exenatide and Overweight

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

To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean duration of 51 RCTs was 31 weeks. Exenatide 10 μg twice daily (EX10BID) reduced weight compared with exenatide 5 μg twice daily (EX5BID), liraglutide 0.6 mg once daily (LIR0.6QD), liraglutide-1.2 mg once daily (LIR1.2QD), and placebo treatment, with mean differences of -1.07 kg (95% CI: -2.41, -0.02), -2.38 kg (95% CI: -3.71, -1.06), -1.62 kg (95% CI: -2.79, -0.43), and -1.92 kg (95% CI: -2.61, -1.24), respectively. Reductions of weight treated with liraglutide-1.8 mg once daily (LIR1.8QD) reach statistical significance (-1.43 kg (95% CI: -2.73, -0.15)) versus LIR1.2QD and (-0.98 kg (95% CI: -1.94, -0.02)) versus placebo. Network meta-analysis found that EX10BID, LIR1.8QD, and EX2QW obtained a higher proportion of patients with weight loss than other traditional hypoglycemic agents. Our results suggest GLP-1 RAs are promising candidates for weight control in comparison with traditional hypoglycemic drugs, and EX10BID, LIR1.8QD, and EX2QW rank the top three drugs.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Obesity; Overweight; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Venoms; Weight Loss

To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.. Systematic review with meta-analyses.. Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011). Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.. Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.. 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference -2.9 kg, 95% confidence interval -3.6 to -2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (-3.2 kg, -4.3 to -2.1; three trials) as well as patients with diabetes (-2.8 kg, -3.4 to -2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.. The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Overweight; Peptides; Receptors, Glucagon; Treatment Outcome; Venoms; Weight Loss

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

Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive beta-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Life Style; Liraglutide; Obesity; Overweight; Peptides; Receptors, Glucagon; Venoms; Weight Loss

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in beta cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon like peptide 1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incidence; Incretins; Insulin; Insulin Secretion; Life Style; Liraglutide; Obesity; Overweight; Peptides; Prevalence; Venoms

Obesity and smoking are the two leading causes of preventable death in the USA. Unfortunately, most smokers gain weight after quitting. Postcessation weight gain (PCWG) is frequently cited as one of the primary barriers to a quit attempt and a common cause of relapse. Further, excessive PCWG may contribute to the onset or progression of metabolic conditions, such as hyperglycaemia and obesity. The efficacy of the current treatments for smoking cessation is modest, and these treatments have no clinically meaningful impact on mitigating PCWG. Here, we outline a novel approach using glucagon-like peptide 1 receptor agonists (GLP-1RA), which have demonstrated efficacy in reducing both food and nicotine intake. This report describes the design of a double-blind, placebo-controlled, randomised clinical trial that evaluates the effects of the GLP-1RA exenatide as an adjunct to nicotine patches on smoking abstinence and PCWG.. The study will be conducted at two university-affiliated research sites in Houston, Texas, the UTHealth Center for Neurobehavioral Research on Addiction and Baylor College of Medicine Michael E. DeBakey VA Medical Centre. The sample will consist of 216 treatment-seeking smokers with pre-diabetes (haemoglobin A1c of 5.7%-6.4%) and/or overweight (body mass index of 25 kg/m. The study has been approved by the UTHealth Committee for the Protection of Human Subjects (HSC-MS-21-0639) and Baylor College of Medicine Institutional Review Board (H-50543). All participants will sign informed consent. The study results will be disseminated via peer-reviewed publications and conference presentations.. NCT05610800.

Topics: Exenatide; Humans; Nicotine; Obesity; Overweight; Prediabetic State; Randomized Controlled Trials as Topic; Smokers; Smoking Cessation; Tobacco Use Cessation Devices; Weight Gain

