glycemic control with low hypoglycemia risk in patients with type 2 diabetes mellitus. The Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly (DURATION) program comprised 6 randomized, comparator-controlled, 24- to 30-week trials of exenatide once weekly (EQW), an extended-release formulation. This post hoc analysis pooled data from patients taking EQW across 6 trials to assess efficacy and safety in a large, varied patient population.. The intent-to-treat (ITT) population contained 1379 patients (baseline mean ± standard deviation glycated hemoglobin [HbA1c] levels of 8.4% ± 1.1%) who were treated with EQW over the course of 24 to 30 weeks. Changes from baseline in efficacy parameters for the ITT population and a completer population (1195 patients with ≥ 22 weeks of exposure) were evaluated.. The ITT population experienced significant reductions from baseline (least-squares mean [95% CI]) in HbA1c levels (-1.4% [-1.5% to -1.4%]), fasting blood glucose levels (-36 mg/dL [-38.4 mg/dL to -33.8 mg/dL]), and body weight (-2.5 kg [-2.8 kg to -2.3 kg]) after 24 to 30 weeks of EQW treatment. Reductions in HbA1c and fasting blood glucose levels were observed across baseline HbA1c level strata; patients with higher baseline HbA1c levels experienced greater reductions. Treatment with EQW was associated with modest, significant reductions in blood pressure (systolic blood pressure, -2.8 mm Hg [-3.5 mm Hg to -2.1 mm Hg]; diastolic blood pressure, -0.8 mm Hg [-1.2 mm Hg to -0.4 mm Hg]), and fasting lipid levels (total cholesterol, -6.5 mg/dL [-8.2 mg/dL to -4.7 mg/dL]; low-density lipoprotein cholesterol, -3.9 mg/dL [5.3 mg/dL to -2.5 mg/dL]; and triglyceride [geometric least-squares mean percent change (95% CI)], -6% [-8% to -4%] levels). Similar reductions were observed in the completer population. Exenatide once weekly was generally well tolerated. Transient, mild-to-moderate gastrointestinal treatment-emergent adverse events and injection-site treatment-emergent adverse events were reported most frequently, but were seldom treatment limiting. No major hypoglycemic events were observed; minor hypoglycemic events occurred infrequently in patients not using a sulfonylurea.. This post hoc analysis of > 1300 patients demonstrated that EQW was associated with significant reductions in HbA1c levels, body weight, blood pressure, and fasting lipid levels, with minimal hypoglycemia risk. Consistent with established safety profiles, EQW therapy was generally well tolerated.. www.ClinicalTrials.gov identifiers: NCT00308139, NCT00637273, NCT00641056, NCT00676338, NCT00877890, NCT01029886.

Topics: Blood Glucose; Blood Pressure; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Peptides; Treatment Outcome; Venoms

Therapies for type 2 diabetes mellitus that leverage the glucagon-like peptide-1 (GLP-1) receptor signaling pathway have been shown to reduce rates of hyperglycemia and have beneficial effects on body weight. This post hoc analysis compared the effects of 2 GLP-1 receptor- based therapies, exenatide once weekly (EQW), a GLP-1 receptor agonist, and sitagliptin (sita), a dipeptidyl peptidase-4 inhibitor, on glucose control across the range of baseline glycated hemoglobin (HbA1c) levels specified in the American Association of Clinical Endocrinologists and American College of Endocrinology treatment algorithm.. Data from patients treated with either EQW or sita for 26 weeks in 2 randomized, double-blind, comparator-controlled clinical trials were pooled and analyzed. Glycemic endpoints and cardiovascular risk factors were evaluated in subgroups and the overall population.. Analysis included 737 patients on background therapies of diet and exercise and/or metformin. While both agents reduced HbA1c and fasting blood glucose (FBG) levels from baseline, significantly greater reductions in HbA1c and FBG levels occurred with EQW compared with sita across all baseline HbA1c level strata, and significantly more patients in the EQW group achieved goal HbA1c levels compared with the sita group. Patients treated with EQW also experienced significantly greater reductions in body weight and cholesterol levels compared with patients treated with sita. The incidences of the most common adverse events of nausea and diarrhea were higher in the EQW group compared with the sita group, and incidences of these adverse events decreased over time. Both groups experienced a low incidence of minor hypoglycemic events.. Significantly greater improvements in HbA1c and FBG levels were observed in EQW- compared with sita-treated patients across all baseline HbA1c level strata. Additionally, greater reductions in body weight and some cardiovascular risk factors were observed with EQW treatment compared with sita treatment. Both EQW and sita were generally well tolerated; sita-treated patients experienced fewer adverse events than EQW-treated patients.. www.ClinicalTrials.gov identifiers: NCT00637273, NCT00676338.

Topics: Blood Glucose; Body Weight; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Pyrazines; Retrospective Studies; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms

To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD).. One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks.. After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were markedly lower, and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group.. Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD.

Topics: Adiponectin; Adult; Aged; Alanine Transaminase; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Time Factors; Treatment Outcome; Venoms; Waist-Hip Ratio

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9-16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m(2)) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (-1.7 kg/m(2), 95% confidence interval (CI) (-3.0, -0.4), P = 0.01), body weight (-3.9 kg, 95% CI (-7.11, -0.69), P = 0.02), and fasting insulin (-7.5 mU/l, 95% CI (-13.71, -1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and β-cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

Topics: Adolescent; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Child; Cross-Over Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Glucose Tolerance Test; Humans; Injections, Subcutaneous; Male; Minnesota; Obesity, Morbid; Peptides; Pilot Projects; Risk Factors; Risk Reduction Behavior; Time Factors; Treatment Outcome; Venoms; Weight Loss

Studies of the glucagon-like peptide-1 receptor agonists (GLP-1RAs) are needed to determine the durability of metabolic response and tolerability associated with long-term treatment.. The present study was conducted to provide long-term data on glycemic control, weight changes, and tolerability of exenatide 10 μg BID treatment in patients with type 2 diabetes mellitus who have failed to achieve glycemic targets with oral antihyperglycemic medication.. In this uncontrolled, open-label trial with treatment up to 156 weeks, patients received exenatide 10 μg BID while continuing treatment with metformin and/or a sulfonylurea (SFU). Intent-to-treat (ITT), 52-, 100-, and 132-week completer populations were defined. Metabolic changes were analyzed in the completer and ITT populations; adverse events (AEs) were summarized in the ITT population. Descriptive statistics were used for absolute and change-from-baseline data. Within-treatment comparisons were conducted using the paired t test.. Of 155 patients in the ITT population (mean [SD]: age, 59 [9] years; 56% female; duration of diabetes, 9.1 [5.9] years; weight, 88.8 [16.5] kg; body mass index, 31.9 [4.7] kg/m(2); hemoglobin [Hb] A(1c), 8.7% [1.2%]), 133, 111, and 103 patients completed 52, 100, and 132 weeks of treatment, respectively. In the ITT population, the mean (SE) change in HbA(1c) from baseline to week 132 was -1.0% (0.10%) (P < 0.0001). In patients completing 52, 100, and 132 weeks, HbA(1c) changes from baseline to end point were -1.3% (0.10%), -1.0% (0.12%), and -1.0 (0.13%) (P < 0.0001), with 40% of patients achieving HbA(1c) <7% at 132 weeks. Patients in the ITT and completer populations experienced mean (SE) weight changes of -3.7 (0.39) kg and -3.9 (0.51) kg (P < 0.0001) at week 132. Improved glycemic control and weight loss occurred in 63% of patients in the completer population at week 132. In addition, 38% of completers at week 132 achieved HbA(1c) <7% without weight gain. No relationship was found between the development of antiexenatide antibodies and change in HbA(1c). The most common AEs were gastrointestinal in nature, reported in 46% of patients and leading to discontinuation in 7 cases. Serious AEs were reported in 26% of patients, and 18% withdrew due to a treatment-emergent AE. Of 24% of patients in whom hypoglycemia was reported, 22% were on SFU or metformin + SFU combination, and 2% were on metformin.. The findings from this open-label, single-arm study characterized the response to exenatide 10 μg BID for up to 132 weeks. Significant, persistent improvements in HbA(1c) and weight were observed in patients receiving exenatide BID, with reported AEs consistent with those from studies of shorter duration. ClinicalTrials.gov identifier: NCT00044668.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Humans; Hungary; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Venoms

Exenatide once weekly (QW) is an extended-release formulation of exenatide, a glucagon-like peptide-1 receptor agonist that reportedly improves glycemic control in patients with type 2 diabetes.. The goal of this study was to test the hypothesis that exenatide QW is noninferior to insulin glargine, as measured by change in glycosylated hemoglobin (HbA(1c)) from baseline to end point (week 26 [primary end point]) in Japanese patients with type 2 diabetes who have inadequate glycemic control with oral antidiabetes drugs.. In this open-label, parallel-group, multicenter, noninferiority registration study, patients were randomized (1:1) to add exenatide QW (2 mg) or once-daily insulin glargine (starting dose, 4 U) to their current oral antidiabetes drug treatment. The primary analysis was change in HbA(1c) from baseline to end point, evaluated by using a last-observation-carried-forward ANCOVA model, with a predefined noninferiority margin of 0.4%. Secondary analyses (a priori) included analysis of superiority for between-group comparisons of change in weight and the proportion of patients reaching HbA(1c) target levels of ≤7.0% or ≤6.5%.. The baseline characteristics of the exenatide QW (215 patients) and insulin glargine (212 patients) treatment groups were similar: mean (SD) age, 57 (10) years and 56 (11) years, respectively; 66.0% and 69.8% male; mean HbA(1c), 8.5% (0.82%) and 8.5% (0.79%); and mean weight, 69.9 (13.2) kg and 71.0 (13.9) kg. Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point (least squares mean difference, -0.43% [95% CI, -0.59 to -0.26]; P < 0.001), with the 95% CI upper limit less than the predefined noninferiority margin (0.4%). A significantly greater proportion of patients receiving exenatide QW compared with insulin glargine achieved HbA(1c) target levels of ≤7.0% (89 of 211 [42.2%] vs 44 of 210 [21.0%]) or ≤6.5% (44 of 214 [20.6%] vs 9 of 212 [4.2%]) at end point (P < 0.001 for both). Patient weight was reduced with exenatide QW compared with insulin glargine at end point (least squares mean difference, -2.01 kg [95% CI, -2.46 to -1.56]; P < 0.001). Exenatide QW was well tolerated, with a lower risk of hypoglycemia compared with insulin glargine but a higher incidence of injection-site induration.. Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point; these results suggest that exenatide QW may provide an effective alternative treatment for Japanese patients who require additional therapy to control their diabetes. ClinicalTrials.gov identifier: NCT00935532.

Topics: Administration, Oral; Aged; Blood Glucose; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Japan; Least-Squares Analysis; Male; Middle Aged; Peptides; Venoms

Cyslipidemia and type 2 diabetes are two of the most significant risk factors for the development of cardiovascular disease. Measurement of lipoprotein subclasses provides important information about derangements in lipid metabolism and helps refine cardiovascular risk assessment. Exenatide, a glucagon-like peptide 1 receptor agonist, improved glycemic control, obesity, hypertension, and dyslipidemia in patients with type 2 diabetes in clinical trials.. In the DURATION-1 trial, patients with type 2 diabetes were treated with exenatide once weekly or twice daily for 30 weeks. This post hoc analysis evaluated the impact of exenatide on lipoprotein subclasses in 211 DURATION-1 patients using vertical auto profile methodology and the Statistical Package for the Social Sciences general linear model adjusted for glycosylated hemoglobin (HbA(1c)) and weight.. Baseline lipids and high sensitivity C-reactive protein were normal overall based on the standard lipid panel. Once-weekly exenatide reduced apolipoprotein B and the apolipoprotein B to apolipoprotein A1 ratio (P < 0.05), independent of glycemic improvement and weight loss. A significant shift in lipoprotein pattern away from small, dense low-density lipoprotein-4 cholesterol was also observed (P < 0.05). Exenatide once weekly increased high-density lipoprotein-2 cholesterol, even after adjustment for changes in HbA(1c) and weight (P < 0.05). Triglycerides, very low-density lipoprotein cholesterol, and high sensitivity C-reactive protein were reduced with both the once-weekly and twice-daily exenatide regimens (P < 0.05).. In this post hoc analysis, exenatide significantly improved a number of cardiovascular risk markers. Continuous exenatide exposure with exenatide once weekly elicited a greater response than did immediate-release exenatide twice daily, generally independent of glycemic improvement and weight loss. Thus, in addition to improving glycemic control, exenatide induced favorable changes in lipid and lipoprotein metabolism and decreased systemic inflammation.

Topics: Apolipoproteins; Biomarkers; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipoproteins; Male; Middle Aged; Peptides; Risk Factors; Venoms

Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A₁(c) (HbA₁(c)) targets.. To test whether twice-daily exenatide injections reduce HbA₁(c) levels more than placebo in people receiving insulin glargine.. Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA₁(c) level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817). 59 centers in 5 countries.. Adults with type 2 diabetes and an HbA₁(c) level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents).. Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 µg twice daily, or placebo for 30 weeks.. The primary outcome was change in HbA₁(c) level. Secondary outcomes included the percentage of participants with HbA₁(c) values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events.. 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA₁(c) level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo.. The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA₁(c) levels, and more exenatide recipients than placebo recipients withdrew because of adverse events.. Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation.. Alliance of Eli Lilly and Company and Amylin Pharmaceuticals.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Metformin; Middle Aged; Peptides; Pioglitazone; Sensitivity and Specificity; Thiazolidinediones; Venoms

To assess change in patient-reported outcomes in subjects with type 2 diabetes treated with exenatide once weekly compared with those treated with sitagliptin or pioglitazone.. In this 26-week randomized, multicenter, double-dummy study, 491 subjects received 2 mg of exenatide once weekly or maximum daily doses of sitagliptin (100 mg) or pioglitazone (45 mg) on a background of metformin. Weight-related quality of life, health utility, psychological well-being, and diabetes treatment satisfaction were assessed at baseline and week 26. Mean group changes from baseline to week 26 were estimated by ANCOVA.. Weight-related quality of life total scores improved significantly in the exenatide once weekly and sitagliptin arms only; the exenatide once weekly group experienced significantly greater improvement than the pioglitazone group in weight-related quality of life total scores and in several domain scores. Health utility scores improved significantly for exenatide once weekly and sitagliptin groups (P < 0.05) with no significant difference between the exenatide once weekly group and either comparison group. All groups experienced significant improvements on the psychological well-being global scale and all six domain scores, with no significant difference between the exenatide once weekly group and either comparator. All groups experienced significant improvements in total diabetes treatment satisfaction scores. The exenatide once weekly group experienced greater improvement than the sitagliptin group in treatment satisfaction total scores.. In combination with clinical outcomes from this study, these results indicate it is possible for patients treated with metformin to initiate exenatide therapy with potential benefits in both clinical and patient-reported outcomes.

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Health Status; Humans; Hypoglycemic Agents; Male; Mental Health; Middle Aged; Patient Satisfaction; Peptides; Pioglitazone; Pyrazines; Quality of Life; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles; Venoms

This study was designed to determine the effect of exenatide on inflammatory and oxidative stress markers in type 2 diabetes mellitus (T2DM) patients who were suboptimally controlled with metformin and/or sulfonylurea.. Twenty-three patients with T2DM with inadequate glucose control were randomly divided into two groups: exenatide group (E group) (12 patients, 5 μg b.d. × 4 weeks followed by 10 μg b.d. × 12 weeks) and placebo group (P group) (11 patients). Glycosylated hemoglobin (HbA1c), the seven-point glucose profile, daily mean glucose, and glycemic excursion were determined. The effects of exenatide on 8-iso-prostaglandin F2α (PGF2α), monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP) were investigated.. Exenatide treatment reduced body weight and body mass index (BMI) and improved HbA1c, the seven-point glucose profile, and daily mean glucose compared with placebo (P < 0.05). Limited glycemic excursion was found in the E group compared with the P group (P < 0.05), including a smaller SD and postprandial glucose excursion. In addition, the oxidative stress maker PGF2α was significantly reduced by exenatide treatment (P < 0.05). The inflammatory markers hs-CRP and MCP-1 were also significantly reduced in the E group compared with the P group (P < 0.05). PGF2α was significantly correlated with glycemic excursion (P < 0.05), whereas MCP-1 was significantly correlated with body weight, BMI, glycemic excursion, and HbA1c (P < 0.05 for all).. Exenatide treatment reduced patient body weight and BMI, improved HbA1c and the seven-point glucose profile, reduced daily mean glucose, limited glycemic excursion, and reduced oxidative stress and inflammatory markers in patients of T2DM having inadequate glucose control.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Chemokine CCL2; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin Resistance; Male; Middle Aged; Oxidative Stress; Peptides; Pilot Projects; Venoms

We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes.. The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety.. This was a 24-wk, randomized, open-label, comparator-controlled study.. The study was conducted at 43 sites in the United States.. The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean ± SD): glycosylated hemoglobin (HbA1c) 8.4 ± 1.2%, fasting plasma glucose 171 ± 47 mg/dl, weight 96 ± 20 kg] that were drug naïve (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications.. Interventions included ExQW 2 mg for 24 wk or ExBID 5 μg for 4 wk followed by ExBID 10 μg for 20 wk.. The change in HbA1c from baseline to wk 24 was measured.. At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean ± SE) vs. ExBID in HbA1c (-1.6 ± 0.1% vs. -0.9 ± 0.1%; P < 0.0001) and fasting plasma glucose (-35 ± 5 mg/dl vs. -12 ± 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 ± 0.4 kg and -1.4 ± 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred.. Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Combined Modality Therapy; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Exenatide; Exercise Therapy; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Risk Factors; Venoms; Weight Loss; Young Adult

The aim of this study was to evaluate the effect of exenatide compared to glimepiride on body weight, glycemic control and insulin resistance in type 2 diabetic patients taking metformin. One hundred and eleven patients with uncontrolled type 2 diabetes mellitus and intolerant to metformin at the highest dosages (2500-3000 mg/day) were enrolled in this study. Patients were randomized to receive exenatide 5 μg twice a day or glimepiride 1mg three times a day and titrated after 1 month to exenatide 10 μg twice a day or glimepiride 2mg three times a day for 12 months in a randomized, single-blind, controlled study. We evaluated at the baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c), glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR) index, adiponectin, tumor necrosis factor-α, and high sensitivity-C reactive protein. Both treatments gave a similar improvement of glycemic control, without any differences between the two groups. Only exenatide gave a decrease of BMI, insulin resistance parameters such as fasting plasma insulin, HOMA-IR, and adiponectin and a decrease of inflammatory parameters such as tumor necrosis factor-α, and high sensitivity-C reactive protein. Furthermore, the values obtained with exenatide were significantly better than the values recorded with glimepiride. We can conclude that exenatide was better than glimepiride in improving insulin resistance and inflammatory state. Furthermore, adiponectin increase, and tumor necrosis factor-α reduction seem to be related to weight loss obtained with exenatide.

Topics: Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Inflammation; Insulin Resistance; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Venoms

We examined the effects of combined pioglitazone (peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist) and exenatide (GLP-1 receptor agonist) therapy on hepatic fat content and plasma adiponectin levels in patients with type 2 diabetes (T2DM). Twenty-one T2DM patients (age = 52 ± 3 years, BMI = 32.0 ± 1.5, hemoglobin A(1c) (HbA(1c)) = 8.2 ± 0.4%) on diet and/or metformin received additional treatment with either pioglitazone 45 mg/day for 12 months (n = 10) or combined therapy with pioglitazone (45 mg/day) and exenatide (10 µg subcutaneously twice daily) for 12 months (n = 11). At baseline, hepatic fat content and plasma adiponectin levels were similar between the two treatment groups. Pioglitazone reduced fasting plasma glucose (FPG) (P < 0.05), fasting free fatty acid (FFA) (P < 0.05), and HbA(1c) (Δ = 1.0%, P < 0.01), while increasing plasma adiponectin concentration by 86% (P < 0.05). Hepatic fat (magnetic resonance spectroscopy (MRS)) was significantly reduced following pioglitazone treatment (11.0 ± 3.1 to 6.5 ± 1.9%, P < 0.05). Plasma triglyceride concentration decreased by 14% (P < 0.05) and body weight increased significantly (Δ = 3.7 kg). Combined pioglitazone and exenatide therapy was associated with a significantly greater increase in plasma adiponectin (Δ = 193%) and a significantly greater decrease in hepatic fat (12.1 ± 1.7 to 4.7 ± 1.3%) and plasma triglyceride (38%) vs. pioglitazone therapy despite the lack of a significant change in body weight (Δ = 0.2 kg). Hepatic injury biomarkers aspartate aminotransferase and alanine aminotransferase (ALT) were significantly decreased by both treatments; however, the reduction in ALT was significantly greater following combined pioglitazone and exenatide therapy. We conclude that combined in patients with T2DM, pioglitazone and exenatide therapy is associated with a greater reduction in hepatic fat content as compared to the addition of pioglitazone therapy (Δ = 61% vs. 41%, P < 0.05).

Topics: Adiponectin; Adipose Tissue; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Fasting; Fatty Acids, Nonesterified; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liver; Magnetic Resonance Spectroscopy; Metformin; Middle Aged; Obesity; Peptides; Pioglitazone; PPAR gamma; Receptors, Glucagon; Thiazolidinediones; Triglycerides; Venoms

We previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure.. Sixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI).. At 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ± 0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (-7.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and -0.99 ± 0.65, respectively; P = 0.028).. EXE and GLAR sustained HbA(1c) over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin-Secreting Cells; Insulin, Long-Acting; Male; Metformin; Middle Aged; Peptides; Venoms

Systemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients, suggesting FGF21 resistance. We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity (DIO).. Type 2 diabetes mellitus patients (n = 24) on diet and/or metformin were randomised (using a table of random numbers) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone (45 mg/day) and exenatide (10 μg twice daily) for 12 months in an open label parallel study at the Baylor Clinic.. Twenty-one patients completed the entire study and were included in the analysis. Pioglitazone treatment (n = 10) reduced hepatic fat as assessed by magnetic resonance spectroscopy, despite a significant increase in body weight (Δ = 3.7 kg); plasma FGF21 levels did not change (1.9  ±  0.6 to 2.2  ±  0.6 ng/ml [mean ± SEM]). However, combined pioglitazone and exenatide therapy (n = 11) was associated with a significant reduction of FGF21 levels (2.3  ±  0.5 to 1.1  ±  0.3 ng/ml) and a greater decrease in hepatic fat. Besides weight gain observed in the pioglitazone-treated patients, lower extremity oedema was observed as a side effect in two of the ten patients. Three patients who received pioglitazone and exenatide combination therapy complained of significant nausea that was self-limiting and did not require them to leave the study. In DIO mice, exendin-4 for 4 weeks significantly reduced hepatic triacylglycerol content, decreased hepatic FGF21 protein and mRNA, and enhanced phosphorylation of hepatic AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, although no significant difference in weight and body fat was observed. Hepatic FGF21 correlated inversely with hepatic AMPK phosphorylation. In type 2 diabetes mellitus, combined pioglitazone and exenatide therapy is associated with a reduction in plasma FGF21 levels, as well as a greater decrease in hepatic fat than that achieved with pioglitazone therapy. In DIO mice, exendin-4 treatment reduces hepatic triacylglycerol and FGF21 protein, and enhances hepatic AMPK phosphorylation, suggesting an improvement of hepatic FGF21 resistance.. ClinicalTrials.gov NCT 01432405.

Topics: Adult; Aged; Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Edema; Exenatide; Fatty Liver; Female; Fibroblast Growth Factors; Humans; Hypoglycemic Agents; Liver; Lower Extremity; Male; Metformin; Mice; Middle Aged; Nausea; Non-alcoholic Fatty Liver Disease; Obesity; Peptides; Pioglitazone; Thiazolidinediones; Venoms

Cardiovascular effects of glucose-lowering agents are of increasing interest. Our aim was to assess the effects of the glucagon-like peptide-1 receptor agonist exenatide on heart rate (HR) and blood pressure (BP) in subjects with type 2 diabetes mellitus (T2DM).. In this double-blind, placebo-controlled trial, subjects with T2DM on metformin and/or a thiazolidinedione were randomized to receive exenatide (5 microg for 4 weeks followed by 10 microg) or placebo BID for 12 weeks. Heart rate and BP were assessed with 24-hour ambulatory BP monitoring. The primary measure was change from baseline in mean 24-hour HR.. Fifty-four subjects (28 exenatide, 26 placebo) were randomized and comprised the intent-to-treat population. Baseline values (exenatide and placebo) were (mean +/- SE) 74.4 +/- 2.1 and 74.5 +/- 1.9 beats/minute for HR, 126.4 +/- 3.2 and 119.9 +/- 2.8 mm Hg for systolic BP (SBP), and 75.2 +/- 2.1 and 70.5 +/- 2.0 mm Hg for diastolic BP (DBP). At 12 weeks, no significant change from baseline in 24-hour HR was observed with exenatide or placebo (LS mean +/- SE, 2.1 +/- 1.4 versus -0.7 +/- 1.4 beats/minute, respectively; between treatments, p = 0.16). Exenatide therapy was associated with trends toward lower 24-hour, daytime, and nighttime SBP; changes in DBP were similar between groups. No changes in daytime or nighttime rate pressure product were observed. With exenatide, body weight decreased from baseline by -1.8 +/- 0.4 kg (p < 0.0001; treatment difference -1.5 +/- 0.6 kg, p < 0.05). The most frequently reported adverse event with exenatide was mild to moderate nausea.. Exenatide demonstrated no clinically meaningful effects on HR over 12 weeks of treatment in subjects with T2DM. The observed trends toward lower SBP with exenatide warrant future investigation.. NCT00516074.

Topics: Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Glycated Hemoglobin; Heart Rate; Humans; Hypoglycemic Agents; Monitoring, Ambulatory; Peptides; Pilot Projects; Placebos; Venoms

Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes.. One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months.. Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide.. Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Peptides; Proinsulin; Resistin; Retinol-Binding Proteins, Plasma; Venoms; Young Adult

To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).. Obese subjects (n = 152; age 46 +/- 12 years, female 82%, weight 108.6 +/- 23.0 kg, BMI 39.6 +/- 7.0 kg/m(2), IGT or IFG 25%) were randomized to receive exenatide (n = 73) or placebo (n = 79), along with lifestyle intervention, for 24 weeks. RESULTS Exenatide-treated subjects lost 5.1 +/- 0.5 kg from baseline versus 1.6 +/- 0.5 kg with placebo (exenatide--placebo, P < 0.001). Placebo-subtracted difference in percent weight reduction was -3.3 +/- 0.5% (P < 0.001). Both groups reduced their daily calorie intake (exenatide, -449 cal; placebo, -387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively.. Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Topics: Adult; Blood Glucose; Body Weight; Exenatide; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Male; Middle Aged; Motor Activity; Obesity; Peptides; Prediabetic State; Venoms

To determine the effect of a lifestyle modification program plus exenatide versus lifestyle modification program plus placebo on weight loss in overweight or obese participants with type 2 diabetes treated with metformin and/or sulfonylurea.. In this 24-week, multicenter, randomized, double-blind, placebo-controlled study, 194 patients participated in a lifestyle modification program, consisting of goals of 600 kcal/day deficit and physical activity of at least 2.5 hours/week. Participants were randomized to 5 microg exenatide twice daily injection + lifestyle modification program (n = 96) or placebo + lifestyle modification program (n = 98), and after 4 weeks increased their exenatide dose to 10 microg twice daily or volume equivalent of placebo.. Baseline characteristics: (mean +/- standard deviation) age, 54.8 +/- 9.5 years; weight, 95.5 +/- 16.0 kg; hemoglobin A(1c), 7.6 +/- 0.8%. At 24 weeks (least squares mean +/- standard error), treatments showed similar decreases in caloric intake (-378 +/- 58 vs -295 +/- 58 kcal/day, exenatide + lifestyle modification program vs placebo + lifestyle modification program, P = .27) and increases in exercise-derived energy expenditure. Exenatide + lifestyle modification program showed greater change in weight (-6.16 +/- 0.54 kg vs -3.97 +/- 0.52 kg, P = .003), hemoglobin A(1c) (-1.21 +/- 0.09% vs -0.73 +/- 0.09%, P <.0001), systolic (-9.44 +/- 1.40 vs -1.97 +/- 1.40 mm Hg, P <.001) and diastolic blood pressure (-2.22 +/- 1.00 vs 0.47 +/- 0.99 mm Hg, P = .04). Nausea was reported more for exenatide + lifestyle modification program than placebo + lifestyle modification program (44.8% vs 19.4%, respectively, P <.001), with no difference in withdrawal rates due to adverse events (4.2% vs 5.1%, respectively, P = 1.0) or rates of hypoglycemia.. When combined with lifestyle modification, exenatide treatment led to significant weight loss, improved glycemic control, and decreased blood pressure compared with lifestyle modification alone in overweight or obese participants with type 2 diabetes on metformin and/or sulfonylurea treatment.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Life Style; Male; Middle Aged; Peptides; Venoms

To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers.. Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured.. Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight.. Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.

Topics: Absorptiometry, Photon; Adiponectin; Body Composition; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Endothelin-1; Exenatide; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Peptides; Risk Factors; Venoms; Waist Circumference

Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A(1c) (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of > or = 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.. Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 mug exenatide, or 10 mug exenatide for 30 weeks, followed by 5 mug exenatide BID for 4 weeks, then 10 mug exenatide BID for > or = 3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.. 217 patients (64% male, age 58 +/- 10 years, weight 99 +/- 18 kg, BMI 34 +/- 5 kg/m(2), A1C 8.2 +/- 1.0% [mean +/- SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (-1.1 +/- 0.1% [mean +/- SEM]) were sustained to 3 years (-1.0 +/- 0.1%; p < 0.0001), with 46% achieving A1C < or = 7%. Exenatide progressively reduced body weight from baseline (-5.3 +/- 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (-10.4 +/- 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (-6.1 +/- 0.6 kg vs. -4.4 +/- 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = -0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.. Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.

