The role of incretin hormones in glucose homeostasis

grantor: University of TorontoIncretins are hormones that are released from the gut in response to nutrient ingestion and act to enhance glucose-stimulated insulin secretion. The two major peptides which have been identified as incretin hormones are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Previous glucoregulatory studies using receptor knockout mice models suggest that the role of GIP is restricted to that of an incretin, whereas GLP-1 also exhibits non-incretin effects. However, studies with genetically-modified mice can be complicated by compensatory adaptive changes. To avoid this possibility, we assessed the incretin and nonincretin actions of GIP and GLP-1 in wild-type mice using the GLP-1 receptor antagonist exendin(9-39) and immunopurified anti-GIP receptor antisera to antagonize GLP-1 and GIP action, respectively. Our results indicate that GLP-1, but not GIP, plays an important role in regulating blood glucose levels in mice in a manner independent of oral nutrient ingestion. In addition to its role as an incretin, GLP-1 contributes to blood glucose lowering through several different mechanisms and thus its therapeutic value as a treatment for diabetes is currently under investigation. However, GLP-1 is rapidly catabolized by dipeptidylpeptidase IV (DPP-IV) and therefore has a short plasma half-life, which may, in turn, limit its therapeutic potential. Inhibition of DPP-IV activity could thus provide a means to extend the half-life of GLP-1. However, DPP-IV may also act upon other substrates important for glucoregulation. To investigate this possibility, we examined the effects of DPP-IV inhibition in GLP-1 receptor knockout mice. Our results suggest that in addition to GLP-1, other substrates are involved in the DPP-IV-mediated regulation of blood glucose control. Exendin-4 is a potent GLP-1 receptor agonist that was originally purified from lizard venom and is currently being evaluated in clinical trials as a treatment for diabetes. Limited information is available regarding the long-term effects of exendin-4 treatment 'in vivo'. To assess the physiological effects of chronic exendin-4 expression 'in vivo', we have generated transgenic mice in which exendin-4 expression is under the control of an inducible promoter. Our data indicate that sustained elevation of circulating exendin-4 has both predicted and unanticipated effects on GLP-1 receptor-dependent physiological end points.Ph.D