This is a secondary analysis of a randomized controlled trial (RCT) on the effects of the glucagon-like peptide-1 receptor agonists exenatide and insulin aspartate 30 injection on carotid intima-media thickness. Here, we report the renal outcomes of the intervention in patients with type 2 diabetes mellitus (T2DM). Data from the RCT study was used to evaluate the effect of exenatide or insulin given for 52 weeks on estimated glomerular filtration rate (eGFR) in patients with T2DM. The primary end point was the change in the eGFR from baseline between the exenatide and insulin groups in normal versus overweight patients and patients with obesity. The secondary end point was the correlation between change in eGFR and oxidative stress, glycemic control, and dyslipidemia. There was a significant difference in eGFR between the insulin and exenatide groups at 52 weeks (p=0.0135). Within the insulin group, the eGFR remained below baseline at 52 weeks in all patients, and there was an increase in body weight in the normal group compared with the overweight patients and patients with obesity. The opposite was observed in the exenatide group. A decrease in body weight was prominent in the exenatide group at 52 weeks (p<0.05), the eGFR was below baseline in overweight patients and patients with obesity and significantly above baseline in the normal group (p<0.05). The eGFR was positively correlated to 8-oxo-7,8-dihydroguanosine in the insulin group (p<0.05) but not the exenatide group. It can be concluded that compared with insulin, exenatide may improve renal function in overweight patients and patients with obesity more than in normal-weight patients with T2DM, but a further RCT is needed to confirm this effect.

Topics: Aspartic Acid; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Kidney; Obesity; Overweight; Peptides; Venoms

The majority of Polycystic ovary syndrome (PCOS) are overweight or obese with increased infertility and high risk of pregnancy complications. We aim to compare efficacy of metformin and exenatide on spontaneous pregnancy rate, overall pregnancy rate after assisted reproductive technology treatment (ART) and pregnancy outcomes in overweight or obese infertility PCOS.. In this long-term follow-up study, 160 overweight or obese infertility Chinese PCOS were randomized to exenatide or metformin treatment for 12 weeks. Afterward, all were treated with metformin alone until pregnancy confirmed and followed until delivery. If patients failed spontaneous pregnancy during the second 12 weeks, ART could be offered until end of 64 weeks. The primary outcome was spontaneous pregnancy rate.. At week 24, 29.2% of women in exenatide group conceived spontaneously while 14.7% in metformin group (p = 0.03). At week 64, total pregnancy rates were 79.2% in exenatide group and 76% in metformin group without significant difference (p = 0.65). Between two groups, there was no significant difference of pregnancy outcomes (p > 0.05). A stepwise logistic regression showed that spontaneous pregnancy was positively associated with body weight reduction and HOMA-IR improvement in either group.. In overweight or obese infertility Chinese PCOS, 12 weeks pregestational exenatide treatment resulted in more spontaneous pregnancy likely due to greater weight reduction and improvement of insulin resistance compared with metformin treatment without obvious benefit on overall pregnancy rate after ART or pregnancy outcomes of successful conceived women.. This clinical trial was registered at Chinese Clinical Trials Registry (ChiCTR-IIR-16008084) on 13/3/2016.

Topics: Exenatide; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Infertility, Female; Metformin; Obesity; Overweight; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Weight Loss

In this study, we investigated the effect of exenatide (EXE), a glucagon-like peptide (GLP)-1 receptor agonist, on kidney function, obesity indices, and glucose control in overweight/obese patients with type 2 diabetes mellitus (T2DM). A total of 159 overweight/obese patients with T2DM were randomized to the EXE group or insulin glargine (GLAR) control group for a total treatment period of 24 weeks. EXE intervention significantly reduced the urine albumin concentration (UAC) at week 12 and 24 endpoints (P < 0.001 at week 12 and 24). The levels of the anthropometric, glucose and lipid parameters (TG and HDL-c), and inflammation biomarkers (CRP and TNF-α) in the EXE group were improved at 12 weeks or 24 weeks, respectively. Meanwhile, a comparison between two groups showed significant changes in anthropometric parameters, glucose parameters, lipid parameters (TG and HDL-c), and Inflammation biomarkers (CRP, IL-6, and TNF-α). Serum fibroblast growth factor 21 (FGF21) was increased in the EXE group (P = 0.005) at week 24, and the change was significantly improved compared with GLAR group (P = 0.003). Correlation network analysis showed that FGF21 had a more central role in improving metabolism in the EXE group, and the change of FGF 21 was significantly negatively correlated with UAC at week 12 and week 24, respectively (r = - 0.297, P = 0.010; r = - 0.294, P = 0.012). Our results showed that EXE could help patients improve UAC, glycemic levels, and inflammatory biomarkers after a follow-up period of 24 weeks intervention. These EXE effects may be partly mediated by FGF 21, indicating that EXE is an effective and safe way to control albuminuria in overweight/obese patients with T2DM.

