exenatide and Glucose-Intolerance

The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown.. To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these.. We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017.. We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these.. Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence using the GRADE instrument.. We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the plac. There is no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Glucagon-Like Peptide 1; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Metformin; Nitriles; Peptides; Pyrrolidines; Randomized Controlled Trials as Topic; Risk Factors; Venoms; Vildagliptin

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

Impaired glucose tolerance (IGT) in cystic fibrosis (CF) manifests as postprandial hyperglycaemia. Pancreatic enzyme supplementation reduces the latter; restoring incretin secretion and slowing gastric emptying. We aimed to determine the acute effect of exenatide on postprandial glycaemia in young people with CF and IGT. Six participants with CF and IGT were studied on 2 days, in a double-blind randomized crossover trial. After overnight fasting, they received exenatide 2.5 mcg or placebo (0.9% saline) subcutaneously 15 minutes before a pancake meal labelled with

Topics: Adolescent; Adult; Blood Glucose; Child; Cross-Over Studies; Cystic Fibrosis; Double-Blind Method; Exenatide; Female; Gastric Emptying; Glucose Intolerance; Humans; Hyperglycemia; Incretins; Male; Postprandial Period; 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

Glucocorticoids (GCs) are regarded as diabetogenic because they impair insulin sensitivity and islet-cell function. This study assessed whether treatment with the glucagon-like peptide receptor agonist (GLP-1 RA) exenatide (EXE) could prevent GC-induced glucose intolerance.. A randomized, placebo-controlled, double-blind, crossover study in eight healthy men (age: 23.5 [20.0-28.3] years; BMI: 26.4 [24.3-28.0] kg/m(2)) was conducted. Participants received three therapeutic regimens for 2 consecutive days: 1) 80 mg of oral prednisolone (PRED) every day (q.d.) and intravenous (IV) EXE infusion (PRED+EXE); 2) 80 mg of oral PRED q.d. and IV saline infusion (PRED+SAL); and 3) oral placebo-PRED q.d. and intravenous saline infusion (PLB+SAL). On day 1, glucose tolerance was assessed during a meal challenge test. On day 2, participants underwent a clamp procedure to measure insulin secretion and insulin sensitivity.. PRED+SAL treatment increased postprandial glucose levels (vs. PLB+SAL, P = 0.012), which was prevented by concomitant EXE (vs. PLB+SAL, P = NS). EXE reduced PRED-induced hyperglucagonemia during the meal challenge (P = 0.018) and decreased gastric emptying (vs. PRED+SAL, P = 0.028; vs. PLB+SAL, P = 0.046). PRED+SAL decreased first-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL, P = 0.017 and P = 0.05, respectively), whereas PRED+EXE improved first- and second-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL; P = 0.017, 0.012, and 0.093, respectively).. The GLP-1 RA EXE prevented PRED-induced glucose intolerance and islet-cell dysfunction in healthy humans. Incretin-based therapies should be explored as a potential strategy to prevent steroid diabetes.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Exenatide; Glucagon-Like Peptide 1; Glucocorticoids; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Male; Peptides; Prednisone; Venoms; Young Adult

Endothelial dysfunction is frequently present in individuals with insulin resistance or type 2 diabetes and can be induced by high-fat or high-carbohydrate meals. Because exenatide reduces postprandial glucose and lipid excursions, we hypothesized that it may also improve postprandial endothelial function.. In a double-blinded randomized crossover design, postprandial endothelial function was examined in 28 individuals with impaired glucose tolerance or recent-onset type 2 diabetes after a single injection of exenatide or placebo given just before a high-fat meal. Endothelial function was determined with peripheral arterial tonometry pre- and postprandially.. Postprandial endothelial function was higher after exenatide compared with placebo (P = 0.0002). In the placebo phase, postprandial change in endothelial function was inversely associated with mean postprandial concentrations of triglycerides (r = -0.62, P = 0.0004). Changes in postprandial triglyceride concentrations explained 64% of exenatide's effect on postprandial endothelial function.. Exenatide ameliorates postprandial endothelial dysfunction after a high-fat meal.

