Exenatide Augments First- and Second-Phase Insulin Secretion in Response to Intravenous Glucose in Subjects with Type 2 Diabetes

Fehse, Frauke; Trautmann, Michael E.; Holst, Jens J.; Halseth, Amy E.; Nanayakkara, Nuwan D.; Nielsen, Loretta L.; Fineman, Mark; Kim, Dennis Dong Hwan; Nauck, Michael A.

doi:10.1210/jc.2005-1093

Cited by 283 publications

(251 citation statements)

References 54 publications

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“…20 In patients with type 2 DM, therapy with the GLP-1 receptor agonist exenatide resulted in an insulin secretory pattern similar to that seen in healthy individuals for both first-and secondphase insulin responses after an intravenous glucose challenge. 27 Similar results were observed with administration of the incretin mimetic liraglutide at 1.25 mg/d in individuals with DM. 28 Exenatide lowers HbA 1c and both fasting and postprandial plasma glucose levels.…”

Section: Modulating the Incretin System In Type 2 Dmsupporting

confidence: 66%

A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes Mellitus

Freeman

2010

Mayo Clinic Proceedings

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Philadelphia, PA 19131-1626 (jeffreyfreemando@aol.com). © 2010 Mayo Foundation for Medical Education and ResearchT he pathophysiologic defects that characterize type 2 diabetes mellitus (DM) include insulin resistance in liver and skeletal muscle and pancreatic β-cell dysfunction. Initially, β cells are able to increase insulin secretion sufficiently to offset insulin resistance, thus maintaining normoglycemia. When β cells are no longer able to compensate, plasma glucose levels increase. 1 Recent findings indicate that defects in β-cell function and increased insulin resistance occur early in the natural history of type 2 DM and can be present for 3 to 6 years before diagnosis. 2 Also, DM-related complications or tissue damage is evident in approximately 50% of individuals with type 2 DM at the time of diagnosis. 3 Progressive β-cell dysfunction is pathognomonic of the natural history of type 2 DM. Data from the longitudinal United Kingdom Prospective Diabetes Study (UKPDS) 16 showed that, over time, patients experience increasing A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes MellitusJeffrey S. Freeman, DO Progressive deterioration of β-cell function is a hallmark of type 2 diabetes mellitus (DM). Together with increasing insulin resistance in peripheral tissues (in both the liver and the skeletal muscle), the inability of pancreatic insulin secretion to manage fasting and postprandial glucose levels results in hyperglycemia. Currently available oral antidiabetes agents improve glycemic parameters, but no single drug addresses the numerous pathophysiologic defects known to contribute to hyperglycemia in patients with type 2 DM. Dysregulation in the incretin system is another component of the pathophysiologic processes that lead to DM. Agents used to correct defects in the incretin system, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, offer the potential to restore glucose-dependent insulin secretion and improve β-cell function. Glucagon-like peptide 1 receptor agonists also promote weight loss and provide beneficial effects on cardiovascular risk factors. A new approach that promotes the selection of pharmacotherapy for the treatment of patients with DM, with the goal of slowing or reversing the natural history of the disease, may be in order. Clinicians can select agents to address specific pathophysiologic defects to improve glycemia, with the hope of preventing the development of complications. Even patients receiving intensive therapy that improved mean hemoglobin A 1c (HbA 1c ) levels from 6.9% at baseline to 6.1% at 1 year showed deterioration of results over time; after 6 years, the mean HbA 1c level for these patients was 7.1%. 4 In UKPDS 49, the proportion of patients who maintained target glycemic levels decreased markedly during 9 years of follow-up. This decrease is consistent with progressive deterioration in β-cell function, such that only 50% of patients maintained their glycemic goal...

