Open Collections

The pro-survival effects of glucose-dependent insulinotropic polypeptide receptor signalling on beta cells

University of British Columbia

Gastrointestinal incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have been targeted for the treatment of diabetes due, in large part, to their physiological actions on pancreatic β-cells in potentiating glucose-stimulated insulin secretion and increasing insulin biosynthesis. In recent years, incretins have also been revealed to exert potent actions on β-cell proliferation and survival. However, most studies have focused on GLP-1, and so there is a relative paucity of evidence regarding GIP. In the current thesis, it was hypothesized that GIP receptor (GIPR) activation in β-cells enhances critical anti-apoptotic signalling networks and promotes β-cell survival, which in rodent models of type 2 diabetes mellitus results in an elevation in β-cell mass and improvement in glycaemic control. This hypothesis was initially tested by examining the effects of GIPR activation on the protein-serine/threonine kinase Akt, which is known to exert potent pro-survival actions in β-cells. It was revealed that GIPR stimulation activates Akt signalling through both canonical and non-canonical mechanisms. Next, the effects of GIPR activation on pro- and anti-apoptotic Bcl-2 family proteins were examined on β-cells under pro-apoptotic stress. GIPR activation was found to suppress the onset of stress-induced apoptosis by preventing mitochondrial translocation of pro-apoptotic proteins Bad and Bim as well as activation of the key pro-apoptotic protein Bax, and this effect was due to Akt-mediated inhibition of the apoptosis signal regulating kinase-1. Lastly, the effects of GIPR activation on β-cell survival were examined in vivo by administering a long acting GIP analogue to multiple rodent models of diabetes that exhibit elevated β-cell apoptosis. In all models the GIP analogue promoted β-cell survival and improved glycaemic control. Overall, these studies supported the hypothesis proposed. In conclusion, similar to the signalling actions of the GLP-1 receptor, GIPR signalling exerts potent actions on β-cell survival, and therefore, therapeutics that enhance GIPR signalling in β-cells merit consideration for the treatment of type 2 diabetes mellitus.

Text

2010-07-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/26713

Physiology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/