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

Obesity and insulin resistance (IR) are common features of polycystic ovary syndrome (PCOS). Metformin (MET) increases insulin sensitivity, but it is associated with unsatisfactory weight loss. The glucagon-like peptide-1 receptor agonist exenatide has been shown to reduce weight and IR in patients with diabetes. This study aimed to explore the therapeutic effects of exenatide once-weekly (QW) combined with MET on body weight, as well as metabolic and endocrinological parameters in overweight/obese women with PCOS.. Fifty overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomized to one of two treatment groups: MET (500 mg three times a day [TID]) or combination treatment (COM) (MET 500 mg TID, exenatide 2 mg QW) for 12 weeks. The primary outcomes were anthropometric changes associated with obesity, and the secondary outcomes included changes in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein.. Forty (80%) patients completed the study. COM therapy was superior to MET monotherapy in reducing weight (P = 0.045), body mass index (BMI) (P = 0.041), and waist circumference (P = 0.023). Patients in the COM group on an average lost 3.8 ± 2.4 kg compared with 2.1 ± 3.0 kg in the MET group. In the COM group, BMI and waist circumference decreased by 1.4 ± 0.87 kg/m2 and 4.63 ± 4.42 cm compared with 0.77 ± 1.17 kg/m2 and 1.72 ± 3.07 cm in the MET group, respectively. Moreover, levels of fasting glucose, oral glucose tolerance test (OGTT) 2-h glucose, and OGTT 2-h insulin were significantly lower with COM therapy than with MET (P < 0.050). Mild and moderate gastrointestinal reactions were the most common adverse events in both groups.. COM therapy was more effective than MET alone in reducing body weight, BMI, and waist circumference, and improving insulin sensitivity in overweight/obese women with PCOS, with acceptable short-term side effects.. ClinicalTrials.gov, NCT04029272. https://clinicaltrials.gov/ct2/show/NCT04029272.

Topics: Exenatide; Female; Humans; Metformin; Obesity; Overweight; Polycystic Ovary Syndrome

As there is significant heterogeneity in the weight loss response to pharmacotherapy, one of the most important clinical questions in obesity medicine is how to predict an individual's response to pharmacotherapy. The present study examines patterns of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment compared to those treated with hypocaloric diet and matched placebo injections.. We randomized 182 women (BMI 25-48 kg/m2) to treatment with exenatide alone or matched placebo injections plus hypocaloric diet. In both treatment groups, women who demonstrated ≥ 5% weight loss at 12 weeks were characterized as high responders and those who lost ≥10% of body weight were classified as super responders. Our primary outcome was long-term change in body weight among early high responders to either treatment. An exploratory metabolomic analysis was also performed.. We observed individual variability in weight loss with both exenatide and hypocaloric diet plus placebo injections. There was a trend toward a higher percentage of subjects who achieved ≥ 5% weight loss with exenatide compared to diet (56% of those treated with exenatide, 76% of those treated with diet, p = 0.05) but no significant difference in those who achieved ≥ 10% weight loss (23% of individuals treated with exenatide and 36% of those treated with diet, p = 0.55). In both treatment groups, higher weight loss at 3 months of treatment predicted super responder status (diet p=0.0098, exenatide p=0.0080). Both treatment groups also demonstrated similar peak weight loss during the study period. We observed lower cysteine concentrations in the exenatide responder group (0.81. In a population of early high responders, longer term weight loss with exenatide treatment is similar to that achieved with a hypocaloric diet.. www.clinicaltrialsgov, identifier NCT01590433.

Topics: Adult; Anti-Obesity Agents; Body Mass Index; Combined Modality Therapy; Cysteine; Diet, Reducing; Double-Blind Method; Exenatide; Female; Humans; Metabolomics; Middle Aged; Obesity; Overweight; Treatment Outcome; Weight Loss