Topics: Adult; Age of Onset; Aged; Cohort Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Fats; Endothelium; Exenatide; Female; Glucose Intolerance; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Peptides; Triglycerides; Venoms

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

Chronic exenatide treatment in type 2 diabetes is associated with improved glucose control and fasting lipid levels, as well as weight loss. Less established is whether exenatide directly reduces postprandial lipid and lipoprotein levels without the reduction in body weight or fasting glucose and triglycerides levels that frequently occur with prolonged therapy. Therefore, the effect of a single injection of exenatide on postprandial lipids, remnant lipoproteins, and apolipoproteins was studied.. A double-blinded, randomized, placebo-controlled, crossover study was conducted in 35 subjects (31 men and 4 women) with impaired glucose tolerance (n=20) or recent onset type 2 diabetes (n=15). A single subcutaneous injection of exenatide (10 microg) or normal saline was administered just prior to a high-calorie, fat-enriched breakfast meal. Concentrations of triglycerides (TG), apolipoproteins B-48 and CIII, non-esterified fatty acids (NEFA), and remnant lipoprotein (RLP) cholesterol and TG in serum or plasma were measured prior to the injection and for up to 8 h postprandially.. Exenatide markedly reduced postprandial elevation of TG, apolipoproteins B-48 and CIII, RLP-cholesterol and RLP-triglyceride (all p<0.001). Postprandial declines in NEFA were less pronounced but persisted longer with exenatide compared to placebo (p<0.05). These effects of exenatide were not affected either by glucose tolerance status or by treatment with statins.. These results demonstrate that exenatide acutely and profoundly inhibits postprandial excursions of proatherogenic lipids and lipoproteins and may offer additional cardiovascular risk reduction (NCT00974272).

Topics: Adult; Aged; Apolipoprotein B-48; Apolipoprotein C-III; Arizona; Biomarkers; Blood Glucose; Cholesterol; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Fats; Double-Blind Method; Energy Intake; Exenatide; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Humans; Hyperlipidemias; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Lipids; Lipoproteins; Male; Middle Aged; Peptides; Postprandial Period; Time Factors; Treatment Outcome; Triglycerides; Venoms

While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise.. We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined.. B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4.. These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.

Topics: Animals; Appetite Regulation; Behavior, Animal; Blood-Brain Barrier; Drug Stability; Energy Intake; Energy Metabolism; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; HEK293 Cells; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Nausea; Rats, Sprague-Dawley; Recombinant Proteins; Tissue Distribution; Vitamin B 12

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

Pancreatic stellate cells (PSCs) play a major role to fibrotic islet destruction observed in diabetic patients and animal model of diabetes. Exendin-4 (Ex-4) is a potent insulinotropic agent and has been approved for the treatment of type 2 diabetes. However, there have been no reports demonstrating the effects of Ex-4 on pancreatic islet fibrosis. In this study, Ex-4 treatment clearly attenuated fibrotic islet destruction and improved glucose tolerance and islet survival. GLP-1 receptor expression was upregulated during activation and proliferation of PSCs by hyperglycemia. The activation of PKA pathway by Ex-4 plays a role in ROS production and angiotensin II (Ang II) production. Exposure to high glucose stimulated ERK activation and Ang II-TGF- β1 production in PSCs. Interestingly, Ex-4 significantly reduced Ang II and TGF-β1 production by inhibition of ROS production but not ERK phosphorylation. Ex-4 may be useful not only as an anti-diabetic agent but also as an anti-fibrotic agent in type 2 diabetes due to its ability to inhibit PSC activation and proliferation and improve islet fibrosis in OLETF rats.

Topics: Angiotensin II; Animals; Cell Survival; Cyclic AMP-Dependent Protein Kinases; Exenatide; Fibrosis; Glucose; Glucose Intolerance; Islets of Langerhans; Pancreatic Stellate Cells; Peptides; Rats; Rats, Inbred OLETF; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta1; Venoms

