| Summary: | 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. === Medicine, Faculty of === Cellular and Physiological Sciences, Department of === Graduate
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