Up to 40% of patients with polycystic ovary syndrome (PCOS) have prediabetes; an optimal pharmacotherapy regimen for diabetes prevention in PCOS is yet to be established.. To evaluate clinical efficacy of exenatide (EX), metformin (MET), or combination (COM) for prediabetes in PCOS.. Randomized, open-label, parallel-group controlled trial.. Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine.. PCOS with prediabetes (fasting plasma glucose 5.6-6.9 mmol/L and/or 2 hour post glucose 7.8-11.0 mmol/L on oral glucose tolerance test [OGTT]). A total of 150 out of 183 eligible enrollees completed the study.. EX (10-20μg daily), MET (1500-2000 mg daily), or COM (EX plus MET) for 12 weeks.. Sustained remission rate of prediabetes (primary endpoint, a normal OGTT after 12 weeks of treatment followed by 12 weeks of washout on no drug treatment) along with anthropometric, hormonal, metabolic, and pancreatic β-cell function parameters (secondary endpoints) and potential mechanisms were assessed.. Impaired glucose tolerance was found the dominant prediabetes phenotype. Overall sustained prediabetes remission rate was 50.7%. Remission rate of COM group (64%, 32/50) or EX group (56%, 28/50) was significantly higher than that of the MET group (32%, 16/50) (P = .003 and .027, respectively). EX was associated with superior suppression of 2-hour glucose increment in OGTT. A 2-step hyperglycemic clamp study revealed that EX had led to higher postprandial insulin secretion than MET, potentially explaining the higher remission rate.. Compared with MET monotherapy, EX or COM achieved higher rate of remission of prediabetes among PCOS patients by improving postprandial insulin secretion.

Topics: Adolescent; Adult; Blood Glucose; China; Drug Therapy, Combination; Exenatide; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Secretion; Metformin; Middle Aged; Obesity; Overweight; Polycystic Ovary Syndrome; Postprandial Period; Prediabetic State; Treatment Outcome; 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

The study was to investigate circulating zinc-α2-glycoprotein (ZAG) concentrations in women with PCOS, and changes in ZAG levels after exenatide or metformin treatment. One hundred eighty-two women with polycystic ovary syndrome (PCOS) who met the 2003 Rotterdam diagnostic criteria and 150 controls without PCOS were recruited. We partitioned women with PCOS into groups according to body mass index or blood glucose concentrations, determined serum ZAG, anthropometric parameters, metabolic and endocrine indicators, and inflammatory markers, and statistically analyzed the results. Eighty-two overweight/obese subjects of the recruited women with PCOS were then randomly assigned to groups administered either 12 weeks of exenatide injection (10 μg b.i.d.) or oral metformin (1,000 mg b.i.d.). Circulating ZAG levels were determined after 12 weeks of treatment. The results showed that circulating ZAG was significantly lower in PCOS women than in healthy women (p < 0.01). Overweight/obese women and those with higher blood glucose levels had lower circulating ZAG. After 12 weeks of exenatide or metformin treatment, there were significant increases (p < 0.01) in circulating ZAG in both treatment groups (the exenatide baseline level was 46.54 ± 2.38 ng/mL vs. 56.41 ± 2.02 ng/mL after treatment, p < 0.01; metformin baseline was 47.81 ± 2.14 ng/mL vs. 55.67 ± 2.01 ng/mL after treatment, p < 0.01), however there was no statistical difference between the 2 treatments (p > 0.05). Circulating ZAG is closely related to PCOS and could be an important adipokine involved in the occurrence and development of PCOS. ZAG might possibly be applicable as a new observational indicator in the treatment of PCOS.

Topics: Adipokines; Adult; Biomarkers; Blood Glucose; Carrier Proteins; Exenatide; Female; Glycoproteins; Humans; Hypoglycemic Agents; Metformin; Obesity; Overweight; Polycystic Ovary Syndrome; Treatment Outcome

Persons with type 1 diabetes require intensive insulin therapy to achieve glycaemic control, but side effects, including hypoglycaemia and weight gain, may reduce treatment compliance. We hypothesise that add-on treatment of the short-acting glucagon-like peptide-1 receptor agonist, exenatide, to insulin therapy in persons with type 1 diabetes will reduce insulin requirements, glycaemic excursions and body weight and improve glycaemic control without increasing the risk of hypoglycaemia. The present article describes a protocol developed to test this hypothesis.. One-hundred adult persons with type 1 diabetes for more than 1 year, insufficient glycaemic control (glycated haemoglobin A1c (HbA1c) between 58 and 86 mmol/mol) and body mass index >22.0 kg/m. The study is approved by the Danish Medicines Agency, the Regional Scientific Ethics Committee of the Capital Region of Denmark and the Data Protection Agency. The study will be carried out under the surveillance and guidance of the good clinical practice (GCP) unit at Copenhagen University Hospital Bispebjerg in accordance with the ICH-GCP guidelines and the Helsinki Declaration. Positive, negative as well as inconclusive results will be sought disseminated at scientific meetings and in international peer-reviewed scientific journals.. NCT03017352.