Topics: Aged; Biomarkers, Pharmacological; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liver; Male; Middle Aged; Obesity; Peptides; Placebos; Risk Factors; Time Factors; Venoms

Insulin resistance and obesity are common features of the polycystic ovary syndrome (PCOS). Weight loss and use of insulin-lowering drugs have been shown to improve both reproductive and metabolic aspects of PCOS.. We evaluated exenatide (EX) and metformin (MET), alone and in combination (COM), on menstrual cyclicity, hormonal parameters, metabolic profiles, and inflammatory markers in overweight, insulin-resistant women with PCOS.. Sixty overweight oligoovulatory women with PCOS (body mass index > 27; 18-40 yr) were randomized to one of three treatment groups: MET [1000 mg twice daily (BID)], EX (10 microg BID), or COM (MET 1000 mg BID, EX 10 microg BID) for 24 wk. The primary outcome was menstrual frequency; secondary outcome measures included changes in ovulation rate, insulin action, anthropometric measures, androgen levels, and inflammatory markers.. Forty-two (70%) patients completed the study. COM therapy was superior to EX or MET monotherapy in improving menstrual cyclicity, ovulation rate, free androgen index, and insulin sensitivity measures and reducing weight and abdominal fat. Both EX arms were more effective in promoting weight loss than MET (P = 0.003).. COM appears better than either EX or MET alone on menstrual cycle frequency and hormonal and metabolic derangements. A marked decrease in central adiposity could partly explain the improvements in reproductive function, insulin-glucose parameters, and adiponectin observed in these overweight women with PCOS treated with COM therapy. Larger trials of longer duration are warranted to assess the long-term efficacy and safety of combined EX-MET therapy in overweight women with PCOS.

Topics: Adiponectin; Adult; Body Weight; Drug Therapy, Combination; Exenatide; Female; Humans; Lipids; Menstruation; Metformin; Overweight; Peptides; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Venoms

In patients with type 2 diabetes, exenatide reduces A1C, postprandial and fasting glucose, and weight. In this study we investigated the effects of continuous exenatide administration from a long-acting release (LAR) formulation.. In this randomized, placebo-controlled phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for 15 weeks to subjects with type 2 diabetes (n = 45) suboptimally controlled with metformin (60%) and/or diet and exercise (40%): 40% female, A1C (mean +/- SD) 8.5 +/- 1.2%, fasting plasma glucose 9.9 +/- 2.3 mmol/l, weight 106 +/- 20 kg, and diabetes duration 5 +/- 4 years.. From baseline to week 15, exenatide LAR reduced mean +/- SE A1C by -1.4 +/- 0.3% (0.8 mg) and -1.7 +/- 0.3% (2.0 mg), compared with +0.4 +/- 0.3% with placebo LAR (P < 0.0001 for both). A1C of < or =7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by -2.4 +/- 0.9 mmol/l (0.8 mg) and -2.2 +/- 0.5 mmol/l (2.0 mg) compared with +1.0 +/- 0.7 mmol/l with placebo LAR (P < 0.001 for both). Exenatide LAR reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had body weight reductions (-3.8 +/- 1.4 kg) (P < 0.05), whereas body weight was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event. No subjects treated with exenatide LAR withdrew from the study.. Exenatide LAR offers the potential of 24-h glycemic control and weight reduction with a novel once-weekly treatment for type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Exenatide; Humans; Hypoglycemic Agents; Middle Aged; Peptides; Venoms; Weight Loss

This study was conducted to compare the efficacy and safety profiles of exenatide and insulin glargine therapy in patients with type 2 diabetes who had not achieved glucose control with metformin or sulfonylurea monotherapy.. This multinational, randomized, open-label, crossover noninferiority study compared the efficacy of exenatide 10 pg BID and insulin glargine QD (titrated targeting a fasting serum glucose (FSG) level < or =5.6 mmol/L) in patients with type 2 diabetes treated with a single oral antidiabetic agent. The study included two 16-week treatment periods. The primary a priori outcome variable was the change in glycosylated hemoglobin (HbA(lc)). Secondary outcomes included the proportion of patients achieving the American Diabetes Association (ADA) target HbA(lc) of < or =7% and the European Association for the Study of Diabetes target of < or =6.5%, the change in FSG, end-point values and change in the 7-point self-monitored glucose profile, and change in body weight. Adverse events were assessed based on standard laboratory tests and patient reports.. One hundred thirty-eight patients were randomized to study treatment (52.9% female, 47.1% male; 79.7% white; mean [SEM] age, 54.9 [0.8] years; duration of diabetes, 7.4 [0.4] years; body mass index, 31.1 [0.4] kg/m(2); weight, 84.8 [1.4] kg) while continuing to receive metformin (55.1%) or a sulfonylurea (44.9%). The population had a baseline least squares (LS) mean (SEM) HbA(lc) of 8.95% (0.09%) and an LS mean FSG concentration of 12.0 (0.3) mmol/L. Both exenatide and titrated insulin glargine therapy were associated with similar significant changes from baseline in HbA(1c) (both, -1.36% [0.09%]; P < 0.001); the difference between groups was not statistically significant. The LS mean HbA(1c) at end point was above the ADA target with both treatments (exenatide, 7.57% [0.09%]; insulin glargine, 7.58% [0.09%]). Similar proportions of patients achieved an HbA(1c) < or =7% (37.5% and 39.8%, respectively; P = NS) or < or =6.5% (21.5% and 13.6%). Patients lost weight during exenatide treatment, whereas they gained weight during insulin glargine treatment; the between-group difference in weight change was statistically significant (LS mean difference, -2.2 [0.3] kg; 95% CI, -2.8 to-1.7; P < 0.001). Both exenatide and insulin glargine were associated with significant reductions from baseline in FSG (-2.9 [0.2] and -4.1 [0.2] mmol/L, respectively; both, P < 0.001), although the reduction was significantly greater with insulin glargine compared with exenatide (LS mean difference, 1.2 [0.3] mmol/L; 95% CI, 0.7 to 1.7; P < 0.001). Compared with insulin glargine, exenatide was associated with significantly lower 2-hour postprandial glucose (PPG) excursions (P < 0.016) and total daily mean glucose excursion (P < 0.001). The proportions of patients reporting nausea during exenatide and insulin glargine treatment were 42.6% and 3.1%, respectively; the proportions reporting vomiting were 9.6% and 3.1%. The incidence of hypoglycemia in the 2 groups was 14.7% and 25.2% (P = NS).. In this open-label, crossover study, treatment with exenatide or insulin glargine for 16 weeks was associated with similar significant improvements from baseline in HbA(1c), independent of treatment order. The improvements in HbA(1c) from baseline did not differ significantly between treatment groups. Exenatide therapy was associated with significant reductions in body weight and PPG excursions compared with insulin glargine, whereas insulin glargine was associated with a significantly greater reduction in FSG compared with exenatide. These findings provide additional information to guide treatment decisions in patients with type 2 diabetes who are potential candidates for either therapy.

Topics: Adult; Blood Glucose; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Resistance; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Metformin; Peptides; Sulfonylurea Compounds; Venoms

Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET).. This interim analysis is of 314 patients who received exenatide in the 30-week placebo-controlled trials and subsequently in 52 weeks of open-label uncontrolled extension studies for 82 weeks of exenatide in total. Patients continued their SU and/or MET regimens throughout.. Patients completed 82 weeks of exenatide treatment [n = 314, 63% M, age 56 +/- 10 years, weight 99 +/- 21 kg, body mass index 34 +/- 6 kg/m2, A1C 8.3 +/- 1.0% (mean +/- SD)]. Reduction in A1C from baseline to week 30 [-0.9 +/- 0.1% (mean +/- SE)] was sustained to week 82 (-1.1 +/- 0.1%), with 48% of patients achieving A1C < or = 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (-2.1 +/- 0.2 kg), with progressive reduction at week 82 (-4.4 +/- 0.3 kg). Similar results were observed for the intent-to-treat population (n = 551), with reductions in A1C and weight at week 82 of -0.8 +/- 0.1% and -3.5 +/- 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia.. In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Overweight; Peptides; Risk Factors; Sulfonylurea Compounds; Venoms; Weight Loss

This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metformin-sulfonylurea combination therapy.. A 30-week, double-blind, placebo-controlled study was performed in 733 subjects (aged 55 +/- 10 years, BMI 33.6 +/- 5.7 kg/m(2), A1C 8.5 +/- 1.0%; means +/- SD) randomized to 5 microg subcutaneous exenatide b.i.d. (arms A and B) or placebo for 4 weeks. Thereafter, arm A remained at 5 microg b.i.d. and arm B escalated to 10 microg b.i.d. Subjects continued taking their dose of metformin and were randomized to either maximally effective (MAX) or minimum recommended (MIN) doses of sulfonylurea.. Week 30 A1C changes from baseline (+/-SE) were -0.8 +/- 0.1% (10 microg), -0.6 +/- 0.1% (5 microg), and +0.2 +/- 0.1% (placebo; adjusted P < 0.0001 vs. placebo), yielding placebo-adjusted reductions of -1.0% (10 microg) and -0.8% (5 microg). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C < or =7% than placebo-treated subjects (34% [10 microg], 27% [5 microg], and 9% [placebo]; P < 0.0001). Both exenatide arms demonstrated significant weight loss (-1.6 +/- 0.2 kg from baseline each exenatide arm, -0.9 +/- 0.2 kg placebo; P < or = 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 microg), 19% (5 microg), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment.. Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.

Topics: Adult; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Venoms

This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses.. A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m(2) and HbA(1c) of 8.2 +/- 1.1%. After 4 weeks of placebo, subjects self-administered 5 microg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 microg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.. At week 30, HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg), -0.40 +/- 0.11% (5 microg), and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 microg), 32% (5 microg), and 13% (placebo) achieved HbA(1c) < or =7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg], -1.6 +/- 0.4 kg [5 microg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia.. Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

Topics: Adult; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Peptides; Proinsulin; Venoms

Exenatide is the first of a new class of agents known as incretin mimetics that are in development for the treatment of type 2 diabetes. Exenatide has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes, as well as provide sustained reductions in hemoglobin A 1c (HbA 1c). This study was designed to assess the dose dependencies of the glucoregulatory effects and tolerability of exenatide when added to diet and exercise or metformin monotherapy in patients with type 2 diabetes.. In this randomized, triple-blinded, placebo-controlled Phase 2 clinical trial, 156 patients were randomized to placebo or exenatide at 2.5, 5.0, 7.5, or 10.0 microg administered b.i.d. for 28 days.. After 28 days of therapy, exenatide was associated with significant (P < 0.0001, linear contrast testing), dose-dependent reductions in HbA 1c (0.1 +/- 0.1%, -0.3 +/- 0.1%, -0.4 +/- 0.1%, +/-0.5 +/- 0.0%, and -0.5 +/- 0.1% for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) and significant (P = 0.0006, linear contrast testing) reductions in fasting plasma glucose (+6.8 +/- 4.1, -20.1 +/- 5.2, -21.2 +/- 3.9, -17.7 +/- 4.8, and -17.3 +/- 4.4 mg/dL for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) by Day 28. These reductions were similar for patients treated with diet/exercise and those treated with metformin. In addition, patients receiving exenatide exhibited dose-dependent reductions in body weight (0.0 +/- 0.3, -0.7 +/- 0.3, -0.7 +/- 0.2, -1.4 +/- 0.3, and -1.8 +/- 0.3 kg for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively; P < 0.01 for 7.5 and 10.0 microg b.i.d. exenatide doses compared with placebo) at Day 28. The most common adverse event was mild-to-moderate nausea that was dose-dependent (seven of 123 patients randomized to exenatide withdrew from the study because of gastrointestinal effects).. Exenatide dose-dependently improved glycemic control and reduced body weight over 28 days in patients with type 2 diabetes treated with diet/exercise or metformin.

Topics: Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Peptides; Placebos; Racial Groups; Research Design; Venoms; Weight Loss

Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs.. To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea.. 26-week multicenter, open-label, randomized, controlled trial.. 82 outpatient study centers in 13 countries.. 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy.. Exenatide, 10 microg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL).. Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability.. Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [CI, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/patient-year; difference, -1.6 events/patient-year [CI, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%).. The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL).. Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Nausea; Peptides; Venoms; Vomiting

This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy.. This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy.. At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA(1c) > 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c)

Topics: Adult; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Exenatide; Fasting; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Peptides; Proinsulin; Retreatment; Sulfonylurea Compounds; Treatment Failure; Venoms; Weight Loss

AC2993 (synthetic exendin-4; exenatide) is a peptide that enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. AC2993 also promotes beta-cell proliferation and neogenesis in vitro and in animal models. This study examines the activity and safety of subcutaneously injected AC2993 in patients with type 2 diabetes currently treated with diet and/or oral antidiabetic agents (OAAs).. A total of 109 patients treated with diet and a sulfonylurea and/or metformin were enrolled in a blinded study. Patients were randomly assigned to one of three subcutaneously (SC) injected regimens of AC2993 (0.08 micro g/kg) or placebo for 28 days.. All three AC2993 regimens led to significant reductions in serum fructosamine relative to placebo (P

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Fructosamine; Glycated Hemoglobin; Heart Rate; Humans; Hypoglycemic Agents; Islets of Langerhans; Lipids; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Treatment Outcome; Venoms

Glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in patients with type 2 diabetes and obesity leads to a significant reduction in serum thyrotropin (TSH) levels but it is unclear whether this is related to weight loss and improvement in sensitivity to thyroid hormones (TH).. We prospectively analysed clinical and biochemical data in patients with type 2 diabetes and obesity who were commenced on the GLP-1 RA exenatide and followed them for 12 months. We assessed the relationship between changes in body weight and serum TSH and resistance to TH indices.. Exenatide therapy reduces serum TSH levels and improves central sensitivity to TH action over 12 months via its effect on weight loss. The effectiveness of weight loss strategies, rather than TH replacement, should be investigated in individuals with obesity and mildly raised serum TSH levels.

Topics: Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Middle Aged; Obesity; Thyroid Hormones; Thyrotropin; Weight Loss

The modern food environment facilitates excessive calorie intake, a major driver of obesity. Glucagon-like peptide 1 (GLP1) is a neuroendocrine peptide that has been the basis for developing new pharmacotherapies against obesity. The GLP1 receptor (GLP1R) is expressed in central and peripheral tissues, and activation of GLP1R reduces food intake, increases the expression of thermogenic proteins in brown adipose tissue (BAT), and enhances lipolysis in white adipose tissue (WAT). Obesity decreases the efficiency of GLP1R agonists in reducing food intake and body weight. Still, whether palatable food intake before or during the early development of obesity reduces the effects of GLP1R agonists on food intake and adipose tissue metabolism remains undetermined. Further, whether GLP1R expressed in WAT contributes to these effects is unclear.. Food intake, expression of thermogenic BAT proteins, and WAT lipolysis were measured after central or peripheral administration of Exendin-4 (EX4), a GLP1R agonist, to mice under intermittent-short exposure to CAF diet (3 h/d for 8 days) or a longer-continuous exposure to CAF diet (24 h/d for 15 days).. During intermittent-short exposure to CAF diet (3 h/d for 8 days), third ventricle injection (ICV) and intra-peritoneal administration of EX4 reduced palatable food intake. Yet, during a longer-continuous exposure to CAF diet (24 h/d for 15 days), only ICV EX4 administration reduced food intake and body weight. However, this exposure to CAF diet blocked the increase in uncoupling protein 1 (UCP1) caused by ICV EX4 administration in mice fed control diet. Finally, GLP1R expression in WAT was minimal, and EX4 failed to increase lipolysis. Exposure to a CAF diet during the early stages of obesity reduces the effects of peripheral and central GLP1R agonists, and WAT does not express a functional GLP1 receptor. These data support that exposure to the obesogenic food environment, without the development or manifestation of obesity, can alter the response to GLP1R agonists. .

Topics: Adipose Tissue, White; Animals; Body Weight; Diet; Eating; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Lipolysis; Mice; Obesity

Exenatide could reduce blood glucose and alleviate cognitive dysfunction induced by diabetes mellitus (DM). In the present study, a diabetic model was established in Sprague‑Dawley rats to further explore the mechanism of exenatide on diabetes‑induced cognitive impairment. Notably, the model rats performed poorly in the Morris water maze test and had more apoptotic neurons compared with the control rats. By contrast, exenatide attenuated cognitive impairment and inhibited neuronal apoptosis in the DM rat model. To explore the neuroprotective mechanisms of exenatide, western blotting was performed to detect the expression levels of markers of endoplasmic reticulum stress, including cytochrome c (Cyt‑c), Caspase‑3, JNK and c‑JUN, in hippocampal tissue. Reverse transcription‑quantitative PCR was also performed to measure the mRNA expression levels of Cyt‑c and Caspase‑3. After 16 weeks of treatment, exenatide treatment downregulated Cyt‑c, Caspase‑3, phosphorylated (p)‑JNK and p‑c‑JUN expression in the hippocampal tissue of diabetic rats. Moreover, Cyt‑c, Caspase‑3, JNK and JUN expression levels were detected following treatment with a specific inhibitor of JNK (SP600125). The results revealed that SP600125 had similar inhibitory effects on the JNK pathway and ERS‑related protein expression (Cyt‑t, Caspase‑3, p‑JNK and p‑c‑JUN). These results suggested that exenatide improved cognitive dysfunction in DM rats and that the underlying mechanism may be associated with inhibiting apoptosis by suppressing the activation of JNK/c‑JUN.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Caspase 3; Cognitive Dysfunction; Cytochromes c; Diabetes Mellitus, Experimental; Exenatide; Genes, jun; Hippocampus; Insulin; Learning; Male; MAP Kinase Signaling System; Memory; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley

To explore the efficacy and underlying mechanisms of metformin and exenatide in reversing reproductive and metabolic disturbances in letrozole combined with high-fat diet-induced polycystic ovary syndrome (PCOS) rats.. Rats with PCOS and insulin resistance (IR) were induced by intra-gastric instillation of letrozole combined with a high-fat diet and verified by histological screening of vaginal exfoliated cells. After metformin and exenatide supplementation, body weight, chow intake and ovarian morphology were observed. Serum biochemical profiles were analyzed using ELISA, while the levels of key anabolism-related proteins, including sex hormone binding globulin (SHBG), hepatocyte nuclear factor-4α (HNF-4α), PI3K, and AKT, were determined using western blotting.. The estrus cycle and ovarian morphology of rats with PCOS and IR were significantly recovered following metformin and exenatide treatment, with decreased body weight and chow intake. Furthermore, PCOS-induced changes in metabolic disorders including IR and hepatic triglyceride (TG) deposition, and hyperandrogenemia were reversed by treatment with both drugs. Specifically, the levels of HNF-4α and SHBG in liver tissue of rats with PCOS and IR were upregulated significantly.. Both metformin and exenatide could recover the estrous cycle and ovarian morphology, reduce body weight and high-fat chow intake, and improve glycolipid metabolism disorders and hyperandrogenemia in PCOS with IR rat models. Interestingly, our findings also highlight the potential of both therapeutic agents for improving IR by regulating the liver PI3K/AKT pathway, reducing the deposition of hepatic TG, as well as upregulating the levels of SHBG and HNF-4α in PCOS with IR rat liver tissue.

Topics: Animals; Body Weight; Estrous Cycle; Exenatide; Female; Glucose Tolerance Test; Hepatocyte Nuclear Factor 4; Insulin Resistance; Liver; Metformin; Phosphatidylinositol 3-Kinases; Polycystic Ovary Syndrome; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sex Hormone-Binding Globulin; Triglycerides; Up-Regulation

It is well known that GLP-1 activates GLP-1R to reduce body weight by inhibiting eating. GLP-1 is cleaved by the neutral endopeptidase (NEP) 24.11 into a pentapeptide GLP-1 (32-36) amide, which increases basal energy expenditure and inhibits weight gain in obese mice. It is well known that GLP-1 analogs can reduce weight by suppressing eating. However, there are few reports of reducing weight through the dual effects of inhibiting eating and increasing basic energy. Here, we report the peptide EGLP-1, a GLP-1 analogue, which can reduce food intake and increase basal energy expenditure. In C2C12 myotubes, EGLP-1 can increase both phosphorylation of acetyl CoA carboxylase (ACC) and the ratio between phosphorylation of ACC and the total expression of ACC (pACC/ACC). In diet-induced obese mice, EGLP-1 is more effective than exendin-4 in reducing body weight, reducing fat mass and improving hepatic steatosis. At the same time, EGLP-1 can improve hyperglycemia, reduce food intake, and improve insulin resistance, just like exendin-4. In addition, EGLP-1, not exendin-4, can improve physiological parameters associated with lipid metabolism and increase oxygen consumption by increasing uncoupling proteins 3 (UCP3) expression and pACC/ACC ratio in skeletal muscle. Taken together, this data showed that EGLP-1 is able to reduce body weight by reducing food intake and increasing basal energy expenditure, suggesting it may be more effective in treating diabetic and non-diabetic overweight or obese people than pure GLP-1R agonist exendin-4.

Topics: Animals; Anti-Obesity Agents; Body Weight; Cells, Cultured; Diet, High-Fat; Eating; Energy Metabolism; Exenatide; Glucagon-Like Peptide 1; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide Fragments

Saturated free fatty acid (FFA)-induced lipotoxicity plays an important role in obesity-induced kidney injury. Exenatide, a Glucagon-like peptide-1 receptor agonist(GLP-1RA), protects against high-fat diet (HFD)-induced kidney injury. The precise mechanism needs to be further explored. This study investigated whether exenatide protects against FFA-induced tubular epithelial cells (TECs) lipotoxicity and elucidated its underlying mechanisms. Here, we show that exenatide treatment reversed HFD induced TECs injuries, including TECs apoptosis and SIRT1 downregulation. The efficacy of exenatide was better than simvastatin. In palmitate (PA)-stimulated HK2 cells, exenatide treatment reversed the downregulation of SIRT1 and prevented an increase in reactive oxygen species (ROS) production, a decrease in mitochondrial membrane potential, and mitochondrial apoptosis. The renal-protective effects of exenatide on the generation of mitochondrial ROS and mitochondrial apoptosis were blocked by inhibiting SIRT1 activation. Collectively, these findings show that exenatide was superior to simvastatin in the treatment of obesity-TECs injuries, the mechanism is partially through SIRT1 restoration, which directly reverses mitochondrial dysfunction and apoptosis.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cell Line; Diet, High-Fat; Down-Regulation; Exenatide; Humans; Hypoglycemic Agents; In Vitro Techniques; Kidney Tubules; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Obesity; Palmitates; Reactive Oxygen Species; Simvastatin; Sirtuin 1

Ectopic lipid deposition is closely associated with type 2 diabetes (T2D). Accumulating evidence shows that GLP-1 receptor agonists (GLP-1 RAs) improve obesity and liver steatosis. However, it remains unknown whether and how they ameliorate lipid deposition in skeletal muscle. This study aimed to investigate the effect of exenatide (a GLP-1 RA) on intramyocellular lipid deposition in the skeletal muscle of T2D models and its dependence on weight loss.. Ob/ob mice and diet-induced obese (DIO) mice were treated with exenatide (24 nmol/kg), leptin (1 mg/kg), or saline control intraperitoneally once daily for 4 weeks. Phenotypic evaluations were performed during and after the intervention. PA-induced myoblast C2C12 cells were used as an in vitro model. The expression of key enzymes involved in lipid metabolism was assessed in the skeletal muscle of ob/ob mice and DIO mice.. In ob/ob mice, 4-week exenatide treatment did not improve the body weight and fat mass, but modestly ameliorated intramyocellular lipid deposition and lipid profiles. In DIO mice, it remarkably alleviated the body weight, lipid profiles, and intramyocellular lipid deposition. In the skeletal muscle of these two models, exenatide treatment activated the AMP-activated protein kinase (AMPK) signaling pathway, stimulated lipid oxidation enzymes, and upregulated the insulin signaling pathway. In vitro, exendin-4 activated the AMPK signaling pathway and stimulated lipid metabolism to improve lipid accumulation in palmitate-induced myoblast C2C12 cells.. Exenatide ameliorated intramyocellular lipid deposition without body weight reduction in ob/ob mice, but alleviated body weight and intramyocellular lipid deposition in DIO mice. The underlying mechanism included the activation of AMPK signaling pathway and improvement in insulin sensitivity, independent of weight loss in ob/ob mice.

Topics: AMP-Activated Protein Kinases; Animals; Body Weight; Cells, Cultured; Exenatide; Glucagon-Like Peptide-1 Receptor; Lipid Metabolism; Male; Mice; Mice, Obese; Signal Transduction; Weight Loss

High glucose affects the function of endothelial cells by increasing oxidative stress. Studies have found that exendin-4 can improve wound healing in diabetic mice and mice with normal blood glucose. However, the mechanism of exendin-4 in endothelial progenitor cells under high-glucose condition has not been fully elucidated.. Diabetic mouse models were established to investigate the effects of exendin-4 on endothelial progenitor cells in diabetic mice. Serum superoxide dismutase (SOD) and malondialdehyde (MDA) were determined by WST-8 and thiobarbituric acid (TBA) colorimetry, respectively. Cell viability, apoptosis and reactive oxygen species (ROS) were detected by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry. Gene and protein expressions were determined by Quantitative reverse transcription PCR (qRT-PCR) assay and Western blot (WB).. The results showed that in diabetic mice, exendin-4 did not affect blood glucose or body weight, moreover, it improved aortic diastolic function, increased SOD activity and down-regulated malondialdehyde (MDA) level in the mice. In addition, exendin-4 also increased endothelial progenitor cell (EPCs) viability and reduced cell apoptosis through inhibiting p38 MAPK pathway and reducing endoplasmic reticulum stress and ROS.. Exndin-4 can alleviate diabetes-caused damage to mice, moreover, it reduced endoplasmic reticulum stress and ROS through inhibiting p38 MAPK pathway in MPCs cells under high-glucose condition, thus increasing cell viability and reducing cell apoptosis.

Topics: Animals; Apoptosis; Body Weight; Cell Survival; Cells, Cultured; Diabetes Mellitus, Experimental; Endoplasmic Reticulum Stress; Endothelial Progenitor Cells; Exenatide; Glucose; Male; Malondialdehyde; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Reactive Oxygen Species; Superoxide Dismutase

Once-weekly semaglutide 1 mg is a novel glucagon-like peptide 1 receptor agonist (GLP-1 RA) that, in the SUSTAIN clinical trials, has demonstrated greater reductions in glycated haemoglobin (HbA1c) and body weight than the other GLP-1 RAs exenatide extended-release (ER) 2 mg, dulaglutide 1.5 mg and liraglutide 1.2 mg. The aim of this analysis was to evaluate the relative cost of control of achieving treatment goals in people with type 2 diabetes (T2D) treated with once-weekly semaglutide versus exenatide ER, dulaglutide and liraglutide from a UK perspective.. Proportions of patients reaching HbA1c targets (< 7.0% and < 7.5%), weight loss targets (≥ 5% reduction in body weight) and composite endpoints (HbA1c < 7.0% without weight gain or hypoglycaemia; reduction in HbA1c of ≥ 1% and weight loss of ≥ 5%) were obtained from the SUSTAIN clinical trials. Annual per patient treatment costs were based on wholesale acquisition costs from July 2019 in the UK. Cost of control was calculated by plotting relative treatment costs against relative efficacy.. The annual per patient cost was similar for all GLP-1 RAs. Once-weekly semaglutide was superior to exenatide ER, dulaglutide and liraglutide in bringing patients to HbA1c and weight loss targets, and to composite endpoints. When looking at the composite endpoint of HbA1c < 7.0% without weight gain or hypoglycaemia, exenatide ER, dulaglutide and liraglutide were 50.0%, 21.6% and 51.3% less efficacious in achieving this, respectively, than once-weekly semaglutide. Consequently, the efficacy-to-cost ratios for once-weekly semaglutide were superior to all comparators in bringing patients to all endpoints.. The present study showed that once-weekly semaglutide offers superior cost of control versus exenatide ER, dulaglutide and liraglutide in terms of achieving clinically relevant, single and composite endpoints. Once-weekly semaglutide 1 mg would therefore represent good value for money in the UK setting.

Topics: Body Weight; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Male; Middle Aged; Recombinant Fusion Proteins; United Kingdom; Weight Gain

The role of exendin-4 in brown adipose tissue (BAT) activation was not very clear. This study is to verify the role of BAT involved in renal benefits of exendin-4 in diabetes mellitus (DM).. In vivo, C57BL/6 mice were randomly divided into nondiabetic (control) and diabetic groups (DM). The diabetic mice were randomized into a control group (DM-Con), BAT-excision group (DM+Exc), exendin-4-treated group (DM+E4), and BAT-excision plus exendin-4-treated group (DM+Exc+E4). The weight, blood glucose and lipids, 24 h urine albumin and 8-OH-dG, and renal fibrosis were analyzed. In vitro, we investigated the role of exendin-4 in the differentiation process of 3T3-L1 and brown preadipocytes and its effect on the rat mesangial cells induced by oleate.. The expressions of UCP-1, PGC-1. Exendin-4 could decrease the renal lipid deposit and improve diabetic nephropathy via activating the renal AMPK pathway independent of BAT activation.