Glucagon-like peptide-1 (GLP-1)-based medicines have recently been widely used to treat type 2 diabetic patients, whereas adverse effects of nausea and vomiting have been documented. Inhibition of voltage-gated K(+) channel subtype Kv2.1 in pancreatic β-cells has been suggested to contribute to mild depolarization and promotion of insulin release. This study aimed to determine whether the blockade of Kv2.1 channels potentiates the insulinotropic effect of GLP-1 agonists. Kv2.1 channel blocker guangxitoxin-1E (GxTx) and GLP-1 agonist exendin-4 at subthreshold concentrations, when combined, markedly increased the insulin release and cytosolic Ca(2+) concentration ([Ca(2+)]i) in a glucose-dependent manner in mouse islets and β-cells. Exendin-4 at subthreshold concentration alone increased islet insulin release and β-cell [Ca(2+)]i in Kv2.1(+/-) mice. The [Ca(2+)]i response to subthreshold exendin-4 and GxTx in combination was attenuated by pretreatment with protein kinase A inhibitor H-89, indicating the protein kinase A dependency of the cooperative effect. Furthermore, subthreshold doses of GxTx and GLP-1 agonist liraglutide in combination markedly increased plasma insulin and improved glucose tolerance in diabetic db/db mice and NSY mice. These results demonstrate that a modest suppression of Kv2.1 channels dramatically raises insulinotropic potency of GLP-1-based drugs, which opens a new avenue to reduce their doses and associated adverse effects while achieving the same glycemic control in type 2 diabetes.

Topics: Animals; Arthropod Proteins; Cells, Cultured; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Insulin; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Peptides; Shab Potassium Channels; Spider Venoms; Venoms

We used cre-lox technology to test whether the inducible expression of Cre minimize the deleterious effect of the enzyme on beta cell function. We studied mice in which Cre is linked to a modified estrogen receptor (ER), and its expression is controlled by the rat insulin promoter (RIP). Following the injection of tamoxifen (TM), CreER- migrates to the nucleus and promotes the appearance of a reporter protein, enhanced yellow fluorescent protein (EYFP), in cells. Immunocytochemical analysis indicated that 46.6 ± 2.1% insulin cells of adult RIPCreER- EYFP expressed EYFP. RIPCreER-EYFP (+TM) mice were normoglycemic throughout the study, and their glucose tolerance test results were similar to control CD-1 mice. However, an extended exposure to reagents that stimulate insulin synthesis was detrimental to the survival of IN+EYFP+cells. The administration of an inhibitor of the enzyme dipeptidyl-peptidase (DPP4i), which prevents the cleavage of glucagon-like peptide (GLP-1), to adult RIPCreER-EYFP mice lead to a decrease in the percentage of IN+EYFP+ to 17.5 ± 1.73 and a significant increase in apoptotic cells in islets. Similarly, a 2-week administration of the GLP-1 analog exendin 4 (ex-4) induced an almost complete ablation of IN+ expressing a different reporter protein and a significant decrease in the beta cell mass and rate of beta cell proliferation. Since normal beta cells do not die when induced to increase insulin synthesis, our observations indicate that insulin cells expressing an inducible RIPCre transgene are functionally deficient. Studies employing these mice should carefully consider the pitfalls of the Cre-Lox technique.

Topics: Animals; Cell Proliferation; Dipeptidyl Peptidase 4; Exenatide; Genes, Reporter; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Green Fluorescent Proteins; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Integrases; Mice; Peptides; Phenotype; Promoter Regions, Genetic; Protease Inhibitors; Receptors, Estrogen; Receptors, Glucagon; Recombinant Proteins; Selective Estrogen Receptor Modulators; Tamoxifen; Venoms

We tested the exendin-4 and des-fluoro-sitagliptin effects on fructose-induced increase in liver glucokinase activity in rats with impaired glucose tolerance and the exendin-4 effect on glucokinase activity in HepG2 cells incubated with fructose in the presence/absence of exendin-9-39. After 3 weeks of in vivo fructose administration we measured: (1) serum glucose, insulin and triglyceride levels; (2) liver and HepG2 cells glucokinase activity and (3) liver glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein levels. Fructose fed rats had: hypertriglyceridemia, hyperinsulinemia and high liver glucokinase activity (mainly located in the cytosolic fraction) together with higher glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein concentrations compared to control rats. Co-administration of either exendin-4 or des-fluoro-sitagliptin prevented serum and liver changes except glucokinase protein expression. Exendin-4 also prevented fructose-induced increase in glucokinase activity in cultured HepG2 cells, effect blunted by co-incubation with exendin-9-36. In conclusion exendin-4/des-fluro-sitagliptin prevented fructose-induced effect on glucokinase activity, mainly affecting enzyme activity modulators. Exendin 9-39 blunted in vitro protective exendin-4 effect on glucokinase activity, thus suggesting a direct effect of the later on hepatocytes through GLP-1 receptor. Alterations of glucokinase activity modulators could play a role in the pathogenesis of liver dysfunction, becoming a potential new treatment target for GLP-1 receptor agonists.