Topics: Blood Glucose Self-Monitoring; Denmark; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Meals; Overweight; Quality of Life; Randomized Controlled Trials as Topic

Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment.. To evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS.. This is a 24-week open-label prospective, randomized, clinical study.. This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 μg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks.. After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 ± 1.29 kg vs 2.28 ± 0.55 kg, P < .001) and total fat% (4.67 ± 0.09% vs 1.11 ± 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 ± 0.58 vs 0.59 ± 0.12, P < .001) and increased the menstrual frequency ratio (0.62 ± 0.12 vs 0.37 ± 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE-treated patients was significantly higher than MET-treated patients (43.60% vs 18.70%, P < .05).. Short-term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS.

Topics: Adolescent; Adult; Exenatide; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Menstrual Cycle; Obesity; Overweight; Peptides; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Prospective Studies; Venoms; Weight Loss; Young Adult

Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1RA) is consistently associated with heart rate (HR) acceleration in type 2 diabetes patients. We explored the mechanisms underlying this potential safety concern.. Ten healthy overweight males (aged 20-27 years) were examined in an open label, crossover study. Automated oscillometric blood pressure measurements and finger photoplethysmography were performed throughout intravenous administration of placebo (saline 0.9%), exenatide (targeting therapeutic concentrations) and a combination of exenatide and the nitric oxide synthase inhibitor L-N(G) -monomethyl arginine (L-NMMA). Sympathetic nervous system (SNS) activity was measured by heart rate variability and rate-pressure product.. Exenatide increased HR by a mean maximum of 6.8 (95% CI 1.7, 11.9) beats min(-1) (P < 0.05), systolic blood pressure (SBP) by 9.8 (95% CI 3.5, 16.1) mmHg (P < 0.01) and markers of SNS activity (P < 0.05). No changes in total peripheral resistance were observed. Increases in HR, SBP and sympathetic activity were preserved during concomitant L-NMMA infusion.. Our data argue against exenatide-induced reflex tachycardia as a response to vasodilation and rather suggest the involvement of SNS activation in humans.

Topics: Adult; Blood Glucose; Body Mass Index; Cross-Over Studies; Exenatide; Glucagon-Like Peptide 1; Healthy Volunteers; Heart Rate; Humans; Lipids; Male; Overweight; Peptides; Sympathetic Nervous System; Vascular Resistance; Venoms; Young Adult

To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men.. Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20-27 years; BMI 26-31 kg/m(2)) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured.. GFR increased by a mean of 18 ± 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m(2) (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 ± 12 ml/min/1.73 m(2) (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by -33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion.. Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted.

Topics: Adult; Body Mass Index; Enzyme Inhibitors; Exenatide; Glomerular Filtration Rate; Glucagon-Like Peptide-1 Receptor; Heart Rate; Humans; Hypoglycemic Agents; Infusions, Intravenous; Kidney; Kidney Tubules; Male; Metabolic Clearance Rate; Nitric Oxide Synthase; omega-N-Methylarginine; Overweight; Peptides; Renal Circulation; Vascular Resistance; Venoms; Young Adult

This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients.. We included overweight (BMI 25-40 kg/m(2)) men and postmenopausal women, aged 35-75 years with type 2 diabetes (HbA1c 48-75 mmol/mol; 6.5-9.0%) and estimated GFR ≥ 60 ml min(-1) 1.73 m(-2). Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined.. Of the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min(-1) 1.73 m(-2), p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p < 0.05), but did not change RE. Exenatide increased FENa, FEK, urine osmolality and pH, while FEU, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05).. Exenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients.. ClincialTrials.gov NCT01744236 FUNDING : The research leading to these results has been funded from: (1) the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 - the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87.