Topics: 3T3-L1 Cells; 8-Hydroxy-2'-Deoxyguanosine; Adenylate Kinase; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Albuminuria; Animals; Blood Glucose; Blotting, Western; Body Weight; CD36 Antigens; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Exenatide; Fibrosis; Gene Expression; Incretins; Kidney; Lipase; Mesangial Cells; Mice; Mice, Inbred C57BL; Myofibroblasts; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Rats; Real-Time Polymerase Chain Reaction; Triglycerides; Uncoupling Protein 1

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease. This study aimed to evaluate the role of exenatide compared with metformin in halting the progression of fatty liver stimulated by a high-fat diet (HiFD) in rats.. Thirty male Wistar rats were allocated into 6 groups, 5 rats per each group. Group I: maintained on normal diet (normal group) for fourteen weeks. The other five groups were kept on HiFD throughout the experiment, HiFD was administered beside pharmacological treatments/or vehicle. Group II: (NAFLD control group), group III: received metformin (60 mg/kg/day, P.O.), group IV-VI: received exenatide (10, 20, and 40 μg/kg/day, S.C.) respectively for 7 weeks. At the end of the therapeutic period, fasting blood glucose was determined, and body weight was registered. Rats were sacrificed, and blood samples were taken to measure serum insulin, lipids, and liver enzymes. The liver index and homeostasis model of insulin resistance (HOMA-IR) index were calculated. Further, livers were dissected for histopathological examination and Western blot analysis.. NAFLD control group showed hyperglycemia, hyperinsulinemia, increased liver enzymes, hypertriglyceridemia, elevated hepatic lipid peroxides, and inflammatory mediators (interlukin 6, nuclear factor-κB, tumor necrosis factor-α and Toll-like receptor4) in addition to hepatic fatty degeneration. In a dose-dependent manner, exenatide significantly improved most of the above mentioned markers in comparsion with NAFLD at P≤0.05.. The current results suggest that exenatide is equivalent to metformin in controlling insulin resistance, body weight gain, improving liver function, suppressing inflammation, and attenuating NAFLD progression in male rats.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Progression; Dose-Response Relationship, Drug; Exenatide; Hypoglycemic Agents; Inflammation; Insulin Resistance; Male; Metformin; NF-kappa B; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Signal Transduction; Toll-Like Receptor 4

Hypothalamic obesity (HO) in children after treatment for a tumor in the suprasellar region has severe implications. Previous studies have shown various effects of glucagon-like peptide-1 (GLP-1) receptor agonist in acquired HO, but in adults only. We present our experience of GLP-1 receptor agonist (exenatide) treatment during a 1-year period on body mass index (BMI) in children with acquired HO.. Children with severe weight gain after treatment for suprasellar tumor were given 2 mg exenatide weekly for a 12-month period. All had undergone previous dietary intervention. BMI standard deviation score (SDS), weight change, and adverse effects were assessed.. Five children with a mean age of 15.4 years (range 13-18) and a mean follow-up time of 8.4 years (mean age of 7.0 years at the time of brain tumor diagnosis) were treated with GLP-1 receptor agonist. After 1 year, BMI SDS or absolute weight had not changed significantly compared to the period without treatment (BMI SDS change +0.005, 95% CI -0.07 to 0.08, p = 0.89, and absolute weight change +1.5 kg, 95% CI -0.08 to 3.1, p = 0.061). Only 1 patient experienced weight loss after 1 year (-5.4 kg, BMI SDS -0.33). All patients experienced mild side effects, such as injection pain or nausea, and 2 patients stopped treatment upon their own request after 8 and 11 months, respectively.. In this small cohort, we found little effect of GLP-1 receptor agonist in the treatment for acquired HO. Future research should focus on the prevention of HO or, if prevention is not possible, on alternative, individualized interventions.

Topics: Adolescent; Body Mass Index; Body Weight; Child; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Hypothalamic Diseases; Obesity; Weight Loss

The hypoglycemic drug GLP-1 receptor agonist can ameliorate hepatic steatosis but the mechanism is not clear. Intake of high fructose leads to non-alcoholic fatty liver disease by stimulating lipid synthesis, and β-catenin is the key molecule for realizing GLP-1 function in extrahepatic tissues; with the discovery of GLP-1 receptor in liver, we speculate that β-catenin might mediate GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose. Wistar rats were fed with high fructose diet for 8 weeks and then treated with GLP-1 receptor agonist exenatide for 4 weeks; the changes of lipid synthesis pathway factors, the expression and nuclear translocation of β-catenin, and the hepatic steatosis of the rats were observed. After the intervention of exenatide, the hepatic steatosis induced by high fructose was improved, the nuclear translocation and expression of β-catenin were facilitated, and the mRNA and protein expression of the upstream regulator SREBP-1 and the downstream key enzymes ACC, FAS and SCD-1 of de novo lipogenesis were down-regulated. GLP-1 receptor agonist may ameliorate hepatic steatosis induced by high fructose by β-catenin regulating de novo lipogenesis pathway. GLP-1 receptor agonist may be a potential new drug for the treatment of non-alcoholic fatty liver disease, and the β-catenin may be an important target for the drug therapy.

Topics: Animals; beta Catenin; Body Weight; Diet; Exenatide; Fatty Liver; Fructose; Glucagon-Like Peptide-1 Receptor; Lipogenesis; Liver; Male; Rats, Wistar

Glucagon-like peptide-1 (GLP-1) has emerged as a major therapeutic target for the treatment of type 2 diabetes. The nonapeptide GLP-1 (28-36) amide is one of the biological C-terminal products of GLP-1 modified by the neutral endopeptidase (NEP) 24.11 with limited hypoglycemic activity. In this study, we focused on the modification of GLP-1 (28-36) amide for the first time and synthesized a series of GLP-1 (28-36) amide analogues. Results of biological activity evaluation in INS-1 cell, STZ-induced diabetic and diet induced obesity (DIO) mice indicated that S3 as a promising candidate to treat type 2 diabetes and obesity.

Topics: Adipocytes, Brown; Animals; Apoptosis; Body Weight; Cell Line, Tumor; Cell Survival; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Obesity; Oligopeptides; Oxidative Stress

Exenatide is known as the first marketed GLP-1 agonist for antidiabetic treatment, but it need twice injection a day because of its fast clearance. This work aims to prolong the half-life of exenatide by modified with novel lipid chain. Four optimized exenatide analogs named as Cys12-Exenatide (1-39)-NH

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Hypoglycemic Agents; Lipids; Male; Mice; Mice, Inbred Strains; Mice, Obese; Molecular Structure; Rats; Rats, Sprague-Dawley; Streptozocin; Structure-Activity Relationship

The present study has examined the antidiabetic effects of 21 days co-administration of xenin-8-Gln with the dual-acting fusion peptide, exendin-4/gastrin, as well as persistence of beneficial metabolic benefits, in high fat fed (HFF) mice. Xenin-8-Gln, exendin-4 and gastrin represent compounds that activate receptors of the gut-derived hormones, xenin, glucagon-like peptide-1 (GLP-1) and gastrin, respectively. Twice-daily administration of exendin-4/gastrin, xenin-8-Gln or a combination of both peptides significantly reduced circulating glucose, HbA1c and cumulative energy intake. Combination therapy with xenin-8-Gln and exendin-4/gastrin increased circulating insulin. All HFF mice treated with exendin-4/gastrin presented with body weight similar to lean control mice on day 21. Each treatment improved glucose tolerance and the glucose-lowering actions of glucose dependent insulinotropic polypeptide (GIP), as well as augmenting glucose- and GIP-induced insulin secretion, with benefits being most prominent in the combination group. Administration of exendin-4/gastrin alone, and in combination with xenin-8-Gln, increased pancreatic insulin content and improved the insulin sensitivity index. Pancreatic beta-cell area was significantly increased, and alpha cell area decreased, by all treatments, with the combination group also displaying enhanced overall islet area. Notably, metabolic benefits were generally retained in all groups of HFF mice, and especially in the combination group, following discontinuation of the treatment regimens for 21 days. This was associated with maintenance of increased islet and beta-cell areas. Together, these data confirm the antidiabetic effects of co-activation of GLP-1, gastrin and xenin cell signalling pathways, and highlight the sustainable benefits this type of treatment paradigm can offer in T2DM.

Topics: Animals; Body Weight; Diet, High-Fat; Drug Interactions; Energy Metabolism; Exenatide; Gastrins; Glucagon; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metabolism; Mice; Pancreas; Peptide Fragments; Time Factors

Abextide, synthesized by conjugating an albumin-binding moiety-truncated Evans blue-to glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4, shows extended drug release and enhanced hypoglycemic effect in diabetic mice. The aim of this study is to evaluate the pharmacodynamics of Abextide in nonhuman primates. Two batches of elderly cynomolgus monkeys with naturally occurring diabetes are used for this study. During the whole experiment period, no abnormalities such as swelling at the injection site, lethargy, or hypoglycemia are observed in all animals. The monkeys in the Abextide group lose appetite after drug administration and then recover over time. In the single dose treatment, at day 1 and day 3 after treatment, decreased plasma glucose level is observed in the Abextide-treated group but not in placebo or Albiglutide-treated group. For monkeys that receive two doses of drug, the blood glucose level in all subjects in Abextide group decreases rapidly upon drug administration and return to a plateau by day 3. A similar pattern of response is seen after the second dose administration. The delayed drug release and hypoglycemic effect of Abextide make it potentially useful as an antidiabetic drug for weekly subcutaneous administration.

Topics: Animals; Body Weight; Cholesterol; Dose-Response Relationship, Drug; Exenatide; Feeding Behavior; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Lipids; Lipoproteins, HDL; Macaca fascicularis; Naphthalenesulfonates; Peptides; Triglycerides

Peptide YY(3-36) ((PYY(3-36)) and glucagon like peptide 1 (GLP-1) in combination reduce food intake and body weight in an additive or synergistic manner in animal models and in humans. Nevertheless, the mechanisms behind are not completely understood. The present study aims to investigate the effect of combining PYY(3-36) and the GLP-1 receptor agonist exendin-4 (Ex4) by examining acute food intake and global neuronal activation as measured by c-fos in C57BL/6 J mice. An additive reduction in food intake was found 1.5 h after s.c dosing with the combination of PYY(3-36) (200 μg/kg) and Ex4 (2.5 μg/kg). This was associated with a synergistic enhancement of c-fos reactivity in central amygdalar nucleus (CeA), rostral part of the mediobasal arcuate nucleus (ARH), supratrigeminal nucleus (SUT), lateral parabrachial nucleus (PB), area postrema (AP) and nucleus tractus solitarius (NTS) compared to vehicle, PYY(3-36) and Ex4 individually dosed mice. The regions activated by Ex4 individually and PYY(3-36) and Ex4 in combination resembled each other, but the combination group had a significantly stronger c-fos response. Twenty-five brain areas were activated by PYY(3-36) and Ex4 in combination compared to vehicle versus nine brain areas by Ex4 individually. No significant increase in c-fos reactivity was found by PYY(3-36) compared to vehicle dosed mice. The neuronal activation of ARH and the AP/NTS to PB to CeA pathway is important for appetite regulation while SUT has not previously been reported in the regulation of energy balance. As PYY(3-36) and Ex4 act on different neurons leading to recruitment of different signalling pathways within and to the brain, an interaction of these pathways may contribute to their additive/synergistic action. Thus, PYY(3-36) boosts the effect of Ex4 possibly by inducing less inhibition of neuronal activity leading to an enhanced neuronal activity induced by Ex4.

Topics: Amygdala; Animals; Body Weight; Eating; Exenatide; Hypothalamus; Mice; Neurons; Peptide Fragments; Peptide YY; Proto-Oncogene Proteins c-fos

Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats. Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 µg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA. The four-week exenatide (5 µg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P < 0.001) and decreased the level of circulating oxLDL (-42%, P < 0.05) and MCP-1 (-23%, P < 0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P < 0.001) and apoB/apoA-I ratio (-75%, P < 0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction. Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Biomarkers; Body Weight; Eating; Exenatide; Fructose; Male; Oxidative Stress; Rats; Rats, Wistar; Sitagliptin Phosphate

The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 suppresses food intake and decreases body weight. However, the mediating site(s) of action of the anorectic effects induced by peripheral administration of GLP-1R agonists are not well known. The present study investigated the effects of bilateral lesions of the central nucleus of the amygdala (CeA) on the suppression of chow and high-sucrose food intake by exendin-4 in rats. Adult male Sprague-Dawley rats with bilateral sham or electrolytic lesions (400 μA; 25 s) of the CeA were used for this experiment. No significant difference was found in the daily chow intake and high-sucrose food intake in rats with CeA lesion compared to sham-operated rats. Bilateral lesions of the CeA significantly attenuated the suppression of high-sucrose food intake by i.p. exendin-4, but not the suppression of chow intake. These results suggest that a mediating role of the CeA on the peripheral effects of exendin-4.

Topics: Amygdala; Animals; Appetite Regulation; Body Weight; Central Amygdaloid Nucleus; Eating; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Male; Peptides; Rats; Rats, Sprague-Dawley

The SUSTAIN 3 and 7 clinical trials compared the efficacy and safety of once-weekly semaglutide relative to exenatide extended-release (ER) and dulaglutide, respectively, in the treatment of patients with type 2 diabetes (T2D). The trials included a series of clinically relevant single and composite endpoints focused on improving glycemic control and reducing body weight, while avoiding hypoglycemia. The present study combined SUSTAIN 3 and 7 outcomes with short-term treatment costs to evaluate the relative cost of control of once-weekly semaglutide versus exenatide ER and dulaglutide.. Proportions of patients reaching three endpoints were taken from SUSTAIN 3 and 7 for comparisons with exenatide ER and dulaglutide, respectively. The endpoints investigated were HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia or weight gain, and a ≥ 1.0% HbA1c reduction with ≥ 5.0% weight loss. Annual per patient treatment costs were based on US wholesale acquisition costs from July 2018. Relative cost of control was calculated by plotting the ratio of the treatment costs and the ratio of the proportions of patients reaching each endpoint on the cost-efficacy plane.. Once-weekly semaglutide 0.5 mg and 1.0 mg were most effective at bringing patients to each of the three endpoints across both SUSTAIN trials. The efficacy-to-cost ratios for once-weekly semaglutide 0.5 mg and 1.0 mg were also superior to all comparators when assessing both the single endpoint of HbA1c < 7.0% and the two composite endpoints including weight loss and hypoglycemia.. The present study showed that once-weekly semaglutide 0.5 mg and 1.0 mg offer superior cost of control versus exenatide ER and dulaglutide in terms of achieving single and composite endpoints, based on an analysis of retrieved dropout data. Once-weekly semaglutide 0.5 mg and 1.0 mg would therefore represent good value for money in the USA, particularly in the attainment of multi-model T2D treatment goals.. Novo Nordisk A/S.

Topics: Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins; Weight Loss

Exenatide is a glucagon-like peptide 1receptor agonist, having both glycemic and weight loss benefits. Given that previous pharmacogenetic studies reported inconsistent evidence of association between variants in the drug target gene GLP1R and response to exenatide, we set out to examine two common coding variants Chinese population. Materials & methods: Here, we recruited 285 overweight Type 2 diabetes patients from China and investigated the association between two common missense variants and response to exenatide, using multivariate linear model with adjustment for baseline and other covariates. Results: The variant allele T of rs10305420 was associated with a 1.27 kg (p = 0.02) less weight loss and a 0.4% (p = 0.002) lower HbA1c reduction after 6 month of exenatide treatment.. The consistent large clinical impact of rs10305420 on glycemic response and weight response to exenatide makes the variant a strong candidate biomarker for precision medicine, particularly among overweight patients with Type 2 diabetes.

Topics: Adult; Blood Glucose; Body Weight; China; Diabetes Mellitus, Type 2; Exenatide; Female; Genetic Association Studies; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Middle Aged; Mutation, Missense; Overweight

Increasing evidence suggests that metabolism affects brain physiology. Here, we examine the effect of GLP-1 on simple visual-evoked functional Magnetic Resonance Imaging (fMRI) responses in cortical areas.. Lean (n = 10) and nondiabetic obese (n = 10) subjects received exenatide (a GLP-1 agonist) or saline infusion, and fMRI responses to visual stimuli (food and nonfood images) were recorded. We analysed the effect of exenatide on fMRI signals across the cortical surface with special reference to the visual areas. We evaluated the effects of exenatide on the raw fMRI signal and on the fMRI signal change during visual stimulation (vs rest).. In line with previous studies, we find that exenatide eliminates the preference for food (over nonfood) images present under saline infusion in high-level visual cortex (temporal pole). In addition, we find that exenatide (vs saline) also modulates the response of early visual areas, enhancing responses to both food and nonfood images in several extrastriate occipital areas, similarly in obese and lean participants. Unexpectedly, exenatide increased fMRI raw signals (signal intensity during rest periods without stimulation) in a large occipital region, which were negatively correlated to BMI.. In both lean and obese individuals, exenatide affects neural processing in visual cortex, both in early visual areas and in higher order areas. This effect may contribute to the known effect of GLP1 analogues on food-related behaviour.

Topics: Adult; Anti-Obesity Agents; Body Weight; Brain; Exenatide; Female; Follow-Up Studies; Humans; Male; Middle Aged; Obesity; Prognosis; Thinness; Visual Cortex

According to cardiovascular outcome trials, some sodium-glucose contransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are recommended for secondary cardiovascular prevention in type 2 diabetes (T2D). In this real-world study, we compared the simultaneous reductions in HbA1c, body weight and systolic blood pressure after initiation of dapagliflozin or GLP-1RA as second or a more advanced line of therapy.. DARWIN-T2D was a retrospective multi-centre study conducted at diabetes specialist clinics in Italy that compared T2D patients who initiated dapagliflozin or GLP-1RA (exenatide once weekly or liraglutide). Data were collected at baseline and at the first follow-up visit after 3 to 12 months. The primary endpoint was the proportion of patients achieving a simultaneous reduction in HbA1c, body weight and systolic blood pressure. To reduce confounding, we used multivariable adjustment (MVA) or propensity score matching (PSM).. Totals of 473 patients initiating dapagliflozin and 336 patients initiating GLP-1RA were included. The two groups differed in age, diabetes duration, HbA1c, weight and concomitant medications. The median follow-up was 6 months in both groups. Using MVA or PSM, the primary endpoint was observed in 30% to 32% of patients, with no difference between groups. Simultaneous reduction of HbA1c, BP and SBP by specific threshold, as well as achievement of final goals, did not differ between groups. GLP-1RA reduced HbA1c by 0.3% more than the reduction achieved with dapagliflozin.. In routine specialist care, initiation of dapagliflozin can be as effective as initiation of a GLP-1RA for attainment of combined risk factor goals.

Topics: Adult; Aged; Benzhydryl Compounds; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Glucagon-like peptide-1 is a potent hypoglycemic hormone with beneficial properties for the treatment of diabetes. However, its half-life is short because the rapid metabolic degradation. This study aims to prolong the half-life of glucagon-like peptide-1 through conjugation with the fatty acid side chain which helps the conjugates to interact with the albumin. Firstly, we chose two optimized polypeptide chains which have tremendous hypoglycemic effect named Cys

Topics: Adipocytes; Adiponectin; Animals; Blood Glucose; Body Weight; Cell Survival; Drug Stability; Fatty Acids; Glucagon-Like Peptide 1; Half-Life; HEK293 Cells; Humans; Hypoglycemic Agents; Leptin; Lipopeptides; Liraglutide; Male; Mice, Inbred C57BL; Molecular Structure; Pancreas; Rats, Sprague-Dawley; Serum Albumin, Human

Significant attempts are being made to generate multifunctional, hybrid or peptide combinations as novel therapeutic strategies for type 2 diabetes, however this presents key challenges including design and pharmaceutical development. In this study, we evaluated metabolic properties of oral nutritional supplement epigallocatechin gallate (EGCG) in combination with GLP-1 agonist exendin-4 in a mouse model of dietary-induced diabetes and obesity.. EGCG, exendin-4 or combination of both were administered twice-daily over 28 days to high fat (HF) mice on background of low-dose streptozotocin. Energy intake, body weight, fat mass, glucose tolerance, insulin sensitivity, lipid profile, biochemical and hormone markers, and islet histology were examined.. All treatment groups exhibited significantly reduced body weight, fat mass, circulating glucose and insulin concentrations, and HbA1c levels which were independent of changes in energy intake. Similarly, there was marked improvement in glycaemic control, glucose-stimulated insulin release, insulin sensitivity, total cholesterol and triglycerides, with most prominent effects observed following combination therapy. Circulating corticosterone concentrations and 11beta-hydroxysteroid dehydrogenase type1 (11β-HSD1) staining (in pancreas) were beneficially decreased without changes in circulating interleukin 6 (IL-6), alanine transaminase (ALT) and glutathione reductase. Combination therapy resulted in increased islet area and number, beta cell area, and pancreatic insulin content. Generally, metabolic effects were much more pronounced in mice which received combination therapy.. EGCG alone and particularly in combination with exendin-4 exerts positive metabolic properties in HF mice. EGCG may be useful dietary adjunct alongside GLP-1 mimetics in treatment of diabetes and related disorders.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiposity; Alanine Transaminase; Animals; Blood Glucose; Body Weight; Catechin; Corticosterone; Diabetes Mellitus, Experimental; Diet, High-Fat; Drug Therapy, Combination; Energy Intake; Exenatide; Glucose Tolerance Test; Glutathione Reductase; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Interleukin-6; Mice, Obese

To evaluate in a real-world setting the effectiveness of exenatide once-weekly (ExQW) in patients with T2D and to determine predictors of glycaemic and weight response to this drug at 6 months.. Observational, retrospective, multicenter study in adult patients with T2D and BMI ≥30 kg/m. In a real-world setting, ExQW significantly decreased A1C, weight, blood pressure and lipids at 6 months. Our study identified higher baseline A1C as the sole independent predictor of glycaemic response to ExQW and higher BMI and previous DDP4i treatment as predictive factors of meaningful weight response.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Medication Adherence; Middle Aged; Peptides; Venoms; Weight Loss

Exenatide twice daily (EBID) and mealtime insulin are effective add-on therapies to basal insulin for type 2 diabetes patients in clinical trials. This study used electronic medical record (EMR) data to evaluate analogous real-world clinical responses.. Adult patients initiating EBID or mealtime insulin as add-on to basal insulin during January 2008-March 2013 were identified in a US EMR database. EBID patients were propensity score matched 1:1 to mealtime insulin patients. Cohorts were followed for 12 months before (baseline) and 6 months after the index. A1C, hypoglycemic events, change in weight, and other clinical measures were evaluated by A1C attainment level (<6.5, < 7, < 7.5, <8, <9%) and baseline A1C.. In total, 1249 EBID patients were matched to 1249 mealtime insulin patients. During follow-up, the percentage reaching A1C levels was similar for EBID vs mealtime insulin cohorts for all attainment levels (<7%: 27.8% vs 24.2%; < 9%: 79.7% vs 79.2%; p = NS). The percentage reaching A1C < 7% was similar for both cohorts with different baseline A1C. EBID patients had less hypoglycemia at all attainment levels (3.1% vs 11.1% [<6.5%]; 2.5% vs 4.7% [<9%]; all p < .03) and more weight loss (-9.0 vs -3.2 lb [<6.5%]; -3.4 vs +0.8 lb [<9%]; all p < .01).. EBID added to basal insulin was as effective in a real-world setting as mealtime insulin added to basal insulin in reducing A1C, with less weight gain and less hypoglycemia for a wide range of A1C attainment levels and baseline values.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Electronic Health Records; Exenatide; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Meals; Middle Aged; Retrospective Studies; Weight Loss

Men with type 2 diabetes (T2D) and obesity are often characterised by low testosterone (T). We aimed to determine whether exenatide (EXE) combined metformin (MET) treatment has a better effect on serum total testosterone (TT) levels than glimepiride (GLI) combined MET treatment in men with T2D and obesity. In a multicentre, 12-week observational study, 176 obese T2D men with failed glycaemic control were included in the study: ninety men (mean age, 43.00 ± 8.50 years) in EXE + MET group and 86 men (mean age, 44.00 ± 7.00 years) in GLI + MET group. Serum TT levels were more significantly increased in EXE + MET group than GLI + MET group (121.72 ± 56.73 ng/dl versus 34.67 ± 16.30 ng/dl). The increasement of TT levels in those patients who lost body weight ≥5% was significantly greater than those who lost weight <5% in the two groups. The changes in TT levels are closely related to the changes in waist circumference (r = -.443, p < .001). Sexual function assessment of EXE + MET group was more significantly improved than GLI + MET group (p < .001). No serious adverse events were observed. In conclusion, short-term combined treatment with EXE and MET is superior to GLI combined MET treatment in the improvement of serum TT levels, which could lead to an improvement of sexual hypofunction in patients with obesity and T2D.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Obesity; Sexual Dysfunction, Physiological; Sulfonylurea Compounds; Testosterone; Treatment Outcome

To investigate the utility of intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI) derived parameters in hypothalamus for monitoring the effect of Exendin-4 (Ex-4) intervention on the feeding behavior in obese diabetic rats within early feeding.. 21 obese and 19 non-obese rats which were treated with streptozotocin injections were initially divided into an obese diabetes group (OD, n = 10), a non-obese diabetes group (D, n = 8), an obese group (O, n = 9) and a non-obese group (N, n = 9). Then, the rats in the 4 groups received subcutaneous injections of Ex-4, and feeding behavior was examined at 5, 35, 65, 95, and 125 min. The hypothalamic function was evaluated by IVIM-DWI. Finally, the relationship between the hypothalamic function and the amount of food intake was analyzed.. In comparison with the N group, the food intake significantly decreased in the O , OD, and D groups in response to Ex-4. Furthermore, a significant positive correlation was found between food intake and D values at different times from 5 to 125 min after Ex-4 intervention in all 4 groups.. A direct correlation between the change of hypothalamic function and feeding behavior was detected in OD rats with Ex-4 intervention in the early feeding period. The hypothalamic D value derived from IVIM-DWI is promising to reflect the dynamic change of hypothalamic function due to intervention.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diffusion Magnetic Resonance Imaging; Eating; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Hypothalamus; Male; Obesity; Rats; Rats, Sprague-Dawley

Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Blood Glucose; Body Weight; Chromones; Diet, High-Fat; Disease Models, Animal; Eating; Enzyme Inhibitors; Exenatide; Fatty Liver; Gene Expression Regulation; In Vitro Techniques; Insulin; Male; Malondialdehyde; Morpholines; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Peptides; Phosphatidylinositol 3-Kinases; Protective Agents; Rabbits; Superoxide Dismutase; Venoms

Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. On the basis of sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity. Detailed structure-activity relationship data are shown. Further modifications with unnatural and modified amino acids resulted in novel metabolically stable peptides that demonstrated a significant dose-dependent decrease in blood glucose in chronic studies in diabetic db/db mice and reduced body weight in diet-induced obese (DIO) mice. Structural analysis by NMR spectroscopy confirmed that the peptides maintain an exendin-4-like structure with its characteristic tryptophan-cage fold motif that is responsible for favorable chemical and physical stability.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Body Weight; Drug Design; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Mice, Inbred C57BL; Mice, Obese; Molecular Docking Simulation; Obesity; Peptides; Structure-Activity Relationship; Swine; Venoms

Topics: Amino Acid Sequence; Animals; Anti-Obesity Agents; Body Weight; Diet; Inhibitory Concentration 50; Male; Mice; Mice, Knockout; Molecular Structure; Peptide YY

Topics: Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Exenatide; Glucagon-Like Peptide-1 Receptor; Infusions, Subcutaneous; Injections, Subcutaneous; Male; Mice, Inbred C57BL; Models, Biological; Obesity; Peptides; Venoms

Exendin-4 (EX-4), a glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to reduce food intake and to increase proopiomelanocortin (POMC) gene expression in the hypothalamus. In this study, we examined the potential neural mechanisms by which these effects occur. Male Sprague Dawley rats were implanted with a cannula in the third ventricle of the brain through which an inhibitor of phosphatidylinositol-3 kinase (PI3K) (wortmannin) was administered, and EX-4 or vehicle was administered via intraperitoneal (IP) injection. The activity of PI3K/protein kinase B (AKT) and insulin receptor substrate-1 (IRS-1) in the hypothalamic arcuate was determined. We found that EX-4 treatment significantly decreased food intake and body weight. However, there were almost no changes in food intake and body weight when wortmannin injection (into the third ventricle) occurred prior to EX-4 IP injection. EX-4 not only increased the activity of PI3K/AKT, but it also increased IRS-1 activity. These results show that EX-4 likely suppresses food intake due to its ability to enhance insulin signaling.

Topics: Animals; Body Weight; Eating; Exenatide; Hypothalamus; Insulin Receptor Substrate Proteins; Male; Phosphatidylinositol 3-Kinase; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Wortmannin

To evaluate the efficacy and safety of adjuvant exenatide extended release (ER) therapy in patients treated with regular U-500 insulin.. In this retrospective chart review at an ambulatory care center in the Midwest, 18 patients with type 2 diabetes being treated with regular U-500 insulin and adjuvant exenatide ER were identified. These patients were evaluated for outcomes following the addition of exenatide ER. The primary outcome was change in HbA. In patients treated with regular U-500 insulin, adjuvant exenatide ER therapy showed no significant improvement in HbA

Topics: Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptides; Retrospective Studies; Venoms

Randomized clinical trials have shown the efficacy and safety of short-acting exenatide in patients with type 2 diabetes mellitus (T2DM). The aim of this observational study was to investigate the effectiveness and safety of exenatide twice a day in Korean patients with T2DM who are suboptimally controlled with oral hypoglycemic agents.. This study was a post hoc analysis of multi-center (71 centers), prospective, observational, single-arm, post-marketing study of short-acting exenatide 5 to 10 μg twice a day from March 2008 to March 2014 and analyzed those who finished the follow-up over 20 weeks of medication. Changes of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight values before and after exenatide treatment were analyzed. Adverse events and adverse drug reactions were estimated in patients who were treated with exenatide at least once and for whom follow-up for safety has been completed.. After 20 weeks treatment with exenatide, mean HbA1c and body weight were significantly reduced from 8.4% to 7.7% and from 83.4 kg to 80.2 kg, respectively (both p < 0.001). Subjects with higher baseline glucose and HbA1c levels showed an independent association with a greater reduction in glucose level. In addition, short duration of diabetes less than 5 years was an independent predictor for the improvement in glucose level. The majority of study subjects showed a reduction in both body weight and glucose level (63.3%) after exenatide treatment. In terms of safety profile, exenatide treatment was generally well-tolerated and the incidence of severe adverse event was rare (0.8%). The gastrointestinal side effects were most common and hypoglycemia was reported in 1.7% of subjects.. In real clinical practice, 20 weeks treatment with short-acting exenatide was well tolerated and showed a significant body weight and glucose reduction in Korean patients with T2D who are suboptimally controlled with oral hypoglycemic agents.. ClinicalTirals.gov , number NCT02090673 , registered 14 February 2008.