Topics: Animals; Exenatide; Fructose; Gene Expression; Glucokinase; Glucose Intolerance; Hep G2 Cells; Humans; Incretins; Liver; Male; Peptides; Rats; Rats, Wistar; Sitagliptin Phosphate; Venoms

G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes.

Topics: Animals; Blood Glucose; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Exenatide; Gene Knockout Techniques; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Indans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Peptides; Phenylpropionates; Propionates; Rats; Receptors, G-Protein-Coupled; Receptors, Glucagon; Venoms

The hepatoportal area is an important glucohomeostatic metabolic sensor, sensing hypoglycemia, hyperglycemia, and hormones such as glucagon-like peptide-1 (GLP-1). We have reported previously that activation of hepatoportal sensors by intraportal infusion of glucose and GLP-1 or by subcutaneous administration of GLP-1 receptor activator exenatide and of intraportal glucose improved glycemia independent of corresponding changes in pancreatic hormones. It is not clear whether this effect is mediated via the portal vein (PV) or by direct action on the liver itself. To test whether receptors in the PV mediate exenatide's beneficial effect on glucose tolerance, we performed 1) paired oral glucose tolerance tests (OGTT) with and without exenatide and 2) intravenous glucose tolerance tests before and after PV denervation in canines. Denervation of the portal vein affected oral glucose tolerance; post-denervation (POST-DEN) OGTT glucose and insulin AUC were 50% higher than before denervation (P = 0.01). However, portal denervation did not impair exenatide's effect to improve oral glucose tolerance (exenatide effect: 48 ± 12 mmol·l⁻¹·min before vs. 64 ± 26 mmol·l⁻¹·min after, P = 0.67). There were no changes in insulin sensitivity or secretion during IVGTTs. Portal vein sensing might play a role in controlling oral glucose tolerance during physiological conditions but not in pharmacological activation of GLP-1 receptors by exenatide.

Topics: Animals; Biomarkers; Blood Glucose; Crosses, Genetic; Denervation; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Peptides; Portal Vein; Receptors, Glucagon; Tyrosine 3-Monooxygenase; Venoms

Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.

Topics: Animals; Apoptosis; Autophagy; Autophagy-Related Protein 7; Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Gene Expression Regulation; Glucose Intolerance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred NOD; Microtubule-Associated Proteins; Peptides; Transcription Factor TFIIH; Transcription Factors; Venoms

EXf is a C-terminally truncated fragment of Exendin-4 with two amino acid substitutions. Previous studies showed that EXf controls plasma glucose level acting as a glucagon-like peptide 1 (GLP-1) receptor agonist. The purpose of this study was to evaluate the effects of EXf on β-cell function and survival in diabetic KKAy mice. EXf treatment significantly improved the glucose intolerance and reduced non-fasting and fasting plasma glucose levels, as well as plasma triglyceride levels in diabetic KKAy mice. In hyperglycemic clamp test, EXf-treated mice displayed an increased glucose infusion rate and first-phase insulin secretion. Treatment with EXf also led to a significant restoration of islet morphology, an increase in Ki67 expression in β-cells, and a reduction in the number of TUNEL positive β-cells. In the pancreas, comparative transcription analysis showed up-regulation of Akt1. The up-regulation of phosphorylated Akt1 was confirmed by Western blot, and changes in the protein levels of members of the Akt1 pathway, such as PI3K, Bim, Bcl-2, Bax, Caspase-3, and Caspase-9, PDX-1, were observed as well. Therefore, EXf treatment could improve β-cell function and survival in diabetic KKAy mice, likely as a result of islet morphology restoration, stimulation of β-cell proliferation, and inhibition of β-cell apoptosis.

Topics: Animals; Apoptosis; Blood Glucose; Exenatide; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Secretion; Insulin-Secreting Cells; Ki-67 Antigen; Mice; Mice, Inbred NOD; Peptide Fragments; Peptides; Proto-Oncogene Proteins c-akt; Triglycerides; 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

