Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells.

Zhou, Jie; Wang, Xiaolin; Piñeyro, Marco A.; Egan, JM

doi:10.2337/diabetes.48.12.2358

Cited by 299 publications

(196 citation statements)

References 19 publications

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“…These also provide an easier model to study the underlying mechanism in neogenesis as stimulated by GLP-1 treatment. We have examined the effect of chronic GLP-1 R activation in both a rat acinar cell line, AR42J cells (Zhou et al, 1999b) and a human ductal cell line, Capan-1 cells (Zhou et al, 2002).…”

Section: In Vitro Determination Of the Mechanism Of β Cell Differentimentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

584

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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Section: In Vitro Determination Of the Mechanism Of β Cell Differentimentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

584

465

View full text Add to dashboard Cite

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“…Finally and most importantly, GLP-1 has been shown to have trophic effects on beta cells in rodents. Not only does it stimulate beta-cell proliferation [88,89], it also enhances the differentiation of new beta cells from progenitor cells in the pancreatic duct epithelium [90] and has now been shown to also inhibit apoptosis induced by e.g. cytokines or free fatty acids [91].…”

Section: Incretin Hormones As Therapeutic Agentsmentioning

confidence: 99%

Incretins, insulin secretion and Type 2 diabetes mellitus

2004

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When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging. The incretin effectThe incretin effect seems to play a major role in the regulation of glucose metabolism in healthy subjects. "The incretin effect" implies that ingestion of carbohydrates (glucose) causes the release from the intestinal mucosa of substances that enhance insulin secretion beyond the release caused by the absorbed glucose itself [1]. The effect can be quantified by comparing insulin or C-peptide responses to oral or intravenous glucose loads, adjusted to cause identical increases of plasma glucose concentrations. The much higher responses observed after oral administration

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“…But in this respect, the GLP-1-based therapies possess a unique potential: GLP-1 has trophic effects on beta cells [91]. Not only does it stimulate beta cell proliferation [92,93], it also enhances the differentiation of new beta cells from progenitor cells in the pancreatic duct epithelium [94] and, perhaps most importantly, GLP-1 is capable of inhibiting apoptosis of beta cells including human beta cells [95]. Since the normal number of beta cells is maintained in a balance between apoptosis and proliferation, this observation is of considerable interest, and raises the possibility that GLP-1 could be useful in conditions in which beta cell apoptosis is increased.…”

Section: Protective Effects Of Glp-1mentioning

confidence: 99%

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

2006

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The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA 1 c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA 1 c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.

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Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells.

Cited by 299 publications

References 19 publications

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

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

Incretins, insulin secretion and Type 2 diabetes mellitus

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

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