Topics: Adult; Asian People; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Prospective Studies; Venoms

Real world outcomes of addition or switch to insulin therapy in type 2 diabetes (T2DM) patients on glucagon-like paptide-1 receptor agonist (GLP-1RA) with inadequately controlled hyperglycaemia, are not known.. Patients with T2DM (n = 66 583) with a minimum of 6 months of GLP-1RA treatment and without previous insulin treatment were selected. Those who added insulin (n = 39 599) or switched to insulin after GLP-1RA cessation (n = 4706) were identified. Adjusted changes in glycated haemoglobin (HbA1c), weight, systolic blood pressure (SBP), and LDL cholesterol were estimated over 24 months follow-up.. Among those who continued with GLP-1RA treatment without adding or switching to insulin, the highest adjusted mean HbA1c change was achieved within 6 months, with no further glycaemic benefits observed during 24 months of follow-up. Addition of insulin within 6 months of GLP-1RA initiation was associated with 18% higher odds of achieving HbA1c <7% at 24 months, compared with adding insulin later. At 24 months, those who added insulin reduced HbA1c significantly by 0.55%, while no glycaemic benefit was observed in those who switched to insulin. Irrespective of intensification with insulin, weight, SBP and LDL cholesterol were significantly reduced by 3 kg, 3 mm Hg, and 0.2 mmol/L, respectively, over 24 months.. Significant delay in intensification of treatment by addition of insulin is observed in patients with T2DM inadequately controlled with GLP-1RA. Earlier addition of insulin is associated with better glycaemic control, while switching to insulin is not clinically beneficial during 2 years of treatment. Non-responding patients on GLP-1RA would benefit from adding insulin therapy, rather than switching to insulin.

Topics: Aged; Blood Glucose; Blood Preservation; Body Weight; Cholesterol, LDL; Databases, Factual; Diabetes Mellitus, Type 2; Drug Substitution; Drug Therapy, Combination; Electronic Health Records; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Middle Aged; Peptides; Treatment Outcome; Venoms

Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT

Topics: Aminopyridines; Animals; Anorexia; Appetite; Body Weight; Dorsal Raphe Nucleus; Exenatide; Feeding Behavior; Fenclonine; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Indoles; Liraglutide; Male; Peptides; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin Antagonists; Venoms; Weight Loss

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

Topics: Animals; Autophagy; Body Weight; Cells, Cultured; Diet; Drug Evaluation, Preclinical; Energy Intake; Exenatide; Fructose; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Male; Membrane Proteins; Microscopy, Electron; Peptides; Rats, Wistar; RNA, Messenger; Sitagliptin Phosphate; Venoms

Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Body Weight; Brain; Emotions; Exenatide; Feeding Behavior; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Serotonin; Venoms

Insulin resistance and hyperandrogenism are the main features of polycystic ovarian syndrome (PCOS). Low-grade inflammation is also involved in PCOS. This study was performed to evaluate the effect of exenatide on metabolic changes, sexual hormones, inflammatory cytokines, adipokines, and weight changes in a dehydroepiandrosterone (DHEA)-treated rat model. After the model was produced by daily subcutaneous injections of DHEA, rats were given metformin (265 mg/kg), exenatide (10 μg/kg), and saline (1 mL). One group served as a control group. Blood samples and ovarian tissues were removed and prepared for biochemical and hormonal analyses. Exenatide significantly reduced body weight and insulin, testosterone, interleukin 6 (IL-6), PEDF, and visfatin levels. Exenatide also ameliorated changes in ovarian morphology, as evidenced by decreased numbers of cystic follicles and various follicles and elevated numbers of granular cell layers. The effects observed with exenatide were comparable to those observed with metformin. This study has provided evidence that exenatide may be efficient in the treatment of PCOS.

Topics: Adipokines; Animals; Body Weight; Cytokines; Dehydroepiandrosterone; Disease Models, Animal; Exenatide; Female; Gonadal Steroid Hormones; Inflammation Mediators; Metformin; Ovary; Peptides; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Venoms

Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in weight loss. Sirtuin 1 (SIRT1) plays a vital role in the regulation of lipid metabolism. Here, we investigated the contribution of lipolytic and oxidative changes in white adipose tissue (WAT) to the weight-lowering effect induced by the GLP-1 receptor (GLP-1R) agonist exenatide (exendin-4) in mice. We also looked at the role of SIRT1 in this process.. C57BL/6J mice and Sirt1 (+/-) mice were treated with exenatide (24 nmol/kg) or an NaCl solution (154 mmol/l) control i.p. for 8 weeks while receiving a high-fat diet (HFD) after a 12 week HFD challenge. Systemic phenotypic evaluations were carried out during and after the intervention. A lentivirus-mediated short hairpin (sh)RNA vector of the Sirt1 gene was transfected into differentiated 3T3-L1 adipocytes. An in vitro model system used adipocytes induced from Sirt1-null mouse embryonic fibroblasts (MEFs).. Exenatide reduced fat mass and enhanced the lipolytic and oxidative capacity of WAT in diet-induced obese C57BL/6J mice. However, these effects were significantly impaired in Sirt1 (+/-) mice compared with wild-type controls. In vitro, exendin-4 increased lipolysis and fatty acid oxidation by upregulating SIRT1 expression and activity in differentiated 3T3-L1 adipocytes. Conversely, RNA interference (i)-induced knockdown of SIRT1 attenuated the lipolytic and oxidative responses to exendin-4 in differentiated 3T3-L1 adipocytes. Again, these responses were entirely abolished in Sirt1-null MEFs after induction into adipocytes.. These data highlight that a GLP-1R agonist promotes brown remodelling of WAT in a SIRT1-dependent manner; this might be one of the mechanisms underlying its effect on weight loss.

Topics: Adipose Tissue, White; Animals; Body Weight; Diet, High-Fat; Exenatide; Glucagon-Like Peptide-1 Receptor; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Peptides; Sirtuin 1; Venoms

Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristics in offspring. Female Sprague-Dawley rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation, and their offspring were weaned to normal or HFD. The offspring were randomized to Exd-4 or placebo from weaning and their kidneys harvested at Week 9. We found that the kidneys of offspring from obese mothers, regardless of postnatal diet, had significantly increased markers of inflammation, oxidative stress and fibrosis. Exd-4 ameliorated the negative renal effects of maternal obesity and in particular, reduced renal inflammation, oxidative stress and fibrosis. In conclusion, maternal obesity has persisting effects on renal structure in the offspring. GLP-1 analogues are potentially useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring.

Topics: Animals; Animals, Newborn; Body Weight; Diet, High-Fat; Disease Models, Animal; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Kidney; Kidney Diseases; Maternal Nutritional Physiological Phenomena; Obesity; Oxidative Stress; Peptides; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome; Venoms; Weaning

This post hoc analysis assessed the evidence behind common reimbursement practices by evaluating the relationship of body mass index (BMI) ranges (<30, 30-35 and >35 kg/m(2) ) with treatment effects of exenatide twice daily among patients with type 2 diabetes. Patients received exenatide twice daily added to insulin glargine in two 30-week studies (exenatide twice daily vs insulin lispro, n = 627; exenatide twice daily vs placebo, n = 259). No association of baseline BMI with changes in efficacy variables was observed. Glycated haemoglobin (HbA1c) reductions were significant (p < 0.0001) and similar across BMI range groups in the lispro-comparator study and greater for exenatide versus placebo in the placebo-controlled study. Significant weight loss occurred with exenatide across BMI range groups (p < 0.0001), while weight increased with both comparators. Achievement of HbA1c <7.0% (<53 mmol/mol) without weight gain was greater for exenatide versus comparators. Systolic blood pressure decreased across BMI range groups with exenatide in the lispro-comparator study (p < 0.0001); changes in lipids were not clinically meaningful. Minor hypoglycaemia was less frequent for exenatide versus insulin lispro. These findings suggest that BMI alone should not limit clinical decision-making or patient access to medication.

Topics: Aged; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Insulin Glargine; Insulin Lispro; Male; Middle Aged; Obesity; Peptides; Randomized Controlled Trials as Topic; Treatment Outcome; Venoms

Hypothalamic obesity (HO) is a common complication of hypothalamic tumors, and effective therapies are lacking. The objective of this pilot study was to investigate changes in body weight before and during treatment with exenatide.. This was a prospective, open-label, 52-week pilot study of exenatide (10 mcg b.i.d.) in adults with HO. Ten patients enrolled, and eight completed the study. Study measures included indirect calorimetry, body composition, buffet meals, diet recall, actigraphy, and hormone assays.. Participants had obesity with a baseline weight of 137.2 ± 37.6 kg. Exenatide therapy was well tolerated. Change in weight with exenatide therapy was not significant (-1.4 ± 4.3 kg [95% CI -4.9 to 2.2], P = 0.40), but six out of eight completers lost weight (-6.2 to -0.2 kg). Participants reported significantly lower intake on food recall during treatment compared with baseline (7837.8 ± 2796.6 vs. 6258.4 ± 1970.7 kJ [95% CI -2915.8 to -242.6], P = 0.027), but there was no change in intake during buffet meals.. Significant weight loss was not observed in patients with HO treated with exenatide, but 75% of completers had stable or decreasing weight. Further studies are needed to evaluate weight loss efficacy in patients with HO.

Topics: Adult; Body Composition; Body Weight; Exenatide; Female; Humans; Hypoglycemic Agents; Hypothalamic Diseases; Male; Obesity; Peptides; Pilot Projects; Prospective Studies; Venoms; Young Adult

Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20μg/kg) group: mice received exenatide (10 or 20μg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

Topics: 1,2-Dimethylhydrazine; Animals; Antigens, CD34; Body Weight; Cell Proliferation; Cisplatin; Colon; Colonic Neoplasms; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Exenatide; Gene Expression Regulation, Neoplastic; Interleukin-6; Ki-67 Antigen; Male; Mice; Neovascularization, Pathologic; Peptides; RNA, Messenger; Survival Analysis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Venoms

Incretin-based therapies are widely used to treat type 2 diabetes. Although hypoglycemic actions of incretins are mostly due to their insulinotropic/glucagonostatic effects, they may also influence extrapancreatic metabolism. We administered exendin-4 (Ex-4), a long-acting glucagon-like peptide receptor agonist, at low dose (0.1 nmol/kg/day) for a short period (10 days), in obese nondiabetic fa/fa Zucker rats (ZFRs). Ex-4-treated ZFRs were compared to vehicle (saline)-treated ZFRs and vehicle- and Ex-4-treated lean rats (LRs). Blood glucose levels were measured at days 0, 9, and 10. Ingested food and animal weight were recorded daily. On the day of sacrifice (d10), blood was sampled along with liver, epididymal, subcutaneous, brown adipose, and skeletal muscle tissues from animals fasted for 24 h. Plasma insulin and blood glucose levels, food intake, and body and epididymal fat weight were unchanged, but gross morphological changes were observed in insulin-sensitive tissues. The average size of hepatocytes was significantly lower in Ex-4-treated ZFRs, associated with decreased number and size of lipid droplets and 4-hydroxy-2-nonenal (HNE) staining, a marker of oxidative stress (OS). Myocytes, which were smaller in ZFRs than in LRs, were significantly enlarged and depleted of lipid droplets in Ex-4-treated ZFRs. Weak HNE staining was increased by Ex-4. A similar observation was made in brown adipose tissue, whereas the elevated HNE staining observed in epididymal adipocytes of ZFRs, suggestive of strong OS, was decreased by Ex-4. These results suggest that incretins by acting on OS in insulin-sensitive tissues may contribute to weight-independent improvement in insulin sensitivity.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Exenatide; Hepatocytes; Incretins; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Organ Size; Organ Specificity; Oxidative Stress; Peptides; Rats; Rats, Zucker; Venoms

Data comparing real-world effectiveness of the glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide once weekly (QW) and liraglutide in the treatment of type 2 diabetes (T2D) are limited. Furthermore, there is limited information on exenatide QW or liraglutide response by glycemic control and insulin use status. This study identifies 1-year glycosylated hemoglobin (HbA. This retrospective cohort study using national electronic medical record data compared 1-year HbA. The study included 808 exenatide QW and 4333 liraglutide patients. Mean (SD) age was 57 (11) years in both groups. Mean baseline HbA. Exenatide QW and liraglutide lead to similar HbA

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Middle Aged; Peptides; Retrospective Studies; Venoms

Benign prostatic hyperplasia (BPH) is a prevalent disease globally, and accumulating evidence has indicated an association between BPH, insulin resistance (IR) and diabetes. Exendin-4 is widely used in clinics, which could enhance the proliferation of pancreatic β cells. The ability of exendin-4 to promote tumorigenesis has been of concern, and whether exendin-4 would enhance the propagation of BPH is not fully understood. We aimed to determine whether glucagon-like peptide-1 receptors (GLP-1Rs) were expressed in rat prostate and to determine the effect of exendin-4 on prostate of BPH. Male Wistar rats were used and assigned to six groups: normal diet (ND), high-fat diet (HFD), HFD + exendin-4, HFD + BPH, HFD + BPH + exendin-4 and HFD + BPH + rosiglitazone group. After castration, steroids were injected subcutaneously for 4 weeks to induce BPH. Rats were kept on high-fat diet to induce IR. Treatment groups were treated with exendin-4 and rosiglitazone. Prostatic index and HOMA-IR index were used to evaluate the prostatic hyperplasia status and the degree of IR respectively. The expression of GLP-1R was indicated not only by immunohistochemistry, but also by Western blot analysis. The expression of GLP-1R was significantly higher, and HOMA-IR index and body weight significantly decreased after administration of exendin-4. However, no significant differences in the prostatic index were observed between exendin-4 treatment groups and non-exendin-4 treatment groups. Prostatic index was not influenced by exendin-4 maybe by improving IR and weight loss.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Exenatide; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Male; Peptides; Prostate; Prostatic Hyperplasia; Rats; Rats, Wistar; Receptors, Glucagon; Rosiglitazone; Severity of Illness Index; Thiazolidinediones; Venoms

The recent type 2 diabetes American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement suggested insulin is the most effective glucose-lowering therapy, especially when glycated haemoglobin (HbA1c) is very high. However, randomized studies comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide once-weekly [OW; DURATION-3 (Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce-Weekly)] and liraglutide once-daily [OD; LEAD-5 (Liraglutide Effect and Action in Diabetes)] with insulin glargine documented greater HbA1c reduction with GLP-1RAs, from baseline HbA1c ∼8.3% (67 mmol/mol). This post hoc analysis of DURATION-3 and LEAD-5 examined changes in HbA1c, fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile.. Descriptive statistics were provided for change in HbA1c, fasting glucose, weight, and insulin dose, and subjects (%) achieving HbA1c <7.0%, by baseline HbA1c quartile. Inferential statistical analysis on the effect of baseline HbA1c quartile was performed for change in HbA1c. An analysis of covariance (ANCOVA) model was used to evaluate similarity in change in HbA1c across HbA1c quartiles.. At 26 weeks, in both studies, HbA1c reduction, and proportion of subjects reaching HbA1c <7.0%, were similar or numerically greater with the GLP-1RAs than glargine for all baseline HbA1c quartiles. Fasting glucose reduction was similar or numerically greater with glargine. Weight decreased with both GLP-1RAs across all quartiles; subjects taking glargine gained weight, more at higher baseline HbA1c. Adverse events were uncommon although gastrointestinal events occurred more frequently with GLP-1RAs.. HbA1c reduction with the GLP-1RAs appears at least equivalent to that with basal insulin, irrespective of baseline HbA1c. This suggests that liraglutide and exenatide OW may be appropriate alternatives to basal insulin in type 2 diabetes, including when baseline HbA1c is very high (≥9.0%).

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fasting; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Metformin; Middle Aged; Peptides; Treatment Outcome; Venoms

Exenatide is a GLP-1 analogue used in the management of T2DM yet within a subset of patients fails due to adverse side effects or from failure to attain the end goal. This retrospective observational study aimed to determine whether we could predict response to exenatide in patients with T2DM. 112 patients on exenatide were included with patient age, gender, duration of T2DM, medications alongside exenatide and weight, BMI, and HbA1c at baseline and 3 and 6 months of exenatide use being recorded. 63 responded with 11 mmol/mol reduction from baseline HbA1c after six months and 49 did not respond to exenatide. HbA1c solely differed significantly between cohorts at baseline, 3 months, and 6 months (P < 0.05). Regression analyses identified a negative linear relationship with higher baseline HbA1c correlating to greater reductions in HbA1c by 6 months (P < 0.0001). HbA1c was the sole predictor of exenatide response with higher baseline HbA1c increasing the odds of response by 5% (P = 0.004). Patients with HbA1c reductions ≥15-20% by 3 months were more likely to be responders by 6 months (P = 0.033). Our study identified that baseline HbA1c acted as the sole predictor of exenatide response and that response may be determined after 3 months of exenatide administration.

Topics: Aged; Anthropometry; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Linear Models; Liraglutide; Male; Middle Aged; Peptides; Predictive Value of Tests; Regression Analysis; Retrospective Studies; Treatment Outcome; Venoms

This study aimed to investigate the benefits of exendin-4 treatment on brown adipose tissue (BAT) in C57BL/6J mice with high-fat diet (HFD)-induced obesity.. We examined the effects of exendin-4 on body adiposity and the level of genes associated with adipogenesis, glucose/lipid uptake, lipolysis, and thermogenesis in mice with diet-induced obesity.. Exendin-4 treatment deceased body weight, serum-free fatty acid, and triglyceride levels in HFD-induced obese C57BL/6J mice. Exendin-4 treatment increased the expression of genes associated with adipogenesis, glucose/lipid uptake, lipolysis, and thermogenesis in BAT. Compared with HFD-fed mice, exendin-4 treatment also exhibited elevated energy expenditure and reduced respiratory quotient, but showed similar food intake and locomotor activity.. Exendin-4 treatment reduced high-fat-induced obesity by decreasing adiposity and increasing thermogenesis. This result suggests that GLP-1 agonist may be a new approach to combat obesity by shifting the energy balance from obesogenesis to thermogenesis.

Topics: Adipogenesis; Adiponectin; Adipose Tissue, Brown; Animals; Body Weight; Diet, High-Fat; Energy Metabolism; Exenatide; Fasting; Fatty Acids; Feeding Behavior; Gene Expression Regulation; Glucose; Leptin; Lipid Metabolism; Mice, Inbred C57BL; Motor Activity; Obesity; Peptides; Thermogenesis; Triglycerides; Venoms

Maternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity.. Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.. Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue.. Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in preventing the development of metabolic disease.

Topics: Age Factors; Animals; Animals, Newborn; Biomarkers; Body Weight; Brain; Diet, High-Fat; Exenatide; Female; Gene Expression Regulation; Hypoglycemic Agents; Leptin; Liver; Male; Maternal Nutritional Physiological Phenomena; Metabolic Diseases; Obesity; Peptides; Pregnancy; Pregnancy Complications; Rats; Rats, Sprague-Dawley; Venoms

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred ICR; Microscopy, Fluorescence; Pancreas; Peptides; Recombinant Fusion Proteins; Serum Albumin; Serum Albumin, Human; Venoms

Previously, we have identified a novel role for the cytoplasmic protein, synphilin-1(SP1), in the controls of food intake and body weight in both mice and Drosophila. Ubiquitous overexpression of human SP1 in brain neurons in transgenic mice results in hyperphagia expressed as an increase in meal size. However, the mechanisms underlying this action of SP1 remain to be determined. Here we investigate a potential role for altered gut feedback signaling in the effects of SP1 on food intake. We examined responses to peripheral administration of cholecytokinin (CCK), amylin, and the glucagon like peptide-1 (GLP-1) receptor agonist, exendin-4. Intraperitoneal administration of CCK at doses ranging from 1-10 nmol/kg significantly reduced glucose intake in wild type (WT) mice, but failed to affect intake in SP1 transgenic mice. Moreover, there was a significant attenuation of CCK-induced c-Fos expression in the dorsal vagal complex in SP1 transgenic mice. In contrast, WT and SP1 transgenic mice were similarly responsive to both amylin and exendin-4 treatment. These studies demonstrate that SP1 results in a CCK response deficiency that may contribute to the increased meal size and overall hyperphagia in synphillin-1 transgenic mice.

Topics: Animals; Body Weight; Brain; Carrier Proteins; Cholecystokinin; Cytoplasm; Eating; Exenatide; Feeding Behavior; Female; Gene Expression Regulation; Genotype; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperphagia; Infusions, Parenteral; Intestinal Mucosa; Intracellular Signaling Peptides and Proteins; Islet Amyloid Polypeptide; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Obesity; Peptides; Proto-Oncogene Proteins c-fos; Signal Transduction; Venoms

The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild-type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1-ir), cluster of differentiation 68 (CD68-ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1-ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1-ir comparable with WT mice but had significantly lower CD68-ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1-ir, and db/db mice showed increase of CD68-ir. Obese MC4R KO mice fed a SC diet had comparable iba1-ir and CD68-ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon-like peptide-1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; Cytokinins; Diet, High-Fat; Disease Models, Animal; Exenatide; Hormones; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Obesity; Peptides; Receptor, Melanocortin, Type 4; Receptors, Interleukin-8A; Receptors, Leptin; Signal Transduction; Supraoptic Nucleus; Venoms

The combined glucose-lowering effect of exenatide and dapagliflozin has not yet been studied. We investigated this combination (single-dose or 4-week dosing) in diabetic ob/ob mice. Vehicle-corrected basal glucose showed greater reduction 1 h following exenatide + dapagliflozin than with exenatide or dapagliflozin alone, and stayed significantly lower for all groups versus vehicle over 3 h. During an oral glucose tolerance test, glucose excursion (30 min post-dose) was significantly lower for exenatide + dapagliflozin versus exenatide or dapagliflozin, or vehicle. Exenatide + dapagliflozin and exenatide, but not dapagliflozin alone, reduced glucose excretion over 24 h versus vehicle. After dosing for 4 weeks, exenatide, dapagliflozin and exenatide + dapagliflozin similarly decreased haemoglobin A1c (HbA1c). Body weight was reduced only with exenatide or exenatide + dapagliflozin. The glomerular filtration rate was similar with exenatide, dapagliflozin and vehicle, and increased with exenatide + dapagliflozin. Optimized combinatorial dosing of these antidiabetic agents may provide additive glucose lowering in type 2 diabetes mellitus.

Topics: Animals; Benzhydryl Compounds; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Exenatide; Glucosides; Glycated Hemoglobin; Hypoglycemic Agents; Male; Mice; Mice, Inbred NOD; Peptides; Venoms

Maternal obesity leads to increased adiposity, hyperlipidaemia and glucose intolerance in offspring. The analogue of glucagon-like peptide-1, exendin-4 (Ex-4), has been shown to induce weight loss in both adolescence and adulthood. We hypothesised that, in rats, daily injection of Ex-4 would reduce body fat and improve metabolic disorders in offspring from obese dams, especially those consuming a high-fat diet (HFD).. Female Sprague Dawley rats were fed chow or an HFD for 5 weeks before mating, and throughout gestation and lactation. At postnatal day 20, male pups from HFD-fed mothers were weaned onto chow or HFD and those from chow-fed mothers were fed chow. Within each dietary group, half of the pups were injected with Ex-4 (15 μg/kg/day i.p.) for 6 weeks, while the other half received saline.. Maternal obesity alone or combined with postweaning HFD consumption led to increased adiposity, hyperinsulinaemia, hyperlipidaemia, inflammation and impaired regulation of hypothalamic appetite regulators by glucose in offspring, while glucose intolerance was only observed in HFD-fed rats from obese dams. Ex-4 injection significantly reduced adiposity, hyperlipidaemia and insulin resistance in HFD-fed rats from obese dams. It also restored glucose tolerance and the lipid-lowering effect of blood glucose. However, Ex-4 did not change hypothalamic appetite regulation or the response of appetite regulators to hyperglycaemia. Liver and adipose inflammatory cytokine expression was significantly reduced by Ex-4.. Ex-4 reversed the detrimental impact of maternal obesity on lipid and glucose metabolism in offspring regardless of diet, supporting its potential application in reducing metabolic disorders in high-risk populations.

Topics: Adiposity; Animals; Animals, Newborn; Appetite Regulation; Biomarkers; Blood Glucose; Body Weight; Diet, High-Fat; Exenatide; Female; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Hypothalamus; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Overnutrition; Peptides; Pregnancy; Rats; Rats, Sprague-Dawley; Venoms; Weaning

Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are effective weight loss surgeries that also improve glucose metabolism. Rapid, early rises of circulating insulin and glucagon-like peptide-1 (GLP-1) concentrations following food ingestion are characteristic of these procedures. The purpose of the current study was to test the hypothesis that postprandial hormone release is due to increased nutrient emptying from the stomach. Radioscintigraphy and chemical and radiolabeled tracers were used to examine gastric emptying in rat models of VSG and RYGB surgery. Intraduodenal nutrient infusions were used to assess intestinal GLP-1 secretion and nutrient sensitivity in VSG rats compared with shams. Five minutes after a nutrient gavage, the stomachs of RYGB and VSG rats were completely emptied, whereas only 6.1% of the nutrient mixture had emptied from sham animals. Gastric pressure was increased in VSG animals, and rats with this procedure did not inhibit gastric emptying normally in response to increasing caloric loads of dextrose or corn oil, and they did not respond to neural or endocrine effectors of gastric motility. Finally, direct infusion of liquid nutrients into the duodenum caused significantly greater GLP-1 release in VSG compared with shams, indicating that increases in GLP-1 secretion after VSG are the result of both greater gastric emptying rates and altered responses at the level of the intestine. These findings demonstrate greatly accelerated gastric emptying in rat models of RYGB and VSG. In VSG this is likely due to increased gastric pressure and reduced responses to inhibitory feedback from the intestine.

Topics: Animals; Body Weight; Exenatide; Gastrectomy; Gastric Emptying; Gastric Mucosa; Glucagon-Like Peptide 1; Hypoglycemic Agents; Male; Peptides; Postprandial Period; Rats; Rats, Long-Evans; Stomach; Venoms

To extend preliminary studies on the effects on food intake of the combined use of cannabinoid (CB) 1 and glucagon-like peptide-1 (GLP-1) receptor agonists and antagonists, the effect of these drugs on the feeding behavior in rats maintained on a free-choice, high-carbohydrate diet was investigated over a longer period of time. Rats were fed a standard diet for 3 days and then fed with both the standard and the high-sucrose chow. After 4 days of the high-calorie diet, the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days: 1 mg/kg AM 251 (a CB1 receptor antagonist) or 1 mg/kg WIN 55,212-2 (a CB1 receptor agonist) together with 3 µg/kg exendin-4 (Ex-4, a GLP-1 receptor agonist) or 160 µg/kg exendin (9-39) [Ex (9-39), a GLP-1 receptor antagonist]. The total daily caloric intake and body weight were significantly reduced in rats treated with Ex-4 and AM 251 or WIN 55,212-2 compared with either of the drugs injected alone and the saline-injected controls. Both drug combinations selectively inhibited ingestion of the high-sucrose chow. Although Ex (9-39) administration did not significantly affect food consumption, it resulted in a marked body weight gain, indicating that the GLP-1 receptor antagonist caused a positive energy balance. It is concluded that AM 251 or WIN 55,212-2 and Ex-4, injected together, exert additive, inhibitory effects on the consumption of high-sugar food.

Topics: Analysis of Variance; Animals; Benzoxazines; Body Weight; Dietary Carbohydrates; Drug Interactions; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Male; Morpholines; Naphthalenes; Peptide Fragments; Peptides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Glucagon; Venoms

Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the muscularis externa in the stomach and in myenteric plexus neurons throughout the gut. No GLP-1R was seen in primate liver and thyroid. GLP-1R expression seen with immunohistochemistry was confirmed by functional expression using in situ ligand binding with (125)I-GLP-1. In conclusion, these results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLP-1R.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Body Weight; Cell Line; Cricetinae; Duodenum; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Haplorhini; Heart Rate; Humans; Insulin; Insulin Secretion; Ligands; Liraglutide; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptides; Protein Binding; Receptors, Glucagon; Tissue Distribution; Transfection; Venoms

Glucagon-like peptide 1 receptors (GLP-1R) are expressed in multiple tissues and activation results in metabolic benefits including enhanced insulin secretion, slowed gastric emptying, suppressed food intake, and improved hepatic steatosis. Limited and inconclusive knowledge exists regarding whether the effects of chronic exposure to a GLP-1R agonist are solely mediated via this receptor. Therefore, we examined 3-mo dosing of exenatide in mice lacking a functional GLP-1R (Glp1r(-/-)). Exenatide (30 nmol · kg(-1) · day(-1)) was infused subcutaneously for 12 wk in Glp1r(-/-) and wild-type (Glp1r(+/+)) control mice fed a high-fat diet. Glycated hemoglobin A1c (HbA1c), plasma glucose, insulin, amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), body weight, food intake, terminal hepatic lipid content (HLC), and plasma exenatide levels were measured. At the end of the study, oral glucose tolerance test (OGTT) and rate of gastric emptying were assessed. Exenatide produced no significant changes in Glp1r(-/-) mice at study end. In contrast, exenatide decreased body weight, food intake, and glucose in Glp1r(+/+) mice. When compared with vehicle, exenatide reduced insulin, OGTT glucose AUC0-2h, ALT, and HLC in Glp1r(+/+) mice. Exenatide had no effect on plasma amylase or lipase levels. Exenatide concentrations were approximately eightfold higher in Glp1r(-/-) versus Glp1r(+/+) mice after 12 wk of infusion, whereas renal function was similar. These data support the concept that exenatide requires a functional GLP-1R to exert chronic metabolic effects in mice, and that novel "GLP-1" receptors may not substantially contribute to these changes. Differential exenatide plasma levels in Glp1r(+/+) versus Glp1r(-/-) mice suggest that GLP-1R may play an important role in plasma clearance of exenatide and potentially other GLP-1-related peptides.