One major obstacle for successful clinical transplantation of isolated pancreatic islets (PI) is their limited survival in vivo. The aim of this study was to analyze the functional and morphological regeneration of PI in diabetic rats by Exendin-4 (Ex4) treatment in vivo. Male Wistar rats (n = 3/group) received 20 nmol/kg Ex4 i.p. for 20 days (day 0 to day +20). Diabetes was induced with 50 mg/kg streptozotocin i.v. on day -3 or on day +5. Diabetic and normal control rats received 0.9% NaCl i.p. instead. Body weight (BW), daily blood glucose (BG) and levels, oral glucose tolerance (OGT) were tested on day -5, day +10, day +20, and on day +22, ie, 48 hours after the last Ex4 injection. Histology of the pancreata ended the study on day +24. In vivo application of Ex4 could not prevent the development of diabetes. Injection of Ex4 led to a significant decrease in postprandial BG levels to 35% for 12 hours. Surprisingly, Ex4 increased postprandial BG levels up to 20% in normal rats. Ex4-treated rats showed better OGT than untreated controls. Interestingly, 48 hours after the last Ex4 injection on day +22 OGT was completely impaired. The Ex4-treated rats lost BW much faster than the untreated controls, and showed signs of gastroparesis at autopsy. Immunohistochemistry of the pancreata documented no signs of islet regeneration. Improvement of OGT in diabetic rats after Ex4 treatment may be explained by increased insulin release from the individual PI, which was confirmed by perifusion studies with isolated PI in vitro (data not shown). Yet, Ex4 may also exert an influence on the gastrointestinal tract as it delays the uptake of glucose during gastroparesis.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Exenatide; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Islets of Langerhans; Pancreas; Peptides; Rats; Rats, Wistar; Regeneration; Venoms

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and is essential for normal glucose homeostasis. However, the relatively low plasma levels and rapid metabolism of GLP-1 raise questions as to whether direct endocrine action on target organs, such as islet cells, account for all of its effects on glucose tolerance. Recently, an alternative neural pathway initiated by sensors in the hepatic portal region has been proposed to mediate GLP-1 activity. We hypothesized that visceral afferent neurons in the portal bed express the GLP-1 receptor (GLP-1r) and regulate glucose tolerance. Consistent with this hypothesis, GLP-1r mRNA was present in the nodose ganglia, and nerve terminals innervating the portal vein contained the GLP-1r. Rats given an intraportal infusion of the GLP-1r antagonist, [des-His(1),Glu(9)] exendin-4, in a low dose, had glucose intolerance, with a 53% higher glucose excursion compared with a vehicle-infused control group. Infusion of [des-His(1),Glu(9)] exendin-4 at an identical rate into the jugular vein had no effect on glucose tolerance, demonstrating that this dose of GLP-1r antagonist did not affect blood glucose due to spillover into the systemic circulation. These studies demonstrate that GLP-1r are present on nerve terminals in the hepatic portal bed and that GLP-1 antagonism localized to this region impairs glucose tolerance. These data are consistent with an important component of neural mediation of GLP-1 action.

Topics: Animals; Blood Glucose; Cell Line; Dose-Response Relationship, Drug; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Intolerance; Glucose Tolerance Test; Infusions, Intravenous; Liver; Male; Nerve Endings; Nodose Ganglion; Peptides; Portal Vein; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms

Uteroplacental insufficiency resulting in fetal growth retardation is a common complication of pregnancy and a significant cause of perinatal morbidity and mortality. Epidemiological studies show an increased incidence of type 2 diabetes in humans who were growth retarded at birth. The mechanisms by which an abnormal intrauterine milieu leads to the development of diabetes in adulthood are not known. Therefore, a rat model of uteroplacental insufficiency was developed; intrauterine growth-retarded (IUGR) rats develop diabetes with a phenotype similar to that observed in the human with type 2 diabetes. We show here that administration of a pancreatic beta-cell trophic factor, exendin-4 (Ex-4), during the prediabetic neonatal period dramatically prevents the development of diabetes in this model. This occurs because neonatal Ex-4 prevents the progressive reduction in insulin-producing beta-cell mass that is observed in IUGR rats over time. Expression of PDX, a critical regulator of pancreas development and islet differentiation, is restored to normal levels, and islet beta-cell proliferation rates are normalized by the neonatal Ex-4 treatment. These results indicate that exposure to Ex-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of diabetes in adulthood.

Topics: Animals; Animals, Newborn; Blood Glucose; Cell Differentiation; Cell Division; Diabetes Mellitus, Type 2; Exenatide; Female; Fetal Growth Retardation; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Homeodomain Proteins; Homeostasis; Islets of Langerhans; Peptides; Placental Insufficiency; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Trans-Activators; Venoms