Activation of peroxisome proliferator-activated receptor-γ by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3′-kinase-dependent pathway

Background: Type 2 diabetes mellitus ( T2DM) is characterized by a deficit in beta-cell mass, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide ( IAPP). Human IAPP ( h-IAPP) applied to beta-cells forms toxic oligomers that induce apoptosis. Thiazolidinediones, ligands of peroxisome proliferator-activated receptor-gamma ( PPAR-gamma), can delay the onset of T2DM. Objective: We questioned whether activation of endogenous PPAR-gamma 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 mu M) 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 mu M) 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-gamma in human islets prevented the protective effect of RSG. RSG activation of PPAR-gamma 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-gamma 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 beta-cell apoptosis in T2DM and reduce loss of beta-cell mass.