Topics: Alanine Transaminase; Amylases; Animals; Aspartate Aminotransferases; Biomarkers; Blood Glucose; Body Weight; Eating; Exenatide; Gastric Emptying; Glomerular Filtration Rate; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Hypoglycemic Agents; Infusions, Subcutaneous; Insulin; Lipase; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptides; Receptors, Glucagon; Time Factors; Venoms

The glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 potently suppresses food intake in animals and humans. However, little is known about the behavioural specificity of this effect either when administered alone or when co-administered with another anorectic agent.. The present study characterises the effects of exendin-4, both alone and in combination with naltrexone, on behaviours displayed by male rats during tests with palatable mash.. Experiment 1 examined the dose-response effects of exendin-4 (0.025-2.5 μg/kg, IP), while experiment 2 profiled the effects of low-dose combinations of the peptide (0.025 and 0.25 μg/kg) and naltrexone (0.1 mg/kg).. In experiment 1, exendin-4 dose dependently suppressed food intake as well as the frequency and rate of eating. However, these effects were accompanied by dose-dependent reductions in all active behaviours and, at 2.5 μg/kg, a large increase in resting and disruption of the behavioural satiety sequence (BSS). In experiment 2, while exendin-4 (0.25 μg/kg) and naltrexone each produced a significant reduction in intake and feeding behaviour (plus an acceleration in the BSS), co-treatment failed to produce stronger effects than those seen in response to either compound alone.. Similarities between the behavioural signature of exendin-4 and that previously reported for the emetic agent lithium chloride would suggest that exendin-4 anorexia is related to the aversive effects of the peptide. Furthermore, as low-dose combinations of the peptide with naltrexone failed to produce an additive/synergistic anorectic effect, this particular co-treatment strategy would not appear to have therapeutic significance.

Topics: Animals; Appetite Depressants; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Eating; Exenatide; Feeding Behavior; Male; Naltrexone; Peptides; Rats; Venoms

Weight gain and hypoglycaemia are common adverse effects associated with anti-diabetic treatments.. Our aim was to evaluate the long-term effects of adjunctive exenatide therapy on weight loss and glycaemic control in patients with type 2 diabetes.. A review of medical records in a specialist diabetes clinic over 5 years identified 446 patients who were prescribed exenatide therapy. We examined change in glycosylated haemoglobin (HbA1c), weight, albumin-creatinine ratio and hypoglycaemic medication during 24 months follow up.. Subjects were aged 59 ± 10 years (49% women) and received exenatide in combination with oral agents and insulin (47%). During an average of 17 ± 14 months follow up, 51% (more women than men; odds ratio 1.69, 95% confidence interval 1.14–2.49) remained on treatment. Lack of efficacy (33%) and/or gastrointestinal (27%) side-effects were the main reasons for treatment cessation. At 24 months, there was a reduction in HbA1c of 0.7 ± 1.2% and weight loss of 4.3 ± 5.2 kg. Change in HbA1c was similar regardless of concurrent insulin therapy, yet insulin was associated with greater weight reduction (4.8 ± 5.3 vs 3.8 ± 5.1 kg, P = 0.016). Independent predictors of HbA1c response were higher baseline HbA1c, longer duration of diabetes and use of insulin or sulfonylureas at study end. Predictors of weight response were baseline use of insulin or thiazolidinediones, increased age, female sex and sulfonylurea or thiazolidinediones at study end. Longer exenatide treatment duration was favourable for reducing HbA1c and weight.. Exenatide is effective in reducing HbA1c and weight, regardless of concurrent insulin, and in a specialist diabetes outpatient clinic, is recommended for use in clinical practice.

Topics: Ambulatory Care Facilities; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Tolerance; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Retrospective Studies; Time Factors; Treatment Outcome; Venoms

Repeated administration of the long-acting glucagon-like peptide 1 receptor agonist exendin-4 (EX-4) has been shown to reduce food intake and body weight and do so without a rebound increase in food intake after treatment termination. The current study examines the neural mechanisms underlying these actions. After 6 weeks of maintenance on a standard chow or a high-fat (HF) diet, male Sprague Dawley rats were treated with EX-4 (3.2 μg/kg, i.p., twice a day) or vehicle for 9 consecutive days. Food intake and body weight (BW) were monitored daily. Expression of the genes for the hypothalamic arcuate nucleus (ARC) peptides proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti gene-related protein was determined. Expression of the dopamine precursor tyrosine hydroxylase (TH) gene in the ventral tegmental area and genes for dopamine receptors 1 (D1R) and dopamine receptor 2 in the nucleus accumbens were also determined. Pair-fed groups were included to control for the effects of reduced food intake and BW. Treatment with EX-4 significantly decreased food intake and BW over the 9-day period in both the standard chow and HF groups. HF feeding decreased POMC without changing NPY/agouti gene-related protein gene expression in the ARC. Treatment with EX-4 increased POMC and decreased NPY expression independent of the reduction of food intake and BW. Mesolimbic TH and D1R gene expression were decreased significantly in chronic HF diet-fed rats, and these changes were reversed in both EX-4 and pair-fed conditions. These results suggest a role for increased POMC and decreased NPY expression in the ARC in the effects of EX-4 on food intake and BW. Our findings also suggest that EX-4 induced the recovery of mesolimbic TH and D1R expression in HF diet-fed rats may be secondary to HF intake reduction and/or weight loss.

Topics: Animals; Biomarkers; Body Weight; Brain; Eating; Exenatide; Homeostasis; Humans; Male; Neuropeptide Y; Obesity; Peptides; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Venoms

Glucagon‑like peptide‑1 (GLP‑1) is involved in the development of non‑alcoholic steatohepatitis (NASH), which is characterized by fatty acid imbalance. The aim of this study was to investigate the effects of the GLP‑1 receptor (GLP‑1R) agonist, exendin‑4 (Ex‑4), on hepatic fatty acid metabolism and its key enzyme, Δ‑5‑desaturase, in a murine model of NASH. NASH was induced in db/db mice fed a methionine‑choline deficient (MCD) diet. Ex‑4 (n=4) or saline [control (CON); n=4] was administered intraperitoneally for 8 weeks. Steatohepatitis activity was evaluated by non‑alcoholic fatty liver disease (NAFLD) activity score. Hepatic fatty acid composition and Δ‑5‑desaturase index were analyzed by gas chromatography. Ex‑4 treatment significantly reduced body weight and the NAFLD activity score. Hepatic concentrations of long‑chain saturated fatty acids (SFAs) were significantly higher in the Ex‑4 group compared to the CON group (23240±955 vs. 31710±8436 µg/g•liver, P<0.05).Ex‑4 significantly reduced hepatic n‑3 polyunsaturated fatty acid (PUFA)/n‑6 PUFA ratio compared to the CON group (13.83±3.15 vs. 8.73±1.95, P<0.05). In addition, the hepatic Δ‑5‑desaturase index was significantly reduced in the Ex‑4 group compared to the CON group (31.1±12.4 vs. 10.5±3.1, P<0.05). In conclusion, the results showed that Ex‑4 improved steatohepatitis in a murine model of NASH. Furthermore, Ex‑4 altered hepatic long‑chain saturated and PUFA composition and reduced the Δ‑5‑desaturase index. Thus, Ex‑4 may improve NASH by regulating hepatic fatty acid metabolism.

Topics: Animals; Body Weight; Delta-5 Fatty Acid Desaturase; Disease Models, Animal; Exenatide; Fatty Acid Desaturases; Fatty Acids; Glucagon-Like Peptide-1 Receptor; Liver; Male; Mice; Models, Biological; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; Triglycerides; Venoms

Incretins, such as glucagon-like peptide-1 (GLP)-1, have been shown to elevate plasma insulin concentration. The purpose of this study is to investigate the cellular and molecular basis of the beneficial effects of GLP-1. Normal and diabetic male Wistar rats were treated with GLP-1 (50 ng/kg body weight) for 10 weeks. At the end of the experiment, pancreatic tissues were taken for immunohistochemistry, immunoelectron microscopy and real-time polymerase chain reaction studies. Samples of blood were retrieved from the animals for the measurement of enzymes and insulin. The results show that treatment of diabetic rats with GLP-1 caused significant (P < 0.05) reduction in body weight gain and blood glucose level. GLP-1 (10(-12)-10(-6) M) induced significant (P < 0.01) dose-dependent increases in insulin release from the pancreas of normal and diabetic rats compared to basal. Diabetes-induced abnormal liver (aspartate aminotransferase and alanine aminotransferase) and kidney (blood urea nitrogen and uric acid) parameters were corrected in GLP-1-treated rats compared to controls. GLP-1 treatment induced significant (P < 0.05) elevation in the expression of pancreatic duodenal homeobox-1, heat shock protein-70, glutathione peroxidase, insulin receptor and GLP-1-receptor genes in diabetic animals compared to controls. GLP-1 is present in pancreatic beta cells and significantly (P < 0.05) increased the number of insulin-, glutathione reductase- and catalase-immunoreactive islet cells. The results of this study show that GLP-1 is co-localized with insulin and seems to exert its beneficial effects by increasing cellular concentrations of endogenous antioxidant genes and other genes involved in the maintenance of pancreatic beta cell structure and function.

Topics: Animals; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Exenatide; Fluorescent Antibody Technique; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glutathione Reductase; Insulin; Insulin Secretion; Islets of Langerhans; Kidney; Lipids; Liver; Male; Peptides; Rats, Wistar; Time Factors; Venoms

Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse.. C57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices.. Whereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice.. Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Male; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis; Peptides; Sitagliptin Phosphate; Venoms

In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry.. From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m(2), n = 22,015), and metabolic control (HbA(1c) ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21-26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27-40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9-1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0-1.5% with DPP-4 inhibitors.. In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials.

Topics: Adamantane; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Italy; Male; Metformin; Middle Aged; Monitoring, Physiologic; Nitriles; Peptides; Pyrazines; Pyrrolidines; Registries; Sex Factors; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diet, High-Fat; Drug Synergism; Eating; Exenatide; Glucagon; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptides; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Venoms

Aim of the study was to retrospectively analyze the clinical parameters that contribute to the therapeutic outcome of GLP-1 analogues.. We enrolled 106 patients with type 2 diabetes mellitus (T2DM), treated with liraglutide (N.=69) or exenatide (N.=37) for longer than three months. The patients were divided into two groups: good responders and poor responders to GLP-1 analogues, based on pretreatment and post-treatment HbA1c levels. Good responders were those whose HbA1c level had decreased by 1% or more, or maintained at less than 7%. All other patients were categorized as poor responders. We used univariate and multivariate analyses to assess pretreatment parameters between the two groups.. Approximately 35% of the patients were poor responders. Our analysis of the pretreatment clinical parameters revealed that number of anti-diabetic agents and use of sulfonylurea were significantly associated with poor response to liraglutide (P=0.02 and P=0.03, respectively) in a multivariate analysis. We were not able to find any candidate related to clinical response to exenatide.. Our study showed that the therapeutic effects of GLP-1 analogues on T2DM patients were heterogeneous. T2DM patients who require multiple anti-diabetic agents, especially sulfonylurea, do not benefit from liraglutide treatment.

Topics: Adult; Aged; Alanine Transaminase; Anthropometry; Biguanides; Body Weight; Comorbidity; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Liraglutide; Male; Middle Aged; Peptides; Prognosis; Retrospective Studies; Sulfonylurea Compounds; Thiazolidines; Treatment Outcome; Venoms

Gastrointestinal mechanisms involved in the suppression of appetite are compromised in obesity. Glucagon-like peptide-1 (GLP-1) is released in response to nutrients, suppresses food intake, and has been shown to play a role in regulation of energy balance. It is not known whether obese-prone (OP) rats exhibit dysfunctional GLP-1 signaling that could contribute to decreased nutrient-induced satiation and hyperphagia. Therefore, we examined the effects of exogenous intraperitoneal administration of the GLP-1R agonist, exendin-4 (Ex-4), on food intake in OP and obese-resistant (OR) rats during chow or high-energy/high-fat (HE/HF) feeding. All doses of Ex-4 effectively suppressed intake in OP and OR rats fed chow; however, during HE/HF-feeding, OP rats suppressed intake significantly less than OR rats at all Ex-4 doses tested. This was associated with downregulation of GLP-1R mRNA expression in the vagal nodose ganglia of OP rats. Furthermore, HE/HF-fed OP rats had significantly lower plasma GLP-1 levels, decreased protein levels of GLP-1 in the intestinal epithelium, and reduced number of L cells in the distal ileum. These results demonstrate that HE/HF-feeding, coupled with OP phenotype, results in reduced endogenous GLP-1 and GLP-1R activation, indicating that impaired GLP-1 signaling during obesity may exacerbate hyperphagia and weight gain.

Topics: Adiposity; Animals; Body Weight; Diet, High-Fat; Down-Regulation; Eating; Exenatide; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Ileum; Intestinal Mucosa; Male; Nodose Ganglion; Obesity; Peptides; Rats; Receptors, Glucagon; Venoms

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion and that has a range of metabolic effects, including enhancing insulin secretion and decreasing food intake. Postprandial GLP-1 secretion is greatly enhanced in rats and humans after some bariatric procedures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to reduced intake, weight loss, and the improvements in glucose homeostasis after VSG. We tested this hypothesis using two separate models of GLP-1 receptor deficiency. We found that VSG-operated GLP-1 receptor-deficient mice responded similarly to wild-type controls in terms of body weight and body fat loss, improved glucose tolerance, food intake reduction, and altered food selection. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG surgery.

Topics: Animals; Body Composition; Body Weight; Eating; Exenatide; Gastrectomy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Mice; Mice, Knockout; Obesity; Peptides; Postprandial Period; Receptors, Glucagon; Venoms

The aim of this study was to examine the effects of a new sustained-release (SR) microsphere formulation of exenatide, DA-3091, on body weight gain and hepatic injury in high fat diet (HFD)-induced obese mice and high sucrose diet (HSD)-induced non-alcoholic fatty liver disease (NAFLD) mice. Then, we determined whether DA-3091 has the potency as a drug for the treatment of metabolic disease. In obese mice, after 8-week treatment, the body weight gain was significantly more suppressed by both 1 mg/kg and 2 mg/kg of DA-3091, monthly subcutaneous administered, than by 10 mg/kg/day of sibutramin, a drug against obesity. In NAFLD mice, a significant reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, representative markers of hepatic injury, was observed after biweekly subcutaneous administration of 1 mg/kg and 2 mg/kg of DA-3091 for 8 weeks. A significant reduction in hepatic lipid accumulation was observed in DA-3091 treated groups as well. Based on these results, it is demonstrated that DA-3091 has the potency as a drug for the treatment of metabolic disease.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Delayed-Action Preparations; Dietary Fats; Endotoxins; Exenatide; Fatty Liver; Hypoglycemic Agents; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Microspheres; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size; Peptides; Prodrugs; Sucrose; Venoms

Exendin-4 (Ex-4) is a natural agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently being used as a treatment for type 2 diabetes mellitus due to its insulinotropic properties. Previous studies have revealed that acute administration of both GLP-1 and, in particular, Ex-4 potently stimulates hypothalamic-pituitary-adrenal (HPA) axis activity. In this work, the effects of prolonged Ex-4 exposure on HPA function were explored. To this end, Sprague-Dawley rats were subjected to a daily regimen of two Ex-4 injections (5 μg/kg sc) for a minimum of 7 days. We found that subchronic Ex-4 administration produced a number of effects that resemble chronic stress situations, including hyperactivation of the HPA axis during the trough hours, disruption of glucocorticoid circadian secretion, hypertrophy of the adrenal gland, decreased adrenal gland sensitivity, impaired pituitary-adrenal stress responses, and reductions in both food intake and body weight. In addition, a threefold increase in diuresis was observed followed by a 1.5-fold increase in water intake; these latter effects were abolished by adrenalectomy. Together, these findings indicate that Ex-4 induces a profound dysregulation of HPA axis activity that may also affect renal function.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Body Weight; Circadian Rhythm; Corticosterone; Eating; Exenatide; Glucagon-Like Peptide 1; Hypothalamo-Hypophyseal System; Male; Peptides; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Stress, Physiological; Venoms; Water-Electrolyte Balance

Overconsumption of a high-fat diet promotes weight gain that can result in obesity and associated comorbidities, including Type 2 diabetes mellitus. Consumption of a high-fat diet also alters gut-brain communication. Glucagon-like peptide 1 (GLP-1) is an important gastrointestinal signal that modulates both short- and long-term energy balance and is integral in maintenance of glucose homeostasis. In the current study, we investigated whether high-fat diets (40% or 81% kcal from fat) modulated the ability of the GLP-1 receptor (GLP-1r) agonists exendin-4 (Ex4) and liraglutide to reduce food intake and body weight. We observed that rats maintained on high-fat diets had a delayed acute anorexic response to peripheral administration of Ex4 or liraglutide compared with low-fat diet-fed rats (17% kcal from fat). However, once suppression of food intake in response to Ex4 or liraglutide started, the effect persisted for a longer time in the high-fat diet-fed rats compared with low-fat diet-fed rats. In contrast, centrally administered Ex4 suppressed food intake similarly between high-fat diet-fed and low-fat diet-fed rats. Chronic consumption of a high-fat diet did not change the pharmacokinetics of Ex4 but increased intestinal Glp1r expression and decreased hindbrain Glp1r expression. Taken together, these findings demonstrate that dietary composition alters the temporal profile of the anorectic response to exogenous GLP-1r agonists.

Topics: Animals; Body Weight; Diet, Fat-Restricted; Diet, High-Fat; Eating; Energy Metabolism; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Hypoglycemic Agents; Liraglutide; Male; Malnutrition; Models, Animal; Peptides; Rats; Rats, Long-Evans; Receptors, Glucagon; Venoms

The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex-4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver.

Topics: Animals; Benzeneacetamides; Body Weight; Drug Synergism; Eating; Enzyme Activation; Exenatide; Fatty Liver; Glucokinase; Glucose; Glycogen; Homeostasis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Male; Mice; Mice, Inbred C57BL; Peptides; Venoms

Metformin has been reported to increase the expression of the glucagon-like peptide-1 (GLP-1) receptor in pancreatic beta cells in a peroxisome proliferator-activated receptor (PPAR)-α-dependent manner. We investigated whether a PPARα agonist, fenofibrate, exhibits an additive or synergistic effect on glucose metabolism, independent of its lipid-lowering effect, when added to metformin. Non-obese diabetic Goto-Kakizaki (GK) rats were divided into four groups and treated for 28 days with metformin, fenofibrate, metformin plus fenofibrate or vehicle. The random blood glucose levels, body weights, food intake and serum lipid profiles were not significantly different among the groups. After 4 weeks, metformin, but not fenofibrate, markedly reduced the blood glucose levels during oral glucose tolerance tests, and this effect was attenuated by adding fenofibrate. Metformin increased the expression of the GLP-1 receptor in pancreatic islets, whereas fenofibrate did not. During the intraperitoneal glucose tolerance tests with the injection of a GLP-1 analog, metformin and/or fenofibrate did not alter the insulin secretory responses. In conclusion, fenofibrate did not confer any beneficial effect on glucose homeostasis but reduced metformin's glucose-lowering activity in GK rats, thus discouraging the addition of fenofibrate to metformin to improve glycemic control.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Exenatide; Feeding Behavior; Fenofibrate; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Homeostasis; Immunohistochemistry; Injections, Intraperitoneal; Insulin-Secreting Cells; Lipid Metabolism; Male; Metformin; Peptides; Rats; Receptors, Glucagon; Venoms

Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is effective in inducing weight loss. The exact mechanisms are not fully understood. Reduced appetite and food intake may play important roles. Sweet taste contributes to food palatability, which promotes appetite. Interestingly, GLP-1 and its receptor are expressed in the taste buds of rodents and their interaction has an effect on mediating sweet taste sensitivity. Our aim was to investigate whether sweet taste will be changed after long term treatment with exenatide. The results showed that high-fat diet induced obese rats (HF-C) presented metabolic disorders in food intake, body weight, blood glucose and lipid metabolism compared with long term exenatide treated obese rats (EX) and normal chow fed control rats (NC). Meanwhile, greater preference for sweet taste was observed in HF-C rats but not in EX rats. Compared with NC rats, brain activities induced by sweet taste stimulation were stronger in HF-C rats, however these stronger activities were not found in EX rats. We further found reduced sweet taste receptor T1R3 in circumvallte taste buds of HF-C rats, while GLP-1 was increased. Besides, serum leptin was evaluated in HF-C rats with decreased leptin receptor expressed in taste buds. These changes were not observed in EX rats, which suggest them to be the underlying hormone and molecular mechanisms responsible for alterations in sweet taste of HF-C rats and EX rats. In summary, our results suggest that long term treatment with exenatide could benefit dietary obese rats partially by reversing sweet taste changes.

Topics: Animals; Blood Glucose; Body Weight; Choice Behavior; Diet, High-Fat; Drug Administration Schedule; Eating; Exenatide; Gene Expression; Glucagon-Like Peptide 1; Hypoglycemic Agents; Leptin; Lipid Metabolism; Male; Obesity; Peptides; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Taste; Taste Buds; Venoms

One developing strategy for obesity treatment has been to use combinations of differently acting pharmacotherapies to improve weight loss with fewer adverse effects. The purpose of this study was to determine whether the combination of naltrexone (Nal), an opioid antagonist acting on the reward system, and exendin-4 (Ex-4), a glucagon-like peptide 1 agonist acting on satiety signaling, would produce larger reductions in food intake than either alone in rats. Because the anorectic potencies of both compounds have been associated with nausea and malaise, the influence of these drug combinations on the acquisition of a conditioned taste aversion (CTA) was also determined.. In Experiment 1, the acute anorectic effects of Nal (0.32-3.2 mg kg(-1); intraperitoneally (i.p.)) and Ex-4 (1-10 μg kg(-1); i.p.) were assessed alone or in combination. Combinational doses were further investigated by the repeated daily administration of 1 mg kg(-1) Nal+3.2 μg kg(-1) Ex-4 for 4 days. In Experiment 2, both compounds alone or in combination were used as unconditioned stimuli in a series of CTA tests.. Nal and Ex-4, alone or in combination, suppressed food intake in a dose-dependent manner, and the interaction on food intake between Nal and Ex-4 was additive. In the CTA paradigm, Nal (1 mg kg(-1)) alone did not support acquisition, whereas a CTA was evident with doses of Ex-4 (1 or 3.2 μg kg(-1)). Combinations of Nal and Ex-4 also resulted in a more rapid and robust acquisition of a CTA.. Given that the Nal and Ex-4 combination produces additive effects on not only food intake reduction but also food aversion learning, this specific drug combination does not have the benefit of minimizing the adverse effects associated with each individual drug. These data suggest that it is necessary to evaluate both the positive and adverse effects at early stages of combinational drug development.

Topics: Animals; Appetite Depressants; Body Weight; Drug Interactions; Drug Therapy, Combination; Eating; Exenatide; Hypoglycemic Agents; Male; Naltrexone; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Taste; Venoms; Weight Loss

In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes.. The effects repeated dose treatment for 14 days with exendin-4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity.. Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content.. Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gastrins; Glucagon; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Omeprazole; Peptides; Venoms

The potential association of glucagon-like peptide receptor agonists (GLP-1RAs) with the development of pancreatitis or pancreatic malignancies in patients with diabetes has been suggested. This study evaluated the long-term effects of the GLP-1RA exenatide on pancreatic exocrine structure and function in the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes.. Rats received subcutaneous twice-daily injections of 0 (control), 6, 40 and 250 µg/kg/day exenatide for 3 months. Clinical signs, body and pancreas weight, food consumption, HbA1c, fasting serum amylase, lipase, glucose and insulin concentrations were evaluated during treatment and after a 28-day off-drug period to assess the reversibility of any observed effects. Morphometric analysis of pancreatic ductal cell proliferation and apoptosis were performed.. Plasma exenatide concentrations were several-fold higher than therapeutic levels observed in humans. No exenatide-related effects were observed on clinical signs, lipase concentration, pancreatic weight, pancreatic histology, ductal cell proliferation or apoptosis. Exenatide improved animal survival, physical condition, glucose concentrations and HbA1c, decreased food intake, and increased serum insulin concentration. Total amylase concentrations, although within normal ranges, were slightly higher in exenatide-treated rats; following the off-drug period, total amylase concentrations were comparable in treated and untreated rats. Exenatide-related minimal-to-moderate islet hypertrophy was observed at doses ≥6 µg/kg/day, with dose-related increases in incidence and degree. These changes were still present after the off-drug period.. Chronic administration of exenatide in ZDF rats resulted in the expected metabolic benefits and improved animal survival, with no adverse effects noted on pancreatic exocrine structure and function.

Topics: Amylases; Animals; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Eating; Exenatide; Fasting; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Hypoglycemic Agents; Injections, Subcutaneous; Lipase; Male; Organ Size; Pancreas; Pancreatitis; Peptides; Rats; Rats, Zucker; Receptors, Glucagon; Venoms

Glucagon-like peptide-1 (GLP-1) and endocannabinoids are involved in appetite control. Recently we have demonstrated that cannabinoid (CB)1 receptor antagonist and GLP-1 receptor agonist synergistically suppress food intake in the rat. The aim of the present study was to determine the effects of GLP-1 receptor stimulation or blockade on feeding behavior in rats treated with WIN 55,212-2, a CB1 receptor agonist.. Experiments were performed on adult male Wistar rats. In the first experiment the effects of increasing doses (0.5-4.0 mg/kg) of WIN 55,212-2 injected intraperitoneally on 24-hour food consumption were tested. In further experiments a GLP-1 receptor antagonist, exendin (9-39), and WIN 55,212-2 or a GLP-1 receptor agonist, exendin-4, and WIN 55,212-2 were injected intraperitoneally at subthreshold doses (that alone did not change food intake and body weight) to investigate whether these agents may interact to affect food intake in rats.. WIN 55,212-2 administered at low doses (0.5-2 mg/kg) did not markedly change 24-hour food consumption; however, at the highest dose, daily food intake was inhibited. Combined administration of WIN 55,212-2 and exendin (9-39) did not change the amount of food consumed compared to either the control group or to each agent injected alone. Combined injection of WIN 55,212-2 and exendin-4 at subthreshold doses resulted in a significant decrease in food intake and body weight in rats.. Stimulation of the peripheral CB1 receptor by its agonist WIN 55,212-2 can induce anorexigenic effects or potentiate, even at a subthreshold dose, the effects of exendin-4, a known anorectic agent. Hence, this dual action of the cannabinoid system should be considered in the medical use of CB1 agonists.

Topics: Animals; Benzoxazines; Body Weight; Dose-Response Relationship, Drug; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Injections, Intraperitoneal; Male; Morpholines; Naphthalenes; Peptide Fragments; Peptides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Glucagon; Venoms

This open-label, single-period study assessed the pharmacokinetics, safety, tolerability, and pharmacodynamics of exenatide once weekly (q.w.), following single and multiple weekly subcutaneous (s.c.) injections in native Chinese patients with type 2 diabetes (T2D).. Patients (n = 25; mean [±SD] age 51.3 ± 8.2 years; body mass index 25.6 ± 2.4 kg/m(2) ; HbA1c 7.4 ± 1.2%; duration of diabetes 3.1 ± 3.1 years) previously treated with diet modification and exercise alone or incombination with stable metformin doses were enrolled in the study. Twenty-five patients received weekly doses of 2 mg, s.c., exenatide q.w. for 10 weeks, followed by 10 weeks observation. Pharmacokinetic parameters of exenatide, fasting plasma glucose (FPG), HbA1c, and body weight were summarized using descriptive statistics.. Steady state plasma exenatide concentrations (299 pg/mL) were attained within 8 weeks. Exenatide q.w. was generally well tolerated, and the majority of adverse events reported were mild in severity. The most frequent study drug-related adverse events were diarrhea and vomiting. Decreases were observed from baseline to 10 weeks in FPG (~3.0 mmol/L), HbA1c (~1.0%), and body weight (~3.8 kg).. This is the first clinical trial of exenatide q.w. in native Chinese patients with T2D. The results suggest that exenatide q.w. has a pharmacokinetic profile in this patient population similar to that observed in other ethnic and racial populations, and appears to be safe and generally well tolerated, with the potential to improve glycemic control and decrease body weight without increasing the risk of hypoglycemia.

