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Chia-Yu Lin, Tatyana Gurlo, Leena Haataja, Willa A. Hsueh, Peter C. Butler, 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, The Journal of Clinical Endocrinology & Metabolism, Volume 90, Issue 12, 1 December 2005, Pages 6678–6686, https://doi.org/10.1210/jc.2005-0079
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Background: Type 2 diabetes mellitus (T2DM) is characterized by a deficit in β-cell mass, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (h-IAPP) applied to β-cells forms toxic oligomers that induce apoptosis. Thiazolidinediones, ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ), can delay the onset of T2DM.
Objective: We questioned whether activation of endogenous PPAR-γ 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-γ in human islets prevented the protective effect of RSG. RSG activation of PPAR-γ 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-γ 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 β-cell apoptosis in T2DM and reduce loss of β-cell mass.
