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Activation of Peroxisome Proliferator-Activated Receptor- by Rosiglitazone Protects Human Islet Cells against Human Islet Amyloid Polypeptide Toxicity by a Phosphatidylinositol 3'-Kinase-Dependent Pathway

Larry Hillblom Islet Research Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095-7073

Address all correspondence and requests for reprints to: Dr. Peter C. Butler, Larry Hillblom Islet Research Center, Division of Endocrinology, David Geffen School of Medicine at University of California Los Angeles, 900A Weyburn Place North, Los Angeles, California 90095-7073. E-mail: pbutler{at}mednet.ucla.edu.

Background: Type 2 diabetes mellitus (T2DM) is characterized by a deficit in ß-cell mass, increased ß-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (h-IAPP) applied to ß-cells forms toxic oligomers that induce apoptosis. Thiazolidinediones, ligands of peroxisome proliferator-activated receptor- (PPAR-), can delay the onset of T2DM.

Objective: We questioned whether activation of endogenous PPAR- in human islets by rosiglitazone (RSG) inhibits h-IAPP-induced islet cell death and, if so, by which mechanism.

Methods and Results: Vehicle or h-IAPP was applied to human islets with or without RSG (10 and 50 µM) for 48 h. A 2-fold increase in the number of terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling-positive nuclei was detected in h-IAPP-treated human islets (P < 0.001). RSG (10 and 50 µM) prevented h-IAPP-induced apoptosis in human islets (P < 0.001). Thioflavin T binding assays confirmed that this effect was not mediated by interference with h-IAPP oligomerization. Expression of dominant negative PPAR- in human islets prevented the protective effect of RSG. RSG activation of PPAR- resulted in downstream activation of the serine/threonine protein kinase Akt, an outcome that was inhibited by a specific phosphatidylinositol 3-kinase inhibitor, which ablated RSG protection against h-IAPP-induced islet cell apoptosis.

Conclusion: We conclude that in human islets, activation of PPAR- inhibits h-IAPP-induced islet cell apoptosis, and this action is at least in part mediated through activation of the phosphatidylinositol 3'-kinase-Akt cascade. If this action is present in vivo, then thiazolidinediones have the potential to decrease ß-cell apoptosis in T2DM and reduce loss of ß-cell mass.

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