Topics: Adult; Asian People; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Drug Tolerance; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Male; Middle Aged; Peptides; Venoms

We investigated the effects of exendin-4 (Ex4) treatment on expression of clusterin and β cell regeneration in the endocrine pancreas in neonatal streptozotocin (nSTZ) diabetic rats. Three groups were used: (1) n2-STZ group; on the second day after birth 100mg/kg STZ was given i.p. to two groups of newborn rats, (2) n2-STZ+Ex4 group; 3μg/kg/day Ex4 was given for 5 days starting on the third day, and (3) control group. In situ hybridization for mRNAs of insulin and clusterin, double immunostaining for insulin/clusterin and insulin/BrdU were carried out. Immunostaining for insulin, glucagon, somatostatin, clusterin, synaptophysin and pdx-1 was performed. In the n2-STZ+Ex4 group, BrdU/insulin and insulin/clusterin immunopositive cells were significantly increased in the islets of Langerhans in comparison to the other groups. The areas occupied by the insulin mRNA and peptide positive cells and also pdx-1 immunopositive cells were decreased in the n2-STZ diabetic group compared with the other groups. The clusterin mRNA and protein positive cells, and also the glucagon and somatostatin cells, were significantly increased in the islets of the n2-STZ and the n2-STZ+Ex4 groups compared with the control group. The results show that Ex4 treatment induces new beta cell clusters via up-regulation of clusterin, which might be effective on beta-cell proliferation and neogenesis.

Topics: Animals; Animals, Newborn; Biomarkers; Blood Glucose; Body Weight; Cell Proliferation; Clusterin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gene Expression; Glucagon; Homeodomain Proteins; Hypoglycemic Agents; In Situ Hybridization; Insulin-Secreting Cells; Peptides; Rats; Rats, Wistar; Regeneration; RNA, Messenger; Trans-Activators; Venoms

Stress activates the hypothalamus-pituitary-adrenal (HPA) axis leading to the release of glucocorticoids (GC). Increased activity of the HPA axis and GC exposure has been suggested to facilitate the development of obesity and metabolic syndrome. Nonetheless, different stressors can produce distinct effects on food intake and may support different directions of food learning e.g. avoidance or acceptance. This study examined whether interoceptive (LiCl and exendin-4) and restraint stress (RS) support similar or distinct food learning. Female rats were exposed to different stressors after their consumption of a palatable food (butter icing). After four palatable food-stress pairings, distinct intakes of the butter icing were observed in rats treated with different stressors. Rats that received butter icing followed by intraperitoneal injections of LiCl (42.3mg/kg) and exendin-4 (10μg/kg) completely avoided the palatable food with subsequent presentations. In contrast, rats experiencing RS paired with the palatable food increased their consumption of butter icing across trials and did so to a greater degree than rats receiving saline injections. These data indicate that interoceptive and psychosocial stressors support conditioned food avoidance and acceptance, respectively. Examination of c-Fos immunoreactivity revealed distinct neural activation by interoceptive and psychosocial stressors that could provide the neural basis underlying opposite direction of food acceptance learning.

Topics: Animals; Antimanic Agents; Avoidance Learning; Binge-Eating Disorder; Body Weight; Conditioning, Operant; Data Interpretation, Statistical; Eating; Exenatide; Female; Food Preferences; Immunohistochemistry; Lithium Chloride; Peptides; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stress, Psychological; Venoms

Metabolic sensors play an important role in the control of food intake, utilization of nutrients and demonstration of feeding behaviour. In this work we describe the study done in our laboratory on glucokinase (GK) as brain glucose sensor, the AMP kinase (AMPK) as detector of the fall of intracellular energy charge and as the S6K in the signaling pathway of mTOR with opposite effects to AMPK. Glucose sensors are molecular designs that detect with accuracy glucose concentrations, facilitating therefore the homeostasis of this hexose. We consider GK as a component of a glucose sensor system that might modulates the feeding behaviour and indirectly the control of body weight. Our findings indicate that GK and GLUT-2 mRNAs and proteins are coexpressed mainly in areas of the hypothalamus implied in the control of food intake. We have also found a high glucose phosphorylating activity with kinetic properties similar to that reported in the liver, with a high apparent Km for glucose that displays no product inhibition by glucose-6-phosphate. GK may be also regulated by the presence of glucokinase regulatory protein (GKRP), which has been identified in the same brain areas than GK. The coexpression of these molecules might play a role as glucose sensors in which GLUT-2 has a permissive role and the interactions of GK with GKRP made possible a real sensor activity. Furthermore, the effects of anorexigenic peptides in this system should facilitate the transduction of signals required to produce a state of satiety. Thus, GLP-1 reduced significantly the glucose metabolism in areas of the hypothalamus and brainstem related with food intake, which open new ways to the study of pathophysiologicals aspects of feeding behaviour. Besides we have studied the functions of AMPK and mTOR pathway in the hypothalamic areas ventromedial (VMH) and lateral (LH) under situations with alterations of the nutritional status and energy balance. Our results revealed that the activation of AMPK and S6K in VMH y LH occur in response to the changes of glucose concentrations or in the changes in the nutritional state, as well as GLP-1/exendin-4 act by counteracting the activation/inactivation of these kinases, which support a modulating role of these peptides on the kinases. On the other hand, GLP-1/exendin-4 might contribute to the normalization of the altered values of these kinases in pathophysiological states such as obesity.

Topics: Adenylate Kinase; Body Weight; Brain; Energy Metabolism; Exenatide; Feeding Behavior; Glucagon-Like Peptide 1; Glucokinase; Homeostasis; Humans; Hypothalamus; Peptides; Ribosomal Protein S6 Kinases; Signal Transduction; TOR Serine-Threonine Kinases; Venoms

The incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in the regulation of appetite by acting as an anorexigenic gut-brain signal. The postprandial release of GLP-1 can be blunted in obese humans and animals. However, it remains unknown whether obesogenic diets with varying fat and carbohydrate content may differentially influence the effectiveness of GLP-1 feedback. To investigate this, male Sprague-Dawley rats were fed a standard (low fat) chow diet, or one of two high-energy diets varying in fat content (45 or 60 kcal%) for 28 weeks. Intake of sucrose and fructose solutions, two commonly added sugars in the Western diet, was then tested in nondeprived rats following administration of the GLP-1 receptor agonist, Exendin-4 (0, 0.5, 1, 2, 3 µg/kg; s.c.). Exendin-4 dose-dependently reduced short (2 h) sucrose and fructose intake. This effect was significantly attenuated in rats fed more dietary fat, despite both diets resulting in obesity. These findings demonstrate that intake of carbohydrates when offered as treats can be regulated by GLP-1 and suggests that dietary fat consumption, rather than extra calories or obesity, may lead to impaired GLP-1 feedback to curb carbohydrate intake. Future studies are warranted to investigate the relevance of these observations to humans and to elucidate the underlying mechanisms.

Topics: Analysis of Variance; Animals; Appetite Regulation; Body Weight; Dietary Fats; Dietary Sucrose; Dose-Response Relationship, Drug; Exenatide; Fructose; Glucagon-Like Peptide 1; Hypoglycemic Agents; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Venoms

The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea [conditioned taste avoidance (CTA) and pica (ingestion of nonnutritive substances)], results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal-independent pathway involving GLP-1R activation in the brain as the exendin-4-induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9-39), but not by vagotomy. Direct administration of exendin-4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists.

Topics: Animals; Body Weight; Eating; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Liraglutide; Male; Nausea; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Solitary Nucleus; Vagus Nerve; Venoms

The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation.. Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (∼33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery.. Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Injections, Intraventricular; Leptin; Male; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Rhombencephalon; Signal Transduction; Venoms

This observational study evaluated the clinical effectiveness of exenatide BID (exenatide) vs. insulin glargine (glargine) in patients with type 2 diabetes mellitus in ambulatory clinical practice.. Retrospective analyses were conducted using an electronic medical record (EMR) database among adult patients with type 2 diabetes mellitus initiating exenatide or glargine between 1 November 2006 and 30 April 2009. The cohorts were propensity-score matched to control baseline demographics, clinical measures, health status and medication use. The changes from baseline to a 12-month follow-up period for A1C (primary outcome), weight, body mass index (BMI), blood pressure and lipid levels were compared between the matched cohorts using paired tests.. Propensity-score matching between the exenatide (n = 4494) and glargine (n = 5424) cohorts led to 2683 matched pairs with comparable characteristics, including age, gender and baseline clinical values. The exenatide cohort achieved a greater mean reduction in A1C (-0.6% vs. -0.4%, p < 0.01), weight (-2.6 kg vs. -0.2 kg, p < 0.01), BMI (-0.8 kg/m(2) vs. -0.04 kg/m(2) , p < 0.01) and systolic blood pressure (SBP) (-1.8 mmHg vs. -0.1 mmHg, p < 0.01) in the follow-up period. The changes in diastolic blood pressure and lipid levels were not significantly different between cohorts.. Compared to glargine, exenatide-treated patients experienced significant reductions in A1C, weight, BMI and SBP. Acknowledging the limitations of observational research, exenatide showed greater clinical effectiveness than glargine from a large EMR database in the ambulatory care setting.

Topics: Ambulatory Care; Blood Glucose; Body Mass Index; Body Weight; Cohort Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Lipids; Male; Middle Aged; Peptides; Retrospective Studies; Treatment Outcome; Venoms; Weight Loss

Glucagon-like peptide-1 (GLP-1) and its stable analogue exendin-4 maintain glucose homeostasis by modulating insulin secretion from pancreatic β-cells and controlling hepatic glucose output. Glucokinase (GK), by catalysing the first step in glycolysis, plays an important role in glucose-stimulated insulin secretion and hepatic glucose metabolism. In the present study, we investigated the effects of exendin-4 on GK in high fat-fed and alloxan-treated diabetic mice.. The effects of alloxan (5, 10 and 20 μmol/L) on insulin release from isolated murine islets, as well as glycogen synthesis by isolated murine hepatocytes, were assessed. The effects of exendin-4 (10 nmol/kg, twice daily for 4 weeks) were assessed in high fat-fed, alloxan (50 mg/kg, i.v.)-treated C57 mice. Glucokinase activity was assessed in the same model.. Pretreatment with exendin-4 attenuated alloxan-induced decreases in insulin release and glycogen synthesis in islets and hepatocytes. The alloxan-induced decrease in the GK activity in islets and hepatocytes was also ameliorated by exendin-4 treatment. Pretreatment with the GLP-1 receptor antagonist exendin-9 (100 nmol/L) blocked the effects of exendin-4 on the liver and pancreas. Treatment of high-fat fed, alloxan-treated diabetic mice with exendin-4 (10 nmol/L, i.p.) reduced the severity of diabetic symptoms. Specifically, exendin-4 treatment reduced serum glucose by 50% and %HbA1c by 24% compared with control and significantly decreased HOMA-IR by 39% and increased HOMA-β by 150%. In addition, exendin-4 treatment significantly reduced body weight by 6.8% and serum triglycerides by 35%.. The results indicate that glucose-stimulated insulin release and glycogen synthesis are decreased by alloxan due to reduced GK activity. These findings provide further insight into the mechanism by which exendin-4 regulates glucose homeostasis.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Enzyme Activation; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucokinase; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Peptides; Venoms

The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.

Topics: AMP-Activated Protein Kinases; Animals; Body Weight; Cell Line, Tumor; Cytokines; Diet, High-Fat; Exenatide; Fatty Liver; Feeding Behavior; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Glucose; Homeostasis; Humans; Lipogenesis; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Nicotinamide Phosphoribosyltransferase; Oxidation-Reduction; Palmitic Acid; Peptides; Protein Serine-Threonine Kinases; Receptors, Glucagon; Sirtuin 1; Triglycerides; Venoms

Gastric bypass surgery and exenatide therapy represent two relatively new methods in treating morbid obesity and type 2 diabetes, although there are many differences between them. With the data supported from our hospital, we just want to investigate the differences between bypass surgery and exenatide injection and want to answer the question: Which one is the best? And Why?. Data from January 2009 to January 2010 were summarized for comparison at Shengjing hospital, including weight loss, plasma glucose and insulin changes, glycosylated hemoglobin, and the subjective scores of patients themselves. Plasma lipoprotein and serum ions were measured to evaluate the nutrition status.. Patients in the GB group received more weight loss and better glucose control compared with the EX group. At 6 months, feeding insulin level in the GB group was 18.1 ± 3.2 mU/L, which was much lower than that in the EX group (64.5 ± 13.2 mU/L, P < 0.01). The Hb1AC level in the GR group was 6.08 ± 0.56 %, much lower than that in the EX group (7.19 ± 0.72 %, P < 0.01). We did not find any statistical differences in lipoprotein, plasma ions, and subjective scores between the GB and EX groups.. Gastric bypass surgery is better in weight control and in the remission of insulin resistance compared with exenatide therapy. Both methods were safe and have no nutritional disorder in early stage, although the transferring in the GB group was higher than the EX group. The subjective scores from both groups declared that both methods could be accepted by patients.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Eating; Exenatide; Fasting; Female; Gastric Bypass; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipoproteins; Male; Middle Aged; Obesity, Morbid; Peptides; Remission Induction; Treatment Outcome; Venoms; Weight Loss

Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg(-1)·h(-1))] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg(-1)·h(-1)) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats.

Topics: Animals; Body Composition; Body Fat Distribution; Body Weight; Caloric Restriction; Dose-Response Relationship, Drug; Eating; Exenatide; Glucagon-Like Peptide-1 Receptor; Hyperphagia; Leptin; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms; Weight Gain; Weight Loss

The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co-administration of leptin with other weight loss-inducing hormones equally restores leptin responsiveness in diet-induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site-specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin-4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin-4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter-regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin-4. We conclude that leptin re-sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents.

Topics: Animals; Body Weight; Diet; Drug Combinations; Exenatide; Fibroblast Growth Factors; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Models, Molecular; Obesity; Peptides; Polyethylene Glycols; Venoms

Glucagon-like peptide-1 (GLP-1) [GLP-1 (7-36)-amide] plays a fundamental role in regulating postprandial nutrient metabolism. GLP-1 acts through a G-protein-coupled receptor present on the membranes of many tissues, including myocardium and endothelium. GLP-1 is cleaved by the dipeptidyl peptidase-4 enzyme to its metabolite GLP-1 (9-36)-amide within 1-2 min of its release into the circulation. Investigations have been done in humans and in animal models to determine whether GLP-1 has effects on the myocardium. Infusions of GLP-1 increase cardiac function in ischemic and non-ischemic cardiovascular disease. In humans and animal models, constant infusions of GLP-1 decrease the size of infarction and improve myocardial function in ischemic/reperfusion injury. In cardiomyopathy and heart failure, infusions of GLP-1 improve myocardial function. These beneficial effects of GLP-1 on cardiac function are mediated by both GLP-1 receptor activation and GLP-1 receptor independent actions. Infusions of the metabolite GLP-1 (9-36)-amide improve cardiac function in experimental animals with cardiovascular disease even though the metabolite does not bind to the GLP-1 receptor. The beneficial effects of GLP-1 on the heart occur in the presence of a GLP-1 receptor antagonist and in animals devoid of GLP-1 receptors. Preliminary data in animals with available GLP-1 receptor agonists and cardiac disease suggest that exenatide has beneficial effects in porcine models of ischemic heart disease. The animal data with liraglutide are inconclusive. Clinical trials with exenatide and liraglutide show significant improvements in weight, systolic blood pressure, lipid profiles, and other cardiovascular risk factors. Whether these will decrease cardiovascular events is currently under investigation.

Topics: Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Dogs; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Lipids; Liraglutide; Male; Mice; Peptides; Rats; Venoms

Hypothalamic obesity caused by damage of medial hypothalamic nuclei presents a therapeutic challenge. Glucagon-like peptide-1 agonist exenatide (synthetic version of exendin-4 (Ex4)), used for treatment of diabetes, causes weight loss via hindbrain signaling.. We tested Ex4 in an established rat model of medial hypothalamic lesions. Lesion and control animals were administered either daily intraperitoneal injections of 1 µg·kg(-1) Ex4 or saline for 9 days.. In our rat model, a significant difference in percent baseline food intake (lesion -20.8%, control -13.6%; p < 0.001) and percent change in body weight (lesion -4.9%/9 days, control -3.2%/9 days; p < 0.05) was observed during Ex4 treatment compared with saline.. Ex4 resulted in reduction of food intake and body weight. Follow-up studies are required to further elucidate its effects on energy homeostasis and to establish Ex4 as a potential drug for treatment of hypothalamic obesity.

Topics: Animals; Body Weight; Disease Models, Animal; Down-Regulation; Drug Evaluation, Preclinical; Energy Intake; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Hypothalamic Diseases; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Venoms; Weight Loss

The escalation predicted for the incidence of both type 2 diabetes mellitus and obesity has prompted investigators to search for additional pharmacotherapeutic approaches to their treatment. Two of these approaches, combination pharmacotherapy and utilization of leptin-related bioactive synthetic peptides as anti-diabetes/anti-obesity agents, were used in the present study. Exenatide or pramlintide acetate was reconstituted in dodecyl maltoside (DDM) in the absence or presence of [D-Leu-4]-OB3, and delivered orally by gavage to insulin-resistant male C57BLK/6-m db/db mice twice daily for 14 days. Body weight gain, food and water intake, blood glucose, and serum insulin levels were measured. Mice given DDM alone for 14 days were 19.7% heavier than they were at the beginning of the study, while oral delivery of exenatide or [D-Leu-4]-OB3 in DDM reduced body weight gain to only 13.9% and 11.5%, respectively, of initial body weight. Mice receiving exenatide and [D-Leu-4]-OB3 were 4.2% lighter than they were at the beginning of the study. In another study, Intravail® treated control mice gained 38.2% of their initial body weight, while mice receiving pramlintide acetate or [D-Leu-4]-OB3 were only 26.8% and 25.4% heavier, respectively, at the end of the study, Co-administration of pramlintide acetate and [D-Leu-4]-OB3 did not further enhance the effect of pramlintide acetate on body weight gain. Food intake was reduced by exenatide, pramlintide acetate, and [D-Leu-4]-OB3 alone, and co-delivery with [D-Leu-4]-OB3 did not induce a further decrease. Water intake was not affected by exenatide, pramlintide acetate, or [D-Leu-4]-OB3 alone, but co-delivery of exenatide or pramlintide acetate with [D-Leu-4]-OB3 resulted in a significant reduction in water intake. Oral delivery of exenatide or pramlintide acetate in DDM significantly lowered blood glucose levels by 20.4% and 30.2%, respectively. Co-delivery with [D-Leu-4]-OB3 further reduced blood glucose by 38.3% and 50.5%, respectively. A concentration-dependent increase in serum insulin was observed in response to increasing concentrations of exenatide, and [D-Leu-4]-OB3 slightly reduced the insulin response to exenatide at all concentrations tested. Increasing concentrations of pramlintide acetate alone did not elevate serum insulin, and when given in combination with [D-Leu-4]-OB3, serum insulin levels fell below those of DDM-treated control mice. Our data indicate that (1) exenatide and pramlintide acetate, curren

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Drug Combinations; Drug Synergism; Eating; Energy Metabolism; Exenatide; Glucosides; Hypoglycemic Agents; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Peptide Fragments; Peptides; Venoms

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months' GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA(1)c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m(2) (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA(1)c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy ((1)H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA(1c) reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (-59.3, -16.5%). The relative reduction in IHL correlated with that in HbA(1)c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.

Topics: Adiposity; Adult; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Male; Middle Aged; Obesity; Peptides; Prospective Studies; Venoms; Weight Loss

Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.

Topics: Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Eating; Exenatide; Hypoglycemic Agents; Male; Obesity; Peptide Fragments; Peptide YY; Peptides; Rats; Rats, Sprague-Dawley; 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

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Metformin; Middle Aged; Peptides; Pioglitazone; Thiazolidinediones; Venoms

Preclinical studies suggest that incretin-based therapies may be beneficial for the bone; however, clinical data are largely lacking. We assessed whether the differential effects of these therapies on body weight differed with respect to their effect on bone mineral density (BMD) and markers of calcium homeostasis in patients with type 2 diabetes (T2D). Sixty-nine metformin-treated patients with T2D were randomized to exenatide twice daily (n = 36) or insulin glargine once daily (n = 33). Total body BMD, measured by dual-energy X-ray absorptiometry, and serum markers of calcium homeostasis were assessed before and after 44-week treatment. Exenatide or insulin glargine treatment decreased body weight by 6%. Endpoint BMD was similar in both groups after 44-week therapy (LSmean ± s.e.m. between-group difference -0.002 ± 0.007 g/cm(2) ; p = 0.782). Fasting serum alkaline phosphatase, calcium and phosphate remained unaffected. Forty-four-week treatment with exenatide or insulin glargine had no adverse effects on bone density in patients with T2D, despite differential effects on body weight.

Topics: Absorptiometry, Photon; Body Weight; Bone Density; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Male; Middle Aged; Peptides; Radionuclide Imaging; Randomized Controlled Trials as Topic; Venoms

Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

Topics: Animals; Body Weight; Cell Proliferation; Cells, Cultured; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Neointima; Peptides; Rats; Receptors, Glucagon; Signal Transduction; Tunica Intima; Vascular System Injuries; Venoms

Glucagon-like peptide-1 (GLP-1) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation. The aim of this study was to investigate the effect of the GLP-1 pathway on peripheral nerves in streptozotocin-induced diabetic rats.. Diabetic and nondiabetic rats were treated with the GLP-1 receptor agonist, synthetic exendin-4 (i.p., 1 nmol·kg(-1)·day(-1)) or placebo for 24 weeks, and current perception threshold values, cAMP levels and nerve fibre size in the sciatic nerve were measured. We also investigated GLP-1 receptor expression, quantitative changes in PGP9.5-positive intraepidermal nerve fibres and cleaved caspase 3-stained Schwann cells by immunohistochemistry.. GLP-1 receptor expression was detected in the sciatic nerve and skin. After exendin-4 treatment, the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced. Also, the decrease in myelinated fibre size or axon/fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated. These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the cAMP level in exendin-4-treated diabetic rats, compared with placebo-treated animals.. Synthetic exendin-4 may prevent peripheral nerve degeneration induced by diabetes in an animal model, supporting the hypothesis that GLP-1 may be useful in peripheral neuropathy. The neuroprotection is probably attributable to GLP-1 receptor activation, antiapoptotic effects and restoration of cAMP content.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cyclic AMP; Diabetes Mellitus, Experimental; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Male; Nerve Fibers, Myelinated; Neuroprotective Agents; Peptides; Peripheral Nervous System; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Schwann Cells; Sciatic Nerve; Skin; Streptozocin; Venoms

Diet composition alters the metabolic states of adipocytes and hepatocytes in diabetes. The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation and fatty liver have been obscure. We investigated the extrapancreatic effects of DPP-4 inhibition on visceral fat and the liver.. We investigated diet-induced metabolic changes in β-cell-specific glucokinase haploinsufficient (Gck(+/-)) diabetic mice. We challenged animals with a diet containing a combination of sucrose and oleic acid (SO) or sucrose and linoleic acid (SL). Next, we assessed the effects of a DPP-4 inhibitor, des-fluoro-sitagliptin, on adipose tissue inflammation and hepatic steatosis.. The epididymal fat weight and serum leptin level were significantly higher in Gck(+/-) mice fed SL than in mice fed SO, although no significant differences in body weight or adipocyte size were noted. Compared with SO, SL increased the numbers of CD11c(+) M1 macrophages and CD8(+) T-cells in visceral adipose tissue and the expression of E-selectin, P-selectin, and plasminogen activator inhibitor-1 (PAI-1). DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8(+) T-cells and M1 macrophages and decreased the expression of PAI-1. The production of cytokines by activated T-cells was not affected by DPP-4 inhibition. Furthermore, DPP-4 inhibition prevented fatty liver in both wild-type and Gck(+/-) mice. DPP-4 inhibition also decreased the expressions of sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase-1, and fatty acid synthase, and increased the expression of peroxisome proliferator-activated receptor-α in the liver.. Our findings indicated that DPP-4 inhibition has extrapancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Chemokine CCL2; Dietary Fats; Dietary Sucrose; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme-Linked Immunosorbent Assay; Exenatide; Fatty Liver; Female; Glucokinase; Hypertrophy; Insulin; Interferon-gamma; Interleukin-10; Liver; Male; Mice; Peptides; Polymerase Chain Reaction; Triglycerides; Tumor Necrosis Factor-alpha; Venoms

Glucagon-like peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (fourth i.c.v.) GLP-1R activation by Exendin-4 (Ex-4) increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Ex-4, as inhibitors RpcAMP and U0126 (fourth i.c.v.), respectively, attenuated Ex-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (fourth i.c.v.). The PKA, MAPK, and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Body Weight; Butadienes; Cyclic AMP-Dependent Protein Kinases; Eating; Exenatide; Glucagon-Like Peptide-1 Receptor; Male; Mitogen-Activated Protein Kinase Kinases; Nitriles; Peptides; Phosphorylation; Protein Kinases; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Signal Transduction; Solitary Nucleus; Venoms

The aim of this study was to investigate the effects of Roux-en-Y gastric bypass (RYGB) on glucose tolerance and insulin resistance in type 2 diabetic rats and the possible mechanisms involved in this process.. Thirty Goto-Kakizaki (GK) rats were randomly divided into three groups: RYGB operation, sham operation, and food restriction groups. Ten Wistar rats were used as non-diabetic control. The body weight and food consumption of rats were recorded 1 week before or every week after surgery. The fasting blood sugar and oral glucose tolerance test were performed using blood glucose meter. The levels of plasma insulin or glucagon-like peptide-1 (GLP-1) were evaluated by enzyme-linked immunosorbent assay. The insulin resistance was quantified using homeostasis model assessment method. The expression of GLP-1 receptor, Bcl-2, Bax, and caspase-3 was determined by Western blotting.. Our results revealed that RYGB efficiently improved both glucose tolerance and insulin resistance in GK diabetic rats by upregulating GLP-1/GLP-1R expression. In addition, GLP-1R agonist exendin-4 dose-dependently increased insulin secretion in RIN-m5F cells and regulated the proliferation and apoptosis of these cells.. RYGB provides a valuable therapeutic option for patients with type 2 diabetes. GLP-1 may contribute to the regulation of pancreatic β-cell function through its receptor following RYGB.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Eating; Enzyme-Linked Immunosorbent Assay; Exenatide; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Peptides; Random Allocation; Rats; Rats, Wistar; Receptors, Glucagon; Venoms

Type 2 diabetes is highly prevalent in the elderly population. Glucagon like Peptide-1 mimetic such as exendin-4 augments post-prandial insulin secretion. However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied. In this study, we examined the glucose regulatory effects of exendin-4 in mice with different ages.. We treated 3-month and 20 to 22-month old C57/DBA mice with 10 nM/kg exendin-4 for 10 days with measurements of blood glucose and body weight. We performed OGTT and ITT to evaluate the glucose response and insulin sensitivity. Islet morphology and beta cell mass were measured by immuno-staining and beta cell proliferation was evaluated by BrdU incorporation and PCNA staining. Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment.. Exendin-4 treatment improved glycemic control in both 3-month and 20 to 22-month old mice. In both groups of mice, the blood glucose lowering effect was independent of beta cell function as indicated by unchanged beta cell proliferation, insulin secretion or beta cell mass. Moreover, we found that exendin-4 treatment increased hepatic AKT and FOXO1 phosphorylation and inhibited glucose-6-phosphotase (G6P) and Phosphoenolpyruvate carboxykinase (PEPCK) expression in young mice, but this effect was attenuated in aging mice while the insulin sensitivity showed no change in the young group but significantly improved in aging mice.. Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging. We further showed that although there was slight difference in the glucose modulating mechanism of exendin-4 therapy in young and aged mice, the improved glucose control seemed uncorrelated with increased beta cell mass or insulin secretion.

Topics: Aging; Animals; Blood Glucose; Blotting, Western; Body Weight; Enzyme-Linked Immunosorbent Assay; Exenatide; Forkhead Box Protein O1; Forkhead Transcription Factors; Glucose Tolerance Test; Glucose-6-Phosphatase; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Peptides; Phosphoenolpyruvate Carboxykinase (GTP); Phosphorylation; Polymerase Chain Reaction; Venoms

The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after i.p. delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3(rd) ICV)] of the GLP-1R antagonist exendin-(9-39) (100 μg), attenuated the intake suppression by i.p. liraglutide (10 μg) and exendin-4 (3 μg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9-39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after i.p. delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4.. Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

Topics: Animals; Appetite Depressants; Body Weight; Brain; Calcitonin; Eating; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Liraglutide; Male; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Vagus Nerve; Venoms

Both diet and medications are useful in the treatment of the obese patient. Weight loss of about 10% below baseline can be achieved with both, and there is no evidence that the composition of the diet, by itself, has any influence on weight loss. Presently only 1 drug is approved for long-term treatment of overweight patients, and its effectiveness is limited to palliation of the chronic disease of obesity. Combinations of medications and antidiabetic drugs that produce weight loss are being evaluated.

