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UBC Theses and Dissertations

Glucose-dependent insulinotropic polypeptide (GIP) activation of protein kinase B (PKB) and its contribution to pancreatic B-cell survival Winter, Kyle D.

Abstract

In addition to their well-documented insulinotropic actions, the incretin hormones Glucose dependent insulinotropic polypeptide (GIP) and Glucagon Like Peptide-1 (GLP- 1), have recently been shown to exhibit non-insulinotropic effects on pancreatic β-cell proliferation, survival and apoptosis. GIP regulates pancreatic β-ceIl secretion by binding to its cognate Family B, G protein-coupled receptor and elevating intracellular cAMP and Ca2+. The hypothesis for the studies described in this Thesis was that GIP can induce pancreatic β-cell survival through activation of Protein Kinase B (PKB). Using a β-ceIl line, INS-1, and in human islets, it was possible to correlate GIP receptor activation with PKB phosphorylation through lipid signaling (arachidonic acid production). Through molecular biological and pharmacological approaches, GIP was shown to activate PKB. It was also shown that GIP can activate known downstream targets of PKB, namely GSK3α/β, FKHR and BAD. These events were demonstrated to be functionally relevant for (3-cell survival. Studies using the INS-1 cells also displayed the ability of GIP to improve cell survival within a glucolipotoxic environment. GIP treatment reduced the activity of the pro-apoptotic enzyme caspase-3 in both INS-1 cells and human islets. This reduction was shown to be dependent on the PI3K pathway. Further studies verified the protective effect of active PKB for INS-1 cells. Using an animal model of obesity-related diabetes (fa/fa Zucker rat) and a combination of techniques (oral glucose tolerance testing, caspase-3 activity assay, immunoblotting) it was also shown that long-term DP IV (P32/98) treatment can improve the survival of islets and improve glucose tolerance. These findings display a novel role for GIP in regulating β-cell survival.

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