Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans

Holst, Jens J.; Gromada, Jesper

doi:10.1152/ajpendo.00545.2003

Cited by 549 publications

(466 citation statements)

References 92 publications

(77 reference statements)

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“…This may seem paradoxical, since it is generally accepted that GLP-1 acting on the pancreas increases insulin secretion but reduces or leaves glucagon unchanged [40]. It has been shown that the previous assertion is true under conditions of hyper-and euglycaemia.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

et al. 2005

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Section: Discussionmentioning

confidence: 99%

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

et al. 2005

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“…GLP-1's insulinotropic activity, which is strictly glucose dependent, is, at least partly (see below), exerted via interaction with the GLP-1 receptor located on the cell membrane of the beta cells (32). Cyclic AMP generated by activation of the GLP-1 receptor may also influence the exocytotic process directly, and this process has been estimated to account for up to 70 % of the entire secretory response (32).…”

Section: ) Effects On the Isletsmentioning

confidence: 99%

“…Cyclic AMP generated by activation of the GLP-1 receptor may also influence the exocytotic process directly, and this process has been estimated to account for up to 70 % of the entire secretory response (32). Also ATP may directly influence the exocytotic process, and may, A most striking demonstration of the beta cell protective/proliferative effects of GLP-1 receptor activation was provided by Stoffers et al (50), who studied the diabetes developing in rats subjected to intrauterine growth retardation.…”

Section: ) Effects On the Isletsmentioning

confidence: 99%

The incretin system and its role in type 2 diabetes mellitus

Holst

Vilsbøll

Deacon

2009

Molecular and Cellular Endocrinology

444

332

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The incretin hormones are released during meals from gut endocrine cells. They potentiate glucoseinduced insulin secretion and may be responsible for up to 70 % of postprandial insulin secretion.The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. Introduction-The incretin effect.

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“…One such GLP-1 mimetic, exendin-4, has been approved for clinical use in the USA under the tradename Byetta (Amylin Pharmaceuticals, San Diego, CA), and a second palmitoylated derivative of GLP-1, liraglutide, is in late clinical development [6]. Similar exploitation of GIP is at the late preclinical stage, complicated to some extent by the debate that GIP but not GLP-1 action is specifically impaired in type 2 diabetes [12,13]. This insensitivity appears most pronounced in response to continuous infusion rather than bolus injection of native GIP [14], possibly implicating receptor desensitisation.…”

Section: Introductionmentioning

confidence: 99%

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

et al. 2007

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Aims/hypothesis Ablation of gastric inhibitory polypeptide (GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro 3 )GIP is able to counter the development of genetic obesityrelated diabetes. Materials and methods Young (5-7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro 3 )GIP (25 nmol kg −1 day −1 ) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA 1c , circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro 3 )GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose (p< 0.001), HbA 1c (p<0.05), glucose tolerance (p<0.001), meal tolerance (p<0.001) and insulin sensitivity (p<0.05). Remarkably, (Pro 3 )GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro 3 )GIP, while levels of triacylglycerol, LDLcholesterol and resistin were decreased (p<0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro 3 )GIP treatment than in control ob/ob mice (p<0.01), but plasma insulin levels remained substantially raised (p<0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.

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Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans

Cited by 549 publications

References 92 publications

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

The incretin system and its role in type 2 diabetes mellitus

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

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