Topics: Adolescent; Adult; Anti-Obesity Agents; Antidepressive Agents, Second-Generation; Body Weight; Bupropion; Child; Drug Approval; Drug Combinations; Energy Intake; Exenatide; Female; Fructose; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Lactones; Male; Metformin; Naltrexone; Narcotic Antagonists; Obesity; Orlistat; Patient Compliance; Peptides; Randomized Controlled Trials as Topic; Sympathomimetics; Topiramate; United States; United States Food and Drug Administration; Venoms

Pharmacological activation of the glucagon-like peptide-1 (GLP-1) receptor and inhibition of the cannabinoid CB1 receptor were found to reduce food intake and body weight in humans and animals. Since earlier studies revealed that endocannabinoids may interact with other neurotransmitters to affect feeding behavior, we have examined whether a stable GLP-1 agonist, exendin-4 and a CB1 receptor antagonist, AM 251, may reciprocally enhance their inhibitory effects on food consumption in the rat. Additionally, we have tested whether the blockade of the GLP-1 receptor by exendin (9-39) modifies AM 251-dependent effects on energy balance. In a dose-response study, male Wistar rats were injected intraperitoneally with either 1.5-6.0 μg/kg exendin-4, 0.5-2 mg/kg AM 251, 80-320 μg/kg exendin (9-39) or their vehicle and the daily food and water intake as well as body weight changes were monitored two days before and two days after the injection. Exendin-4 at a dose of 3.0 and 6.0 μg/kg and AM 251 at a dose 2 mg/kg decreased significantly 24-hour food intake and body weight. Therefore, in the next study, the effects of lower doses of exendin-4 (1.5 μg/kg) and AM 251 (1.0 mg/kg) administered alone or together on food consumption were compared. As opposed to being injected alone, the co-administration of the two resulted in a marked decrease in both daily food intake and body weight. Exendin (9-39) did not modify the suppressory effect of the highest AM 251 dose on food consumption. Apparently, the effect of AM 251 on the appetite is not mediated by GLP-1. The concomitant stimulation of GLP-1 receptor and blockade of CB1 receptor, however, may act synergistically to inhibit appetite in the rat.

Topics: Animals; Appetite Depressants; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Eating; Energy Metabolism; Exenatide; Glucagon-Like Peptide-1 Receptor; Male; Peptides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Glucagon; Venoms

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%-1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Hypersensitivity; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Pancreatitis; Peptides; Receptors, Glucagon; Venoms

Exendin-4 is a 39 amino acid agonist of the glucagon-like peptide receptor and has been approved for treatment of type 2 diabetes. Many reports describe an increased incidence of acute pancreatitis in humans treated with exendin-4 (exenatide). Previous studies have evaluated the effect of exendin-4 on beta cells and beta cell function. We evaluated the histological and biochemical effects of exendin-4 on the pancreas in rats.. We studied 20 Sprague-Dawley male rats, ten of which were treated with exendin-4 and ten of which were used as controls. The study period was 75 days. Serum and pancreatic tissue were removed for biochemical and histological study. Blood glucose, amylase, lipase, insulin and adipocytokines were compared between the two groups.. Animals treated with exendin-4 had more pancreatic acinar inflammation, more pyknotic nuclei and weighed significantly less than control rats. They also had higher serum lipase than control animals. Exendin-4 treatment was associated with lower insulin and leptin levels as well as lower HOMA values than in the untreated control group.. Although the use of exendin-4 in rats is associated with decreased weight gain, lower insulin resistance and lower leptin levels than in control animals, extended use of exendin-4 in rats leads to pancreatic acinar inflammation and pyknosis. This raises important concerns about the likelihood of inducing acute pancreatitis in humans receiving incretin mimetic therapy.

Topics: Adipokines; Alanine Transaminase; Amylases; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Exenatide; Humans; Hypoglycemic Agents; Insulin; Lipase; Male; Pancreas; Pancreatitis; Peptides; Rats; Rats, Sprague-Dawley; Venoms

Exenatide use in type 2 diabetes is limited in routine clinical practice. We examined a cross-section of 90 patients. Mean weight and HBA(1c) were 114.9+/-20.6 kg, 10.3+/-2.1% at initiation; 108.0+/-15.3 kg (p<0.0001), 9.0+/-2.1% (p<0.001) at 3 months; 109.2+/-18.2 kg (p<0.0001), 9.5+/-2.3% (p=0.08) at 6 months. Exenatide appears effective in reducing HBA(1c) and weight.

Topics: Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Peptides; Sulfonylurea Compounds; Treatment Outcome; Venoms; Weight Loss

The mechanism and route whereby glucagon-like peptide 1 (GLP-1) receptor agonists, such as GLP-1 and exendin-4 (Ex-4), access the central nervous system (CNS) to exert their metabolic effects have yet to be clarified. The primary objective of the present study was to investigate the potential role of two circumventricular organs (CVOs), the area postrema (AP) and the subfornical organ (SFO), in mediating the metabolic and CNS-stimulating effects of Ex-4. We demonstrated that electrolytic ablation of the AP, SFO, or AP + SFO does not acutely prevent the anorectic effects of Ex-4. AP + SFO lesion chronically decreased food intake and body weight and also modulated the effect of Ex-4 on the neuronal activation of brain structures involved in the hypothalamic-pituitary-adrenal axis and glucose metabolism. The results of the study also showed that CVO lesions blunted Ex-4-induced expression of c-fos mRNA (a widely used neuronal activity marker) in 1) limbic structures (bed nucleus of the stria terminalis and central amygdala), 2) hypothalamus (paraventricular hypothalamic nucleus, supraoptic nucleus, and arcuate nucleus), and 3) hindbrain (lateral and lateral-external parabrachial nucleus, medial nucleus of the solitary tract, and ventrolateral medulla). In conclusion, although the present results do not support a role for the CVOs in the anorectic effect induced by a single injection of Ex-4, they suggest that the CVOs play important roles in mediating the actions of Ex-4 in the activation of CNS structures involved in homeostatic control.

Topics: Animals; Area Postrema; Body Composition; Body Weight; Brain; Deglutition Disorders; Energy Intake; Energy Metabolism; Exenatide; Genes, fos; Glucokinase; Hypoglycemic Agents; Male; Organ Size; Peptides; Rats; Rats, Wistar; RNA, Heterogeneous Nuclear; RNA, Messenger; Subfornical Organ; Venoms

Exenatide must be administered serially by twice-daily subcutaneous (SC) injection due to its short half-life. The purpose of the present study is to develop an improved sustained-release exenatide formulation with a therapeutic efficacy comparable to serial, twice-daily injections of exenatide. A novel SR formulation of exenatide, DA-3091, was prepared by single-emulsion solvent evaporation using PLGA. It was administered by SC injection to ZDF rats in single exenatide doses of 0.1, 0.25, 0.5, 1 or 2mg/kg. On the 28th, 49th and 70th days, a 1 or 2mg/kg dose of DA-3091 was further administered to rats in dose groups of 1 or 2mg/kg. The efficacy of DA-3091 was then compared with that of serial, twice-daily SC injections of an exenatide solution for 13 weeks. NFBG and HbA1c concentrations were decreased both significantly and linearly as the exenatide dose in DA-3091 increased. In addition, food intake and body weight were suppressed both significantly and dose-dependently. In equivalent or half doses of exenatide, the efficacy of DA-3091 was comparable to that of twice-daily injections of exenatide solution for 13 weeks. In conclusion, DA-3091 has the potential to be clinically effective when administered every 3 weeks, or less frequently, which promises to significantly improve patient compliance.

Topics: Animals; Blood Glucose; Body Weight; Chemistry, Pharmaceutical; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Feeding Behavior; Glycated Hemoglobin; Hypoglycemic Agents; Male; Microspheres; Peptides; Rats; Rats, Zucker; Venoms

The objective was to compare the treatment effects between exenatide and insulin, which are 2 injectable peptide hormone-based therapy options for the treatment of type 2 diabetes mellitus.. Data from 4 randomized, open-label, comparator-controlled clinical trials in 1423 patients with type 2 diabetes followed for 16 to 52 weeks were pooled and analyzed.. At 26 weeks, glycemic control with exenatide (-1.2% HbA1c) was non-inferior to insulin (-1.1%; exenatide vs insulin; P = 0.09). In a tertile analysis of HbA1c reduction from baseline, exenatide induced similar reductions compared with insulin, with the greatest reductions observed in the tertile with the highest baseline HbA1c (9%-12.7%). Exenatide treatment induced weight loss (-2 kg) and reduced systolic blood pressure (SBP) from baseline (SBP, -4.9 mm Hg, exenatide vs insulin; P < 0.0001). In contrast, insulin treatment increased body weight (1.8 kg) and decreased SBP by -0.4 mm Hg. Overall, about 3-fold more exenatide-treated patients (70%) experienced weight loss compared with those treated with insulin (21%). Occurrence of nocturnal mild-to-moderate hypoglycemia was lower with exenatide (15%) treatment than with insulin (29%; difference, -14; [95% CI, -18, -9.8]). Effects of exenatide on HbA1c and weight were sustained at 52 weeks.. These findings indicate that exenatide is non-inferior to insulin for glycemic control. Further studies are warranted to explore the effects of exenatide on blood pressure and body weight, and the potential for long-term effects on cardiovascular outcomes.

Topics: Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Peptides; Receptors, Glucagon; Venoms

Sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, and exenatide, an injectable glucagon-like peptide-1 receptor agonist, are incretin-based therapies for the treatment of type 2 diabetes. This study examined differences in baseline characteristics between patients with type 2 diabetes initiating sitagliptin vs. exenatide treatment in clinical practice settings in the US.. The General Electric Healthcare's Clinical Data Services electronic medical records database, covering 12 million US patients of all ages from 49 states, was used to identify patients with type 2 diabetes, aged > or =30 years, who received their first sitagliptin or exenatide prescription between October 1, 2006 and June 30, 2008 (index period). Patient's medical records, including demographics, diagnoses, procedures, prescriptions, and laboratory results were extracted for the 12-month period (baseline) prior to the date of the first prescription of sitagliptin or exenatide (ie, the index date). Patient baseline profiles were stratified by mono-, dual, or triple therapy and compared between regimens with sitagliptin or exenatide.. A total of 9543 patients initiated therapy with sitagliptin (n=5589) or exenatide (n=3954) during the index period. For those initiating monotherapy, 876 patients initiated sitagliptin and 476 initiated exenatide. Compared with patients initiating exenatide at baseline, patients on sitagliptin were older (64 vs. 55 years), more likely to be men (45% vs. 35%), and less likely to be obese (60% vs. 87%), and had higher hemoglobin A(1c) (HbA(1c); 7.1% vs. 6.9%), a higher serum creatinine (1.2 mg/dL vs. 1.0 mg/dL), and a higher prevalence of pre-existing cardiovascular complications or microvascular conditions (all P<0.01 for sitagliptin vs. exenatide). For dual therapy, 1885 were prescribed sitagliptin and 1392 were prescribed exenatide. For triple therapy, 2828 were prescribed sitagliptin and 2086 were prescribed exenatide. The observed patient profile differences with dual and triple therapy were generally consistent with those observed with monotherapy.. In a clinical practice setting, there are differences in the baseline characteristics of patients with type 2 diabetes who are prescribed sitagliptin relative to those prescribed exenatide. These findings have important implications for conclusions drawn from observational studies using medical record or claim databases, as estimated clinical and health outcomes measures may be biased due to channeling of patients to different therapies based on different baseline characteristics.

Topics: Adult; Age Factors; Aged; Body Mass Index; Body Weight; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insurance Claim Review; Lipids; Male; Middle Aged; Peptides; Pyrazines; Retrospective Studies; Sex Factors; Sitagliptin Phosphate; Socioeconomic Factors; Triazoles; Venoms

This study reports on the effectiveness of exenatide compared to insulin glargine or NPH insulin in patients with type 2 diabetes mellitus, unable to achieve glycemic control with oral glucose-lowering therapies in a clinical care setting.. Patients with type 2 diabetes mellitus (n = 47) whose glycemia was not controlled adequately with oral hypoglycemic agents at maximum recommended therapeutic doses were initiated on exenatide therapy. Age-, sex-, and body mass index-matched patients receiving insulin glargine (n = 54) or NPH insulin (n = 23) served as controls. Data analysis included glycated hemoglobin, fasting and postprandial plasma glucose, lipid profile, body weight, and the occurrence of hypoglycemia.. A statistically significant reduction in glycated hemoglobin value was noted after initiating exenatide (pre-exenatide 9.7 +/- 1.4% vs. post-exenatide 8.7 +/- 1.5%; P < 0.05), which was comparable to values after insulin glargine (9.8 +/- 1.1% vs. 9.0 +/- 1.5%, respectively; P < 0.05) and NPH insulin (9.6 +/- 1.4% vs. 8.9 +/- 1.3%, respectively; P < 0.05). Exenatide therapy was associated with net weight loss (mean, 1.6 kg), but therapy with insulin glargine and NPH insulin was associated with weight gain (1.8 and 2.3 kg, respectively).. In a group of select Asian Indian type 2 diabetes patients with secondary failure to oral hypoglycemic agents seen at a diabetes center, exenatide treatment in combination with oral drug regimens resulted in significant lowering of glycated hemoglobin similar to insulin glargine or NPH insulin but with the additional benefit of weight loss, albeit a small amount.

Topics: Adult; Aged; Asian People; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; India; Insulin; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Middle Aged; Peptides; Surveys and Questionnaires; Treatment Outcome; Venoms

Exenatide, a GLP-1 analogue, is used in combination with oral anti-diabetic agents in type 2 diabetes and obesity, and promotes weight loss. Exenatide use in combination with insulin in insulin-treated type 2 diabetes and obesity is unlicensed in the UK and outcomes are unclear.. To assess the effectiveness of exenatide in insulin-treated type 2 diabetes with obesity.. This prospective study included 174 consecutive patients with insulin-treated type 2 diabetes and obesity initiated on exenatide in our out-patient, between October 2007 and November 2008. Weight, BMI, HbA1c, serum fructosamine, total cholesterol, HDL-cholesterol and insulin doses were recorded at baseline, 3, 6 and 12 months. Side effect profiles were recorded.. Fourteen patients discontinued exenatide before 3 months of initiation, because of side effects, and were excluded. Data were analysed on remaining 160 people all of whom completed 6 months and 57 completed 12 months treatment. Mean weight loss was 10.7 +/- 5.7 kg and 12.8 +/- 7.5 kg (P < 0.001) at 6 and 12 months. Insulin doses dropped significantly (mean 144 +/- 90 U/day at baseline to 51 +/- 55 U/day and 55 +/- 53 U/day at 6 and 12 months). At 3 months, 25% came off insulin. There was little change in HbA1c.. Exenatide therapy in insulin-treated type 2 diabetes and obesity was associated with very significant reductions in weight and insulin doses. Exenatide should be considered in people with type 2 diabetes on insulin and have obesity, weight gain and poor glycaemic control.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Peptides; Prospective Studies; Venoms

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the Western world. The aim of this study was to evaluate the biochemical and histological effects of omega-3 fatty acid and exendin-4 treatment on NAFLD in an animal model.. Sixty-three 8-week-old outbred Sprague-Dawley male rats were used for this study. Three animals were used as procedure controls, and 30 rats were fed a methionine and choline deficient (MCD) diet and 30 were fed a regular chow diet. In each group of 30 animals, 10 served as controls, 10 received exendin-4, and 10 received omega-3 fatty acids. After 75 days of treatment, the animals were euthanized, the tissues and serum were harvested, and the livers were formalin-fixed for histology.. The MCD diet was exceptionally efficient at producing fatty livers. The MCD control animals had a liver steatosis score of 38+/-6.7 (of 50 possible); treatment with exendin-4 was not associated with a significant reduction of steatosis (44+/-5.16, P=0.07) and the omega-3 fatty acid treatment was associated with a significant decrease in the liver steatosis score (15.6+/-13.46, P<0.001) compared with both the controls and the exendin-4 groups. The omega-3 fatty acid treatment increased serum aspartate aminotransferase significantly, whereas exendin-4 had no effect.. In an animal model of NAFLD, the omega-3 fatty acid therapy was associated with significant improvement in hepatic steatosis compared with exendin-4. These data suggest that omega-3 fatty acid supplements may have a potential therapeutic role in patients with NAFLD.

Topics: Adipokines; Animals; Body Weight; Corn Oil; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Dietary Supplements; Disease Models, Animal; Exenatide; Fatty Acids, Omega-3; Fatty Liver; Fish Oils; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Peptides; Rats; Rats, Sprague-Dawley; Venoms

Topics: Body Composition; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Peptides; Sulfonylurea Compounds; Venoms

Pharmacological approaches that enhance incretin action for the treatment of type 2 diabetes mellitus have recently been developed, i.e. injectable glucagon-like peptide-1 receptor (GLP-1R) agonists with prolonged plasma half-lives and orally available inhibitors of dipeptidyl peptidase (DPP)-4, the main enzyme responsible for the rapid degradation of circulating glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. The mechanism(s) underlying the glucose-lowering effect of these two pharmacotherapies differs and is not yet fully understood. Here we investigated whether acute GLP-1R activation (exendin-4) or DPP-4 inhibition (des-F-sitagliptin) modulates insulin action in mice using a hyperinsulinemic euglycemic clamp. A single iv bolus of des-F-sitagliptin (11 mg/kg) was administered to mice 15 min after the start of the clamp, and its effect was compared with a 50-ng bolus of exendin-4 or the same volume of saline. Despite matched levels of plasma glucose and insulin, within 15 min the glucose infusion rate required to maintain euglycemia was significantly greater after des-F-sitagliptin compared with saline or exendin-4. This difference was entirely due to enhancement of insulin-mediated suppression of endogenous glucose production by des-F-sitagliptin, with no difference in glucose disposal rate. These findings illustrate that DPP-4 inhibition modulates glucose homeostasis through pathways distinct from those used by GLP-1R agonists in mice.

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucose Clamp Technique; Glucose Tolerance Test; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Mice; Mice, Inbred C57BL; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

GLP-1 and GIP are the two key incretin hormones that regulate post-prandial glucose homeostasis. Furthermore, potent enzyme-resistant GIP and GLP-1 receptor agonists such as N-AcGIP and exendin-4 have now been developed. In the present study the effects of stable incretins, exendin-4 and N-AcGIP alone and in combination were examined in mice with high fat feeding induced glucose intolerance. Daily s.c. injections of exendin-4 (50 nmol/kg bw) for 12 days restored glycaemic control and significantly (P<0.05) decreased glucose intolerance compared to saline-treated controls. Food intake was transiently decreased (P<0.05) without effect on body weight. In the following 12 day period, mice either continued the original treatment or were administered an additional dose of N-AcGIP (50 nmol/kg body weight; s.c.). Under these circumstances sub-chronic administration of exendin-4 alone or particularly when combined with N-AcGIP significantly (P<0.05) reduced body weight. Exendin-4, N-AcGIP and combined treatment groups displayed significantly (P<0.05) decreased plasma glucose levels and less severe glucose intolerance. Non-fasting 24-h glycaemic profiles revealed marked (P<0.05 to P<0.01) beneficial effects of all treatment regimes. Insulin resistance was also reduced (P<0.01 to P<0.001) in all exendin-4 treated mice compared to saline controls. Adipose tissue mRNA levels of adiponectin, leptin, resistin, GIP-R, LPL and DGAT-1 were not significantly altered. These results illustrate efficacy of enzyme resistant GIP and GLP-1 analogues for treatment of glucose intolerance induced by high fat feeding.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Dietary Fats; Eating; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin Resistance; Mice; Peptides; Receptors, Gastrointestinal Hormone; 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

Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se.. Three groups of male Sprague-Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored.. Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism.. Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1 replacement therapy might be the most appropriate therapeutic strategy for treating derangements in glucose metabolism in subjects taking these drugs.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Body Composition; Body Weight; Clozapine; Dibenzothiazepines; Dietary Fats; Disease Models, Animal; Eating; Exenatide; Food Preferences; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Male; Obesity; Peptides; Pyrazines; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Triazoles; Venoms

Exenatide is an antidiabctic agent currently indicated as adjunctive therapy with oral agents for the treatment of type 2 diabetes mellitus (T2DM). Limited published data exist on the off-label use of exenatide in conjunction with insulin in the treatment of T2DM.. The aim of this retrospective study was to examine the effects of exenatide on glycemic control, weight, and insulin dose in patients with T2DM treated with insulin.. Patients with T2DM receivirg insulin and adjuvant therapy with exenatide at an endocrinology clinic at a university hospital for up to 27 months were eligible for inclusion. Glycosylated hemoglobin (HbA(1c)), weight, insulin doses (total, prandial, and basal), concurrent oral antidiabetic medications, and adverse events were ascertained by retrospective review of medical records and were considered the clinical parameters of interest. The last observation in 4 specified time intervals (0-6, 6-12, 12-18, and 18-27 months) for each clinical parameter was used in the analysis.. Of the 3397 patients with a confirmed diagnosis of T2DM who were seen at the clinic during the study period, 268 patients met inclusion criteria and were enrolled in the study. Of the 268 patients enrolled, 38 discontinued therapy within the first 2 months, 30 were lost to follow-up, and 12 did not have evaluable data. These latter patients without sufficient data (n = 42) were not included in the primary analysis but were included in the adverse events analysis. Overall, data from 188 patients (mean [SD] age, 56 (9) years; 85 [45%] men; body mass index, 40.4 [8.4] kg/m(2); 160 [85%] white) were evaluated (mean duration of treatment, 350 [208] days) and included in all analyses. The mean baseline values for HbA(1c), weight, and total daily insulin dose before exenatide therapy were 8.05% (1.47%), 117.8 (24.7) kg, and 99.9 (90.0) U, respectively. For the 4 time intervals, the mean changes in HbA(1c) were: -0.66% (1.54%) at 0 to 6 months (P < 0.001); -0.55% (1.4%) at 6 to 12 months (P < 0.001); -0.54% (1.83%) at 12 to 18 months (P = 0.019); and -0.54% (1.37%) at 18 to 27 months (P = 0.020). Mean weight significantly declined with increasing treatment duration. Mean changes in weight were: -2.4 (5.1) kg at 0 to 6 months (P < 0.001); -4.3 (7.2) kg at 6 to 12 months (P < 0.001); -6.2 (9.7) kg at 12 to 18 months (P < 0.001); and -5.5 (10.8) kg at 18 to 27 months (P < 0.01). After 18 months, an increase in weight was observed; but the increase remained lower than baseline. The mean insulin total daily dose (TDD) was decreased in all patients at the 0- to 6-month (-18.0 [49.9] U; P < 0.001) and the 6- to 12-month (-14.8 [35.3] U; P < 0.001) intervals. Mean changes in insulin TDD during the 12- to 18-month and 18- to 27-month intervals were not statistically significant. The mean percent change from baseline in the basal insulin dose at 0 to 6 months, 6 to 12 months, 12 to 18 months, and 18 to 27 months was not statistically significant. For the 4 intervals, the mean percent change from baseline in the prandial insulin dose was -33.5% (56.2%) at 0 to 6 months (P < 0.001); -25.9% (59.7%) at 6 to 12 months (P = 0.002); -29.7% (74.8%) at 12 to 18 months (P = 0.02); and -55.7% (56.8%) at 18 to 27 months (P = 0.005). Of the 226 patients who were treated with exenatide + insulin for any length of time (including within the first 2 months), 59 (26.1%) discontinued exenatide because of adverse events. The adverse events were largely considered mild and included nausea (n. In this retrospective review of patients with T2DM treated in an outpatient setting, the addition of exenatide to insulin-based therapy was associated with reductions in mean HbA(1c), weight, and prandial insulin requirements for treatment periods of up to 27 months, and in total insulin requirements for treatment periods of up to 12 months.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptides; Retrospective Studies; Time Factors; Venoms

Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting GLP-1 receptor (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of GLP-1 and Ex4, but it is possible that the two peptides control feeding via distinct mechanisms.. In this study, the anorectic effects of intracerebroventricular GLP-1 and Ex4, and the sensitivity of these effects to GLP-1r antagonism, were compared in rats. In addition, the GLP-1r dependence of the anorectic effect of intracerebroventricular Ex4 was assessed in GLP-1r(-/-) mice.. Intracerebroventricular Ex4 was 100-fold more potent than GLP-1 at reducing food intake, and this effect was insensitive to GLP-1r antagonism. However, GLP-1r antagonists completely blocked the anorectic effect of intraperitoneal Ex4. Despite the insensitivity of intracerebroventricular Ex4 to GLP-1r antagonism, intracerebroventricular Ex4 failed to reduce food intake in GLP-1r(-/-) mice.. These data suggest that although GLP-1rs are required for the actions of Ex4, there appear to be key differences in how GLP-1 and Ex4 interact with central nervous system GLP-1r and in how Ex4 interacts with GLP-1r in the brain versus the periphery. A better understanding of these unique differences may lead to expansion and/or improvement of GLP-1-based therapies for type 2 diabetes and obesity.

Topics: Animals; Anorexia; Body Weight; Dose-Response Relationship, Drug; Exenatide; Feeding Behavior; Glucagon-Like Peptide 1; Hypoglycemic Agents; Immunohistochemistry; Injections, Intraperitoneal; Injections, Intraventricular; Mice; Mice, Inbred C57BL; Peptides; Proto-Oncogene Proteins c-fos; Rats; Rats, Long-Evans; Venoms

Glucagon-like peptide-1 (GLP-1) ameliorates the symptoms of diabetes through stimulation of insulin secretion. We have investigated the possible components of cellular mechanism triggered by exendin-4, a potent GLP-1 receptor agonist, in streptozotocin (STZ) induced diabetic mice pancreas. BALB/c male mice were divided into four groups for this investigation. The first group was given citrate buffer only, the second group was administered exendin-4 alone, the third group received STZ, and the fourth group was given both STZ and exendin-4. Exendin-4 (3 microg/kg) was administered by daily subcutaneous injection for 30 days after the animals were rendered diabetic by administration of STZ (200 mg/kg). With exendin-4 treatment on diabetic mice, the following results were noted: (i) exendin-4 suppressed the increase in plasma glucose and inhibited somatostatin expression induced by STZ, (ii) reduction of insulin prevalence was inhibited, while expression of p75 neurotrophin receptor (p75NTR), pancreatic nerve growth factor (NGF), and NGF-positive islet cell prevalence increased, (iii) there were no alterations in the severity of proliferated cell nuclear antigen positive or apoptotic beta cells in pancreatic islets, and (iv) pancreatic catalase, glutathione peroxidase, and superoxide dismutase activities significantly increased. In conclusion, these data suggest that exendin-4 might exert its actions through the NGF/p75NTR system and decrease somatostatin expression.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Exenatide; Hypoglycemic Agents; Immunohistochemistry; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Mice, Inbred BALB C; Peptides; Receptors, Nerve Growth Factor; Somatostatin; Streptozocin; Venoms

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

Topics: Animals; Apoptosis; Body Weight; Cell Proliferation; Exenatide; Food; Gene Expression; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Peptides; Receptors, Glucagon; Venoms

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagon-like-peptide-1 agonist, exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given exendin-4 on days 1-6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance.

Topics: Age Factors; Aging; Animals; Animals, Newborn; Biomarkers; Blood Glucose; Body Composition; Body Weight; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Administration Schedule; Exenatide; Female; Fetal Growth Retardation; Gene Expression Regulation, Enzymologic; Glucokinase; Glucose-6-Phosphatase; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Resistance; Liver; Oxidative Stress; Peptides; Phosphoenolpyruvate Carboxykinase (GTP); Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Venoms

This study evaluated changes in clinical effectiveness measures of patients with type 2 diabetes initiating exenatide therapy in a real-world setting.. Eligible patients identified in the General Electric (GE) electronic medical record (EMR) research database from 1 January 2000 through 31 December 2007 were > or =18 years old with type 2 diabetes. Patients had prescription orders in the previous 395 days for metformin, a sulfonylurea, or a thiazolidinedione as monotherapy or in combination, and had at least 6 months of follow-up activity. Baseline clinical measures were documented from 45 days prior up to 15 days after exenatide initiation and follow-up measures documented at 6 months +/- 45 days.. A total of 1709 patients were identified for study inclusion. The overall mean A1C reduction (s.e.m.) at 6 months was -0.8% (0.05) (p<0.001), weight loss was -3.2 kg (0.14) (p<0.001), blood pressure (BP) lowering was -1.9 mmHg (0.46) systolic blood pressure (SBP) (p<0.001) and -0.5 mmHg (0.27) diastolic blood pressure (DBP) (p = 0.078). Changes in low-density lipoprotein (LDL), triglycerides and HDL were -7.4 mg/dl (1.7) (p<0.001), -23.2 mg/dl (6.7) (p = 0.001) and -0.8 mg/dl (0.33) (p = 0.012) respectively. In a quartile analysis by weight loss, mean A1C reduction ranged from -1.1 to -0.65% in the highest to lowest weight loss quartiles respectively.. In a real-world setting, exenatide initiation is associated with significant improvements in the measures of clinical effectiveness for type 2 diabetes. These reductions were comparable to those reported in randomized, controlled registration trials after 6 months of therapy.