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Section: Modulating the Incretin System In Type 2 Dmsupporting

confidence: 66%

A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes Mellitus

Freeman

2010

Mayo Clinic Proceedings

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“…In acute experiments it was found to be insulinotropic and glucagonostatic in both non-diabetic and type 2 diabetic subjects . Additionally, similar to native GLP-1, it restores first phase insulin secretion in type 2 diabetic subjects in response to glucose (Fehse et al, 2005). Furthermore, in subjects with T2DM, twice-daily subcutaneous injections of Ex-4 (daily dose 12 to 96 pmol/kg) for 1 month reduced post-prandial glucose levels and stimulated insulin secretion, leading to a reduction in HbA 1c from 9.1 % to 8.3 % .…”

Section: Glp-1r Agonists and Dpp-1v Inhibitorsmentioning

confidence: 92%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

574

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…One such potential approach is to augment the beta cell response to glucose by a primary stimulus, as has been observed after sequential OGTTs and with IVGTTs or hyperglycaemic clamps [1,2]. Another approach is to target the incretin hormone glucagon-like peptide-1 (GLP-1), which is an important mediator for the postprandial insulin response [3]. Indeed, it has been shown that incretin-based therapies, such as GLP-1 receptor agonists [3] and inhibitors of GLP-1 inactivating protease, dipeptidyl peptidase 4 (DPP-4) [4], augment the insulin secretory response to meal ingestion by enhancing mainly the early phase of insulin secretion in type 2 diabetes patients.…”

Section: Introductionmentioning

confidence: 99%

“…Another approach is to target the incretin hormone glucagon-like peptide-1 (GLP-1), which is an important mediator for the postprandial insulin response [3]. Indeed, it has been shown that incretin-based therapies, such as GLP-1 receptor agonists [3] and inhibitors of GLP-1 inactivating protease, dipeptidyl peptidase 4 (DPP-4) [4], augment the insulin secretory response to meal ingestion by enhancing mainly the early phase of insulin secretion in type 2 diabetes patients. Whether combining these two approaches by using increased GLP-1 secretion as a primary stimulus to a subsequent meal ingestion may further improve insulin secretion is not known.…”

Section: Introductionmentioning

confidence: 99%

Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial

et al. 2014

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Aims/hypothesis Since protein ingestion is known to stimulate the secretion of glucagon-like peptide-1 (GLP-1), we hypothesised that enhancing GLP-1 secretion to harness its insulinotropic/beta cell-stimulating activity with whey protein pre-load may have beneficial glucose-lowering effects in type 2 diabetes. Methods In a randomised, open-label crossover clinical trial, we studied 15 individuals with well-controlled type 2 diabetes who were not taking any medications except for sulfonylurea or metformin. These participants consumed, on two separate days, 50 g whey in 250 ml water or placebo (250 ml water) followed by a standardised high-glycaemic-index breakfast in a hospital setting. Participants were randomised using a coin flip. The primary endpoints of the study were plasma concentrations of glucose, intact GLP-1 and insulin during the 30 min following meal ingestion. Results In each group, 15 patients were analysed. The results showed that over the whole 180 min post-meal period, glucose levels were reduced by 28% after whey pre-load with a uniform reduction during both early and late phases. Insulin and C-peptide responses were both significantly higher (by 105% and 43%, respectively) with whey pre-load. Notably, the early insulin response was 96% higher after whey. Similarly, both total GLP-1 (tGLP-1) and intact GLP-1 (iGLP-1) levels were significantly higher (by 141% and 298%, respectively) with whey pre-load. Dipeptidyl peptidase 4 plasma activity did not display any significant difference after breakfast between the groups. Conclusions/interpretation In summary, consumption of whey protein shortly before a high-glycaemic-index breakfast increased the early prandial and late insulin secretion, augmented tGLP-1 and iGLP-1 responses and reduced postprandial glycaemia in type 2 diabetic patients. Whey protein may therefore represent a novel approach for enhancing glucoselowering strategies in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01571622 Funding The Israeli Ministry of Health and Milk Council funded the research.

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Exenatide Augments First- and Second-Phase Insulin Secretion in Response to Intravenous Glucose in Subjects with Type 2 Diabetes

Cited by 283 publications

References 54 publications

A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes Mellitus

A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes Mellitus

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial

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