Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes

Abstract

The incretin effect denominates the phenomenon that oral glucose elicits a higher insulin response than does intravenous glucose. The two hormones responsible for the incretin effect, glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loads and augment insulin secretion in response to hyperglycemia. In patients with type 2 diabetes, the incretin effect is reduced, and there is a moderate degree of GLP-1 hyposecretion. However, the insulinotropic response to GLP-1 is well maintained in type 2 diabetes. GIP is secreted normally or hypersecreted in type 2 diabetes; however, the responsiveness of the endocrine pancreas to GIP is greatly reduced. In ϳ50% of first-degree relatives of patients with type 2 diabetes, similarly reduced insulinotropic responses toward exogenous GIP can be observed, without significantly changed secretion of GIP or GLP-1 after oral glucose. This opens the possibility that a reduced responsiveness to GIP is an early step in the pathogenesis of type 2 diabetes. On the other hand, this provides a basis to use incretin hormones, especially GLP-1 and its derivatives, to replace a deficiency in incretin-mediated insulin secretion in the treatment of type 2 diabetes. Diabetes 53 (Suppl. 3):S190 -S196, 2004 INCRETIN HORMONESThe study of gut hormones as stimulators of secretion of the endocrine pancreas has a long history, probably starting with attempts to therapeutically administer intestinal mucosal extracts (containing putative insulinotropic hormones) in patients with diabetes (1). Due to improvements in methods to quantify plasma concentrations of potential incretins (2,3) and in the ability to estimate insulin secretion in vivo (4 -6), a clear picture of the true physiological importance of the major incretin hormones, gastric inhibitory polypeptide, also interpreted as glucose-dependent insulinotropic polypeptide (GIP), and glucagonlike peptide-1 (GLP-1), has emerged (7-11). From the beginning (1), the study of intestinal incretin hormones has been driven by the hope to better understand the pathogenesis of diabetes, especially that of type 2 diabetes, or to find new treatments based on properties of gut-derived insulinotropic agents. While the latter has been the object of several comprehensive reviews in recent years (9,12,13), the former will be the topic of the present article. QUANTIFICATION OF THE INCRETIN EFFECTThe incretin effect is a phenomenon in which oral glucose (or any other way for the administration of glucose to not bypass its absorption from the gut) elicits a much higher insulin secretory response than an intravenous infusion of glucose with similar glycemic rises (14,15) or if the same amount of glucose was given by both routes (16). In the latter case, glucose concentrations were much higher with intravenous rather than oral glucose administration (16). State of the art for exactly quantifying the incretin effect is a comparison of the insulin secretory response after oral and "isoglycemic" intravenous gluc...

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Medium-Chain Triacylglycerol Suppresses the Decrease of Plasma Albumin Level through the Insulin-Akt-mTOR Pathway in the Livers of Malnourished Rats

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“…On the other hand defective or blunted GLP-1 secretion has been reported in type 2 diabetes on some occasions [23,[33][34][35]. Despite these observations of impaired GLP-1 secretion in type 2 diabetes GLP-1-based therapies retain an ability to stimulate insulin secretion from pancreatic beta-cells [15].…”

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