Topics: Adult; Aged; Ambulatory Care; Body Weight; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Peptides; Retrospective Studies; Risk Factors; Treatment Outcome; Venoms

Topics: Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Treatment Outcome; Venoms

Exendin-4, a long-acting glucagon-like peptide-1-receptor agonist, is known to enhance beta-cell function, but the active mechanism by which it modulates beta-cell mass still remains unclear. We investigated what the long-term effects of exendin-4 (300 pmol/kg body weight per day) on beta-cell function and mass would be in 90% pancreatectomized (Px) Sprague Dawley rats; half of whom were intraperitoneally injected with streptozotocin (STZ, 20 mg/kg body weight) and half of whom were not. Exendin-4 improved glucose tolerance by elevating serum insulin levels in both STZ-treated and untreated Px rats. At hyperglycemic clamp, STZ attenuated both first and second phase insulin secretion in STZ- and saline-treated Px rats, but exendin-4 incompletely reversed the attenuation. Since STZ mostly removed the remaining beta-cells by increasing apoptosis after Px, their regeneration was initiated through neogenesis, which was determined by the number of beta-cells budding from pancreatic duct layers and small clusters. Exendin-4 enhanced beta-cell proliferation and neogenesis in STZ-treated and -untreated Px rats and reduced beta-cell apoptosis partly by attenuating the expression of endoplasmic reticulum stress-response genes such as X-box-binding protein-1, activating transcription factor (ATF)-4, ATF6, and C/EBP-homologous protein. In conclusion, exendin-4 improved glycemic control by potentiating beta-cell function and increasing beta-cell mass by increasing beta-cell neogenesis and proliferation and by decreasing apoptosis in diabetic rats.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Experimental; Endoplasmic Reticulum; Energy Intake; Exenatide; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Male; Pancreatectomy; Peptides; Rats; Rats, Sprague-Dawley; Stress, Physiological; Transcription Factors; Venoms

A series of conformationally constrained derivatives of glucagon-like peptide-1 (GLP-1) were designed and evaluated. By use of [Gly (8)]GLP-1(7-37)-NH2 (2) peptide as a starting point, 17 cyclic derivatives possessing i to i + 4, i to i + 5, or i to i + 7 side chain to side chain lactam bridges from positions 18 to 30 were prepared. The effect of a helix-promoting alpha-amino-isobutyric acid (Aib) substitution at position 22 was also evaluated. The introduction of i to i + 4 glutamic acid-lysine lactam constraints in c[Glu (18)-Lys (22)][Gly (8)]GLP-1(7-37)-NH2 (6), c[Glu (22)-Lys (26)][Gly (8)]GLP-1(7-37)-NH2 (10), and c[Glu (23)-Lys (27)][Gly (8)]GLP-1(7-37)-NH2 (11) resulted in potent functional activity and receptor affinities comparable to native GLP-1. Selected GLP-1 peptides were chemoselectively PEGylated in order to prolong their in vivo activity. PEGylated peptides [Gly (8),Aib (22)]GLP-1(7-37)-Cys ((PEG))-Ala-NH2 (23) and c[Glu (22)-Lys (26)][Gly (8)]GLP-1(7-37)-Cys ((PEG))-Ser-Gly-NH2 (24) retained picomolar functional potency and avid receptor binding properties. Importantly, PEGylated GLP-1 peptide 23 exhibited sustained in vivo efficacy with respect to blood glucose reduction and decreased body weight for several days in nonhuman primates.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Body Weight; CHO Cells; Cricetinae; Cricetulus; Drug Design; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Macaca fascicularis; Mice; Mice, Mutant Strains; Models, Molecular; Molecular Sequence Data; Plasma; Polyethylene Glycols; Protein Conformation; Radioligand Assay; Receptors, Glucagon; Structure-Activity Relationship

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

Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the "Edmonton protocol." To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial.. Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up.. Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test.. These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.

Topics: Adult; Blood Glucose; Body Weight; C-Peptide; Etanercept; Exenatide; Follow-Up Studies; Graft Survival; Humans; Hypoglycemic Agents; Immunoglobulin G; Immunosuppressive Agents; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Middle Aged; Peptides; Receptors, Tumor Necrosis Factor; Treatment Failure; Venoms

We examined whether chronic administration of a glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (Ex-4), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist D-Ala(2)-GIP (DA-GIP), or a dipeptidyl peptidase-4 (DPP-4) inhibitor (DPP-4i) des-fluoro-sitagliptin produced comparable antidiabetic actions in high fat-fed mice.. High fat-fed mice were administered twice-daily injections of Ex-4, DA-GIP, vehicle (saline), or vehicle with the addition of des-fluoro-sitagliptin (DPP-4i) in food to produce sustained inhibition of DPP-4 activity.. Mice treated with vehicle alone or DA-GIP exhibited progressive weight gain, whereas treatment with Ex-4 or DPP-4i prevented weight gain. Although Ex-4 improved oral glucose tolerance and insulin-to-glucose ratios after an intraperitoneal glucose tolerance test (IPGTT), DPP-4i had no significant effect after IPGTT but improved glucose excursion and insulin levels after an oral glucose tolerance test. The extent of improvement in glycemic control was more sustained with continuous DPP-4 inhibition, as evidenced by loss of glucose control evident 9 h after peptide administration and a significant reduction in A1C observed with DPP-4i but not with DA-GIP or Ex-4 therapy. DA-GIP, but not Ex-4 or DPP-4i, was associated with impairment in insulin sensitivity and increased levels of plasma leptin and resistin. Although none of the therapies increased beta-cell mass, only Ex-4-treated mice exhibited increased pancreatic mRNA transcripts for Irs2, Egfr, and Gck. These findings highlight significant differences between pharmacological administration of incretin receptor agonists and potentiation of endogenous GLP-1 and GIP via DPP-4 inhibition.

Topics: Animals; Blood Glucose; Body Weight; Calorimetry, Indirect; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Energy Intake; Exenatide; Hypoglycemic Agents; Incretins; Insulin; Mice; Mice, Inbred C57BL; Motor Activity; Peptides; Receptors, Gastrointestinal Hormone; Venoms

Glucagon-like peptide 1 (GLP-1) augments glucose-stimulated insulin secretion (GSIS) through cAMP-induced activation of protein kinase A (PKA), and stimulates beta-cell proliferation and reduces beta-cell apoptosis in rodent islets. This study explored islet GSIS, PKA expression, and markers of apoptosis (caspase 3/7 activity) and proliferation (PKBalpha and pancreatic and duodenal homeobox gene 1, Pdx-1) after 2 weeks of treatment with the GLP-1 receptor agonist exendin-4 (2 nmol/kg once daily) in female mice with high-fat diet-induced insulin resistance (HFD; 58% fat by energy). Islets were isolated 20 h after the last exendin-4 injection, when effects of circulating exendin-4 had vanished. The glucose responsiveness in islets from HFD-fed mice at 8.3 mM glucose was reduced compared with islets from control mice fed a normal diet due to increased basal insulin secretion. However, GSIS increased in islets from HFD-fed exendin-4-treated animals (0.124+/-0.012 ng/h per islet in HFD-Ex-4 versus 0.062+/-0.010 in HFD, P=0.006). Furthermore, the insulin response to forskolin was increased (2.7+/-0.3 in HFD-Ex-4 versus 2.0+/-0.2 ng/h per islet in HFD, P=0.011) and PKAcat expression was increased, while PKAreg was reduced in islets from exendin-4-treated mice. In contrast, protein expression of PKBalpha, Pdx-1, and caspase 3/7 activity was not affected by exendin-4 treatment. We conclude that GLP-1 receptor activation in HFD-fed mice has durable effects on GSIS, in association with augmented signaling through the PKA pathway. These effects are seen beyond those induced by circulating exendin-4 already after 2 weeks of once-daily treatment in mice, whereas markers for islet proliferation and apoptosis were unaffected by this treatment.

Topics: Animals; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Caspase 3; Caspase 7; Cell Proliferation; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; Cyclic AMP-Dependent Protein Kinases; Diet; Exenatide; Fatty Acids; Female; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred C57BL; Peptides; Perfusion; Venoms

Not only exendin-4 but also exercise has been reported to improve glucose homeostasis by enhancing insulinotropic action, but the nature of its molecular mechanism has not been clarified. We investigated a mechanism to promote insulinotropic action by means of exendin-4 and exercise training in 90% pancreatectomized (Px) rats fed 40% energy fat diets. Px diabetic rats were divided into 4 groups: 1) exendin-4, 2) exendin-4 plus exercise, 3) saline (control), and 4) exercise. During the 8-week experimental period, rats in the exendin-4 groups were subcutaneously administered with 150 pmol/kg exendin-4 twice a day, while those in the exercise groups ran on an uphill treadmill with a 15 degree incline at 20 m/min for 30 min 5 days a week. First phase insulin secretion was elevated by both the administration of exendin-4 and exercise training during hyperglycemic clamp. However, second phase insulin secretion did not differ among the groups. Individual treatment of exendin-4 and exercise expanded beta-cell mass by increasing its proliferation and reducing its apoptosis, but the administration of exendin-4 plus exercise training did not produce any additional, positive effects. Both exendin-4 and exercise enhanced insulin receptor substrate (IRS)-2 expression through the activation of cAMP responding element binding protein in the islets, which potentiated their insulin/insulin like growth factor-1 signaling. The potentiation of the signaling increased the expression of pancreas duodenum homeobox-1, involved in beta-cell proliferation. In conclusion, exendin-4 and exercise equivalently improved glucose homeostasis due to the induction of IRS-2 in the islets of diabetic rats through a cAMP dependent common pathway.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus; Energy Intake; Exenatide; Gene Expression Regulation; Hypoglycemic Agents; Immunoblotting; Immunohistochemistry; Insulin; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I; Insulin-Secreting Cells; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Male; Pancreatectomy; Peptides; Phosphoproteins; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Venoms

Topics: Body Weight; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin, Isophane; Metformin; Peptides; Pioglitazone; Thiazolidinediones; Venoms

Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; Blood Glucose; Body Weight; Exenatide; Ganglia, Spinal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Male; Molecular Sequence Data; Muscle Tonus; Nerve Degeneration; Neurons, Afferent; Neuroprotective Agents; Peptides; Peripheral Nervous System Diseases; Postural Balance; Pyridoxine; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Sciatic Nerve; Venoms; Vitamins

Long-term treatment with dipeptidyl peptidase IV inhibitors (DPPIV-I) or glucagon-like peptide (GLP)-1 analogs may potentially affect intestinal growth by down- or upregulating the intestinotrophic hormone GLP-2. This study compared the intestinotrophic effects of 12-wk administration of vehicle, exendin-4 (Ex-4; 5 nmol/kg bid sc), or DPPIV-I (NN-7201, 10 mg/kg qd orally) in GK rats. Some animals were observed additionally for 9 wk after the end of treatment. Both treatments lowered glycated hemoglobin A1c at wk 12 vs. control (Ex-4, -0.8%; DPPIV-I, -0.4%). Body weight was reduced by Ex-4 compared with control (361 +/- 4 vs. 399 +/- 5 g; P < 0.001) because of reduced food intake, whereas neither parameter was affected by DPPIV-I. Linear bone growth was unaffected by either treatment. After treatment end, food intake in Ex-4 animals increased, and, by wk 21, body weight was identical in all groups. The small intestine of Ex-4-treated animals was larger at wk 12 compared with control (length, 135.6 +/- 1.6 vs. 124.5 +/- 2.3 cm, P < 0.001; absolute weight, 8.4 +/- 0.2 vs. 6.4 +/- 0.4 g, P < 0.001), being most pronounced proximally, where the absolute cross-sectional area related to body weight increased by 24% because of increased mucosal thickness. These effects were reversible, and 9 wk after the end of treatment, no differences between Ex-4 and control were apparent. Plasma GLP-2 concentrations were unaltered by either treatment, and Ex-4 had no agonistic or antagonistic effects on the transfected GLP-2 receptor. DPPIV-I had no intestinal effects. In conclusion, the continued presence of Ex-4 is necessary to maintain weight loss in GK rats. Effective antihyperglycemic treatment with Ex-4 increases intestinal mass reversibly, whereas DPPIV-I lacks intestinal effects.

Topics: Animals; Body Weight; Cell Proliferation; Chlorocebus aethiops; COS Cells; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Eating; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-2 Receptor; Glycated Hemoglobin; Humans; Intestine, Small; Male; Peptides; Protease Inhibitors; Rats; Receptors, Glucagon; Transfection; Venoms; Xanthines

To evaluate the effect of exenatide on clinical parameters in obese patients with type 2 diabetes mellitus whose hyperglycemia is not adequately controlled despite treatment with oral hypoglycemic agents and insulin.. In this retrospective analysis, clinical progress of 52 obese patients with type 2 diabetes treated with exenatide, 5 mcg twice daily, in an outpatient setting was reviewed. Treatment initiation was between September and December 2005. Mean follow-up period was 26 weeks. Thirty-eight patients took exenatide regularly (Group A); 14 patients discontinued exenatide because of insurance, personal, or economic reasons (Group B). Measurements at baseline and at follow-up included body weight; blood pressure; and levels of hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (CRP), and plasma lipids. Insulin dosage requirements were assessed.. Mean body weight (+/- standard error of the mean) decreased by 6.46 +/- 0.8 kg (P<.001) in Group A and increased by 2.4 +/- 0.6 kg in Group B (P<001). In Group A, mean HbA1c decreased by 0.6 +/- 0.21% (P = .007), and the insulin dosage requirement decreased for rapid-acting and mixed insulins (P<.02). In Group A, means of the following parameters decreased: serum total cholesterol by 8.5 +/- 3.3% (P = .03), triglycerides by 26 +/- 7.6% (P = .01), systolic blood pressure by 9.2 +/- 3.3 mm Hg (P = .02), and high-sensitivity CRP by 34 +/- 14.3% (P = .05). These indices did not change in Group B.. Exenatide effectively treats obese patients with type 2 diabetes on insulin, leading to weight loss and reduction in levels of HbA1c, systolic blood pressure, triglycerides, and high-sensitivity CRP.

Topics: Blood Pressure; Body Weight; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Peptides; Retrospective Studies; Triglycerides; Venoms; Weight Loss

Fetal pancreatic tissue has been suggested as a possible cell source for islet replacement therapy in type 1 diabetes mellitus. This tissue consists of a small amount of beta-cells, but a raft of immature and/or progenitor cells which nonetheless have the potential to proliferate and differentiate into functional insulin-producing cells. Freshly isolated fetal islet-like cell clusters are poorly responsive to glucose challenge, compared with adult islets. Upon exposure to appropriate growth factors and microenvironments, both the expansion and differentiation of fetal islet-like cell clusters can be enhanced. In this study, we investigated the role of exendin-4, a long-acting analogue of glucagon-like peptide 1 in the promotion of functional maturation of transplanted fetal islet-like cell clusters in vivo. Both blood glucose levels and body weights of transplanted diabetic mice treated with exendin-4 improved significantly compared with the transplanted group not subjected to exendin-4 treatment during the 3-month post-transplantation period. In addition, blood glucose levels on formal glucose challenge were also significantly improved by the end of the experiments. In the exendin-4-treated group, there were revascularization and insulin-producing cells as evidenced by positive immunostaining of the Lectins Bandeiraea simplicifolia and insulin, respectively, in the graft bearing kidney. These data indicate that in vivo exendin-4 treatment may enhance the growth and differentiation of fetal mice islet-like cell clusters, thus promoting the functional maturation of the graft after transplantation.

Topics: Animals; Blood Glucose; Body Weight; Cells, Cultured; Diabetes Mellitus, Experimental; Endothelial Cells; Exenatide; Female; Fetal Tissue Transplantation; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Male; Mice; Mice, Inbred C57BL; Peptides; Pregnancy; Venoms

Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents.. To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity.. High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity.. Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

Topics: Animals; Body Composition; Body Weight; Diabetes Mellitus, Type 2; Eating; Exenatide; Female; Hypoglycemic Agents; Kaolin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Venoms

Topics: Body Weight; Diabetes Mellitus; Exenatide; Peptides; Venoms

Topics: Blood Glucose; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Intravenous; Insulin; Insulin Glargine; Insulin, Long-Acting; Peptides; Venoms

The effects of the incretin mimetic exenatide (exendin-4) on metabolic parameters, insulin sensitivity, and beta-cell mass were examined in nondiabetic, insulin-resistant obese fa/fa Zucker rats. After 6 wk of treatment, ad libitum-fed exenatide-treated (EX) and pair-fed vehicle control (PF) rats had comparable food intake, body weight, hemoglobin A(1c) (HbA(1c)), and fasting plasma concentrations of glucose, insulin, and lipids. Concurrent decreases in food intake and weight gain were observed in EX and PF rats, compared with ad libitum-fed vehicle control (CON) rats (P < 0.001). The increases in HbA(1c) and fasting plasma insulin concentrations that occur during the normal progression of this disease model were significantly reduced in EX and PF rats, compared with CON rats (P < 0.001). The insulin sensitivity index (ISI; glucose infusion rate to plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than CON rats (P < 0.001) and 61% higher in EX rats than PF rats (P < 0.004). The latter difference was despite comparable HbA(1c), fasting glucose, fasting insulin, total cholesterol, high-density lipoprotein, and daily food consumption between EX and PF animals. In the absence of exenatide, beta-cell mass was hyperbolically related to ISI (beta-cell mass * ISI was constant). Analogous to the disposition index, the beta-cell mass * ISI product was 63% greater in EX than PF rats (P < 0.05). Thus, exenatide increased beta-cell mass to a greater extent than would be expected in animals of comparable insulin resistance, suggesting a direct trophic effect on islet neogenesis in obese fa/fa rats independent of body weight and glycemia.

Topics: Animals; Blood Glucose; Body Weight; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Insulin; Islets of Langerhans; Male; Obesity; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Zucker; Venoms

Although islet transplantation in diabetes holds great promise, two or three donor pancreases are usually required to achieve normoglycaemia in human or rodent recipients. We investigated whether there were differences between fresh and cultured islets in terms of transplantation outcome. We also investigated the effects of normoglycaemia during engraftment and the effects of exendin-4, a glucagon-like peptide-1 receptor agonist, on islet transplantation.. Seventy-five fresh islets were transplanted to the right kidney of diabetic mice and 425 fresh islets were transplanted to the left kidney. The mice were treated with exendin-4 or vehicle for 14 days, after which the large graft was removed by left nephrectomy. In a separate set of experiments, islets cultured in the presence or absence of exendin-4 for 72 h, or fresh islets, were transplanted to diabetic mice. In both sets of experiments, blood glucose levels were monitored.. Compared with cultured islets, fresh islets were more effective at reversing hyperglycaemia in mice. The treatment of the recipient mice with exendin-4 did not have beneficial effects on glucose homeostasis. However, when islets are cultured, exendin-4 treatment increases the rate of reversal of hyperglycaemia, but not to the degree of fresh islets.. Fresh islets are more effective than cultured islets at reversing hyperglycaemia. Exendin-4 has beneficial effects on islet transplantation.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; DNA; Exenatide; Glucose Tolerance Test; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred C57BL; Nephrectomy; Organ Culture Techniques; Peptides; Venoms

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Nausea; Peptides; Venoms; Vomiting

Topics: Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Peptides; Prospective Studies; Randomized Controlled Trials as Topic; Venoms

NN2211 is a long-acting, metabolically stable glucagon-like peptide-1 (GLP-1) derivative designed for once daily administration in humans. NN2211 dose dependently reduced the glycemic levels in ob/ob mice, with antihyperglycemic activity still evident 24 h postdose. Apart from an initial reduction in food intake, there were no significant differences between NN2211 and vehicle treatment, and body weight was not affected. Histological examination revealed that beta-cell proliferation and mass were not increased significantly in ob/ob mice with NN2211, although there was a strong tendency for increased proliferation. In db/db mice, exendin-4 and NN2211 decreased blood glucose compared with vehicle, but NN2211 had a longer duration of action. Food intake was lowered only on day 1 with both compounds, and body weight was unaffected. beta-Cell proliferation rate and mass were significantly increased with NN2211, but with exendin-4, only the beta-cell proliferation rate was significantly increased. In conclusion, NN2211 reduced blood glucose after acute and chronic treatment in ob/ob and db/db mice and was associated with increased beta-cell mass and proliferation in db/db mice. NN2211 is currently in phase 2 clinical development.

Topics: Animals; Blood Glucose; Body Weight; Cell Division; Diabetes Mellitus, Type 2; Eating; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Hyperglycemia; Insulin; Islets of Langerhans; Liraglutide; Mice; Mice, Inbred C57BL; Mice, Obese; Peptide Fragments; Peptides; Protein Precursors; Venoms

In addition to stimulating insulin secretion, glucagon-like peptide and its long-acting analog exendin 4 have been reported to increase beta-cell mass by both differentiation/neogenesis of precursor cells and enhanced replication of existing beta-cells. Here, we investigated the effect of exendin 4 in the growth and differentiation of beta-cells from undifferentiated precursors in islet-like cell clusters (ICCs) derived from human fetal pancreases. Our results show that the addition of exendin 4 to the culture media stimulates PDX 1 expression in ICCs as shown by immunofluorescence staining. The up-regulation of PDX 1 was not accompanied by changes in insulin expression because we did not find a significant difference in the number of insulin-positive cells in the exendin 4-treated ICCs, compared with controls. We also tested the effects of exendin 4 in the glucose-induced insulin secretion of human ICCs transplanted under the kidney capsule of athymic rats. In the exendin 4-treated rats (given ip during 10 d) 8 wk after the beginning of the treatment, insulin was released in response to glucose as detected by the measurement of circulating human C-peptide. In control (saline-treated) rats, the basal levels of human C-peptide did not change significantly after glucose stimulation. Thus, exendin 4 induces functional maturation of fetal beta-cells in response to glucose. In these rats, serial sections of the kidney-bearing grafts were examined histologically for insulin containing cells. We found a significant increase in beta-cell number, compared with the control rats. Overall, these results show that in vivo exendin 4 causes growth and differentiation of human fetal beta-cells from undifferentiated precursor cells. It also accelerates the functional maturation of fetal beta-cells as evidenced by their glucose-stimulated insulin secretion.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cell Division; Cells, Cultured; Culture Media; Exenatide; Gene Expression Regulation; Gestational Age; Homeodomain Proteins; Humans; Immunohistochemistry; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Peptides; Rats; Rats, Nude; Trans-Activators; Transplantation, Heterologous; Venoms

In the Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes, the neonatal beta-cell mass deficit is considered to be the primary defect leading to basal hyperglycemia, which is detectable for the first time 3 weeks after birth. We investigated in GK females the short- and the long-term effects of a treatment with glucagon-like peptide-1 (GLP-1) or its long-acting analog exendin-4 (Ex-4) during the first postnatal week (during the prediabetic period). GK rats were treated with daily injections of glucagon-like peptide-1 (400 microg x kg(-1) x day(-1)) or Ex-4 (3 microg x kg(-1) x day(-1)) from day 2 to day 6 after birth and were evaluated against Wistar and untreated GK rats. Under these conditions, on day 7 both treatments enhanced pancreatic insulin content and total beta-cell mass by stimulating beta-cell neogenesis and regeneration. Follow-up of biological characteristics from day 7 to adult age (2 months) showed that such a GLP-1 or Ex-4 treatment exerted long-term favorable influences on beta-cell mass and glycemic control at adult age. As compared to untreated GK rats, 2-month-old treated rats exhibited significantly decreased basal plasma glucose. Their glucose-stimulated insulin secretion, in vivo after intravenous glucose load or in vitro using isolated perfused pancreas, was slightly improved. This contributed at least partly to improve the in vivo plasma glucose disappearance rate, which was found to be increased in both treated GK groups compared to the untreated GK group. These findings in the GK model indicated, for the first time, that GLP-1 or Ex-4 treatment limited to the prediabetic period delays the installation and limits the severity of type 2 diabetes. Under these conditions, GLP-1 represents a unique tool because of its beta-cell replenishing effect in spontaneously diabetic rodents. It may prove to be an invaluable agent for the prevention of human type 2 diabetes.

Topics: Age Factors; Animals; Animals, Newborn; Blood Glucose; Body Weight; Cell Division; Diabetes Mellitus, Type 2; Disease Models, Animal; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Insulin; Insulin Secretion; Islets of Langerhans; Longitudinal Studies; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Mutant Strains; Rats, Wistar; Venoms

In neonatal Wistar rats injected with streptozotocin (STZ) at birth (n0-STZ model), a recognized model of beta-cell regeneration, we investigated the capacity of early treatment with glucagon-like peptide 1 (GLP-1) or exendin-4 to promote beta-cell regeneration and thereby improve islet function in the long term, when animals become adults. To this end, n0-STZ rats were submitted to GLP-1 or exendin-4 from postnatal day 2 to day 6 only, and their beta-cell mass and pancreatic functions were tested on day 7 and at 2 months. On day 7, both treatments increased body weight, decreased basal plasma glucose, decreased insulinemia, and increased pancreatic insulin content in n0-STZ rats. At the same age, the beta-cell mass, measured by immunocytochemistry and morphometry methods, was strongly increased in n0-STZ/GLP-1 and n0-STZ/Ex rats compared with n0-STZ rats, representing 51 and 71%, respectively, of the beta-cell mass in Wistar rats, whereas n0-STZ beta-cell mass represented only 21% of the Wistar control value. Despite such early improved beta-cell mass, which is maintained at adult age, the basal and glucose-stimulated insulin secretion (in vivo after intravenous glucose load or in vitro using perfused pancreas) were not improved in the 2-month-old n0-STZ rats previously treated with GLP-1 or exendin-4 compared with untreated n0-STZ rats. However, both treated groups significantly exhibited a decreased basal plasma glucose level and an increased plasma glucose clearance rate compared with the 2-month-old untreated n0-STZ group at adult age. These findings in the n0-STZ model indicate for the first time that GLP-1 or exendin-4 applied during the neonatal diabetic period exert both short- and long-term beneficial effects on beta-cell mass recovery and glucose homeostasis. However, the increase in beta-cell mass, which is still present in the adult n0-STZ rats previously treated, contrasts with the poor beta-cell responsiveness to glucose. Further studies are needed to understand the dissociation between beta-cell regeneration and the lack of improvement in beta-cell function.

Topics: Animals; Animals, Newborn; Apoptosis; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Immunohistochemistry; Insulin; Islets of Langerhans; Organ Size; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Wistar; Venoms

The present study explores the potential utility of peripheral versus central administration of glucagon-like peptide-1 (GLP-1) receptor agonists in the regulation of feeding behavior in Wistar and Zucker obese rats. Acute central (intracerebroventricular [i.c.v.]) and peripheral (subcutaneous [s.c.]) administration of both GLP-1 (7-36) amide and exendin-4 resulted in a reduction in food intake for at least 4 hours, exendin-4 being much more potent than GLP-1 (7-36) amide, especially after peripheral administration. Both Zucker obese rats (fa/fa) and their lean littermates (Fa/-) responded to acute central and peripheral administration of exendin-4. Moreover, in situ hybridization revealed specific labeling for the mRNA for GLP-1 receptors in several brain areas of both the obese and lean rats. The presence of this receptor was also detected by affinity cross-linking assays. Long-term s.c. administration of exendin-4 (1 single injection per day, 1 hour prior to the onset of the dark phase of the cycle) decreased daily food intake and practically blocked weight gain in obese rats. In contrast to previous studies, these findings show that peripheral (s.c.) administration of both GLP-1 receptor agonists also induces satiety and weight loss in rats, and suggest the potential usefulness of exendin-4 as a therapeutic tool for the treatment of diabetes and/or obesity.

Topics: Amines; Animals; Appetite; Body Weight; Brain; Diabetes Mellitus; Drinking; Eating; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; In Situ Hybridization; Injections, Intraventricular; Injections, Subcutaneous; Male; Obesity; Peptide Fragments; Peptides; Rats; Rats, Wistar; Rats, Zucker; Receptors, Glucagon; RNA, Messenger; Venoms

To investigate whether chronic administration of the long-acting glucagon-like peptide-1 receptor agonist exendin-4 can elicit sustained reductions in food intake and body weight and whether its actions require an intact leptin system.. Male lean and obese Zucker (fa/fa) rats were infused intracerebroventricularly with exendin-4 using osmotic minipumps for 8 days.. Exendin-4 reduced body weight in both lean and obese Zucker rats, maximum suppression being reached on Day 5 in obese (8%) and Day 7 in lean (16%) rats. However, epididymal white adipose tissue weight was not reduced, and only in lean rats was there a reduction in plasma leptin concentration. Food intake was maximally suppressed (by 81%) on Day 3 in obese rats but was reduced by only 18% on Day 8. Similarly, in lean rats food intake was maximally reduced (by 93%) on Day 4 of treatment and by 45% on Day 8. Brown adipose tissue temperature was reduced from Days 2 to 4. Plasma corticosterone was elevated by 76% in lean but by only 28% in obese rats.. Chronic exendin-4 treatment reduced body weight in both obese and lean Zucker rats by reducing food intake: metabolic rate was apparently suppressed. These effects did not require an intact leptin system. Neither does the absence of an intact leptin system sensitize animals to exendin-4. Partial tolerance to the anorectic effect of exendin-4 in lean rats may have been due to elevated plasma corticosterone and depressed plasma leptin levels, but other counter-regulatory mechanisms seem to play a role in obese Zucker rats.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Temperature; Body Weight; Brain; Corticosterone; Eating; Epididymis; Exenatide; Glucagon-Like Peptide-1 Receptor; Leptin; Male; Obesity; Organ Size; Peptides; Rats; Rats, Zucker; Receptors, Glucagon; Venoms

Glucagon-like peptide-1 is the main hormonal mediator of the enteroinsular axis. Recently, it has additionally received considerable attention as a possible new treatment for Type II (non-insulin-dependent) diabetes mellitus. Its major disadvantage is that its duration of action is too short to achieve good 24-h metabolic control. Exendin-4, which is produced in the salivary glands of Gila monster lizards, is structurally similar to glucagon-like peptide-1 and shares several useful biological properties with glucagon-like peptide-1. It binds the glucagon-like peptide-1 receptor, stimulates insulin release and increases the cAMP production in beta cells. We report that exendin-4 is a more potent insulinotropic agent when given intravenously to rats than is glucagon-like peptide-1 (ED50 0.19 nmol/kg for glucagon-like peptide-1 vs 0.0143 nmol/kg for exendin-4) and causes a greater elevation in cAMP concentrations in isolated islets. Of even greater interest we found that when given intraperitoneally only once daily to diabetic mice it had a prolonged effect of lowering blood glucose. After 1 week of treatment blood glucoses were 5.0+/-2.6 mmol/l compared to diabetic concentrations of 13.2+/-2.8 mmol/l. After 13 weeks of daily treatment HbA1c was 8.8+/-0.4% in non-treated diabetic animals compared with 4.7+/-0.25% in treated diabetic animals. Blood glucoses also were lower (p < 0.005) and insulin concentrations higher (p < 0.02) in the treated animals. Exendin-4 could therefore be preferable to glucagon-like peptide-1 as a long-term treatment of Type II diabetes.

Topics: Animals; Blood Glucose; Body Weight; Carrier Proteins; Crosses, Genetic; Cyclic AMP; Diabetes Mellitus, Type 2; Drug Administration Schedule; Energy Intake; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Insulin; Islets of Langerhans; Lizards; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Venoms