Gut and Adipocyte Peptides

Abstract

This is the third in a series of articles on presentations at the American Diabetes Association Annual Meeting, San Diego, California, 10–14 June 2005. Daniel Drucker (Toronto, Canada) reviewed evidence that the incretin effect, the phenomenon of enteral glucose loading increasing the insulin secretory response to an increase in blood glucose, is reduced in type 2 diabetes, and that the incretin glucagon-like peptide (GLP)-1 may ameliorate this defect. The major limitation to use of GLP-1 in clinical treatment is its rapid clearance by the enzyme dipeptidyl peptidase (DPP)-IV. GLP-1 stimulates insulin secretion, inhibits glucagon secretion, and delays gastric emptying. Loss-of-function studies with a mouse model not expressing the GLP-1 receptor (GLP-1R−/−), and with the GLP-1R antagonist exendin-(9-39), show effects of GLP-1 on the hypothalamic-pituitary-adrenal (HPA) axis, the reproductive system, the portal glucose receptor, gastric motility, and a number of other potential targets. GLP-1R−/− mice have normal insulin sensitivity, arguing against an effect of the system on insulin action, but have glucose intolerance, and administration of exendin-(9-39) similarly is associated with glucose intolerance in mice, in primates, and in humans. Drucker noted that there is controversy as to whether the product of DPP-IV degradation may act at a second GLP-1R, perhaps having additional effects on metabolism, but that GLP-1 does not lower glucose levels in GLP-1R−/− mice, arguing against such a receptor. In the model, pancreatic insulin mRNA levels are reduced and somatostatin mRNA levels are increased. The perfused pancreas isolated from GLP-1R−/− animals shows normal insulin response to glucose, although without response to GLP-1. GLP-1R−/− β-cells appear to have increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), perhaps representing an adaptive upregulation of GIP and/or of GIP response, and mice neither expressing the GLP-1 nor the GIP receptor show glucose intolerance with decreased insulin …