Topics: Adult; Aged; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Female; Glomerular Filtration Rate; Glucagon-Like Peptide-1 Receptor; Hemodynamics; Humans; Hypoglycemic Agents; Kidney; Male; Middle Aged; Overweight; Peptides; Placebo Effect; 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

The ability of the incretin mimetic exenatide to improve glycaemic control and reduce body weight was assessed over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin.. In this interim 82-week analysis, 150 (total cohort) of an eligible population of 183 patients opted to continue exenatide treatment in an uncontrolled open-label extension of a 30-week double-blind, placebo-controlled trial. Of these, 92 patients (completer cohort) achieved 82 weeks of exenatide therapy. Patients continued metformin throughout the study.. At the end of the placebo-controlled trial, exenatide resulted in an haemoglobin A1c (HbA1c) reduction from baseline of -1.0 +/- 0.1% (mean +/- SE) (exenatide treatment arms), with durable HbA1c reductions after 82 weeks of -1.3 +/- 0.1%. The percent of patients who achieved HbA1c < or = 7% at weeks 30 and 82 was 46 and 59% respectively. After 30 weeks, exenatide caused a reduction in weight from baseline of -3.0 +/- 0.6 kg, with a progressive reduction in weight of -5.3 +/- 0.8 kg after 82 weeks. In addition, exenatide treatment produced clinically significant improvements in cardiovascular risk factors after 82 weeks. The most frequent adverse event after 30 and 82 weeks of exenatide was nausea, which was generally of mild-or-moderate intensity. It decreased in incidence after initiation in the controlled trial and the uncontrolled open-label extension. Hypoglycaemia was rare, with no severe events.. Exenatide was generally well tolerated, producing a durable reduction in HbA1c and a progressive reduction in weight over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with metformin.

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

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

Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown.. In the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.. In male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.. Altogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients.. Swedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.

Topics: 3,4-Dihydroxyphenylacetic Acid; Alcohol Drinking; Alcoholism; Animals; Dopamine; Ethanol; Exenatide; Female; Male; Mice; Overweight; Rats; Recurrence

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

Exenatide is a new agent for diabetes therapy, and its use in polycystic ovary syndrome (PCOS) has gradually increased; however, the clinical benefit and metabolic improvement need further evidence. This research aimed to study the changes in whole metabolites before and after exenatide treatment in overweight/obese PCOS patients to gain a better understanding of exenatide for the treatment of PCOS.. Sixty-seven women, including 32 with PCOS and 35 age-matched controls, were recruited. The metabolite changes were detected with nontargeted gas chromatography-tandem mass spectrometry (NTGC-MS) before and after exenatide treatment, and changes in clinical biochemical characteristics were also observed.. A total of 62 metabolites were differentially expressed between the healthy and PCOS groups, and 31 differentially expressed metabolites were detected before and after exenatide treatment. Abnormal lipid metabolism and amino acid metabolism were the main metabolic disorders. Exenatide improved lipid and amino acid metabolism, especially amino acid metabolites. Three types of branched-chain amino acids (valine, leucine and isoleucine), two types of aromatic amino acids (phenylalanine and tyrosine) and lysine are important potential metabolites for the therapeutic efficacy of exenatide. Many abnormal metabolic disorders are related to insulin resistance, oxidative stress and even ovulatory dysfunction. Moreover, in this small sample clinical study, we also found that exenatide improved insulin sensitivity, reduced body weight and improved glycolipid metabolism in PCOS.. NTGC-MS-based metabolic pathway analysis revealed that exenatide has a beneficial effect on overweight/obese PCOS patients by regulating metabolic disorders, especially amino acid disorders.

Topics: Chromatography, Gas; Exenatide; Female; Glycated Hemoglobin; Humans; Obesity; Overweight; Polycystic Ovary Syndrome; Signal Transduction; Tandem Mass Spectrometry

Topics: Exenatide; Female; Humans; Obesity; Overweight; Polycystic Ovary Syndrome; Pregnancy; Weight Loss

