Gut and Adipocyte Peptides

Abstract

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 response to glucose, and fail to show a glucose-lowering response with administration of DPP-IV inhibitors, suggesting that the mechanism of DPP-IV inhibition involves both peptides. GLP-1R^−/− mice have increased β-cell susceptibility to apoptotic streptozotocin injury. In the ob/ob (leptin-deficient) GLP-1R^−/− mouse, insulin gene levels are upregulated and there is islet hyperplasia to the same extent as seen in the ob/ob mouse with normal GLP-1R function. With partial pancreatectomy, however, although exendin-(9-39) does not block β-cell hyperplasia, the GLP-1R^−/− mouse has reduced β-cell regeneration and is hyperglycemic. Taken together, these studies suggest that trophic effects of GLP-1 on the β-cell occur physiologically. There are areas with high density of GLP-1R binding sites in the hypothalamus, but their role is uncertain. The GLP-1R^−/− mouse has normal body weight and minimal perturbation in food ingestion on a standard diet, although showing lesser degrees of obesity on a high-fat diet. Gastric emptying is not changed in the GLP-1R^−/− mouse, which shows a response to cholecystokinin although not to exendin. Studies in these mice also suggest that there is a neural portal vein and/or liver glucose sensor, which may be in part activated by GLP-1 to enhance the response to ingested food.