Subjects with type-2 diabetes are typically obese with dysfunctional adipose tissue (AT). Glucagon-like peptide-1 (GLP-1) analogues are routinely used to improve glycaemia. Although, they also aid weight loss that improves AT function, their direct effect on AT function is unclear. To explore GLP-1 analogues' influence on human AT's cytokine and extracellular matrix (ECM) regulation, we therefore obtained and treated omental (OMAT) and subcutaneous (SCAT) AT samples with Exendin-4, an agonist of the GLP-1 receptor (GLP-1R).. OMAT and abdominal SCAT samples obtained from women during elective surgery at the Royal Devon & Exeter Hospital (UK) were treated with increasing doses of Exendin-4. Changes in RNA expression of adipokines, inflammatory cytokines, ECM components and their regulators were assessed and protein secretion analysed by ELISA. GLP-1R protein accumulation was compared in paired AT depot samples.. Exendin-4 induced an increase in OMAT adiponectin (P=0.02) and decrease in elastin expression (P=0.03) in parallel with reduced elastin secretion (P=0.04). In contrast to OMAT, we did not observe an effect on SCAT. There was no change in the expression of inflammatory markers (CD14, TNFA, MCP-1), collagens, TGFB1 or CTGF. GLP-1R accumulation was higher in SCAT.. Independently of weight loss, which may bias findings of in vivo studies, GLP-1 analogues modify human OMAT physiology favourably by increasing the insulin-sensitising cytokine adiponectin. However, the reduction of elastin and no apparent effect on AT's inflammatory cytokines suggest that GLP-1 analogues may be less beneficial to AT function, especially if there is no associated weight loss.

Topics: Adipokines; Adiponectin; Adipose Tissue; Aged; Cytokines; Dose-Response Relationship, Drug; Elastin; Exenatide; Extracellular Matrix; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Inflammation; Middle Aged; Overweight; Peptides; Venoms

The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans.. We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m(2)). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor L-N(G)-monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant L-N(G)-monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=-5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=-0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged.. Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in healthy overweight men, suggesting direct actions of this GLP-1RA on microvascular perfusion or interaction with vasoactive factors.

Topics: Adult; Blood Glucose; Blood Pressure; Capillaries; Cross-Over Studies; Exenatide; Glucagon-Like Peptide 1; Humans; Insulin; Male; Microcirculation; Microscopy, Video; Nitric Oxide; omega-N-Methylarginine; Overweight; Peptides; Skin; Venoms; Young Adult

Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair β-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired β-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 μg·kg⁻¹·day⁻¹) and/or exenatide (20 μg·kg⁻¹·day⁻¹) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity.

Topics: Adiposity; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Drug Implants; Drug Synergism; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Leptin; Male; Mice, Inbred C57BL; Overweight; Pancreas; Peptides; Recombinant Proteins; Streptozocin; Triglycerides; Venoms

Topics: Anti-Obesity Agents; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Overweight; Peptides; Receptors, Glucagon; Venoms; Weight Loss

Exenatide is an incretin mimetic licensed for treatment of Type 2 diabetes poorly controlled despite maximally tolerated doses of oral therapy. Similar in structure to the natural incretin hormone glucagon-like peptide 1 (GLP-1), it helps restore underlying pathophysiological abnormalities.. We report the successful use of exenatide, combined with insulin, in a 66-year-old woman initially diagnosed with Type 2 diabetes in 1989 but now exhibiting a Type 1 phenotype. Diet, lifestyle advice and oral glucose-lowering agents were commenced but persisting poor control necessitated insulin therapy in 2005. She later presented twice in diabetic ketoacidosis, suggesting conversion to a Type 1 phenotype (postprandial C-peptide < 94 pmol/l). Despite differing insulin regimens, control remained poor with frequent hyperglycaemic and hypoglycaemic excursions, severely impairing quality of life. Whilst an inpatient in 2007 [glycated haemoglobin (HbA(1c)) 10.2%, body mass index (BMI) 31.5 kg/m(2)] exenatide was commenced in an attempt to stabilize glycaemic control. Dramatic improvements were seen and continued. Eight months later, HbA(1c) had fallen by 2% with an 8-kg weight loss and 10-unit reduction in daily insulin dose. Quality of life dramatically improved. C-peptide remains undetectable.. This patient with features of both Type 1 and Type 2 diabetes benefited greatly from exenatide with insulin therapy. The improvement seen in glycaemic control could not be attributable to enhanced insulin secretion but could be as a result of a combination of the other incretin effects (postprandial glucagon suppression, delayed gastric emptying and weight loss secondary to increased satiety) all improving insulin sensitivity, reducing insulin dose and smoothing control.

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Overweight; Peptides; Treatment Outcome; Venoms