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

• Published in: The journal of clinical endocrinology and metabolism Vol. 90; no. 12; pp. 6678 - 6686
• Main Authors: Lin, Chia-Yu, Gurlo, Tatyana, Haataja, Leena, Hsueh, Willa A., Butler, Peter C.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.12.2005; Copyright by The Endocrine Society; Endocrine Society
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Amylin; Amyloid - poisoning; Apoptosis; Beta cells; Biological and medical sciences; Cell activation; Cell death; Cytoprotection; Diabetes mellitus (non-insulin dependent); DNA nucleotidylexotransferase; Endocrinopathies; Fundamental and applied biological sciences. Psychology; Gene Expression; Genes, Dominant; Glucose - pharmacology; Humans; Hypoglycemic Agents - pharmacology; In Vitro Techniques; Insulin - metabolism; Islet Amyloid Polypeptide; Islet cells; Islets of Langerhans - drug effects; Kinases; Medical sciences; NF-kappa B - metabolism; Oligomerization; Peroxisome proliferator-activated receptors; Phosphatidylinositol; Phosphatidylinositol 3-Kinases - metabolism; Polypeptides; PPAR gamma - drug effects; PPAR gamma - genetics; PPAR gamma - physiology; Protein-serine/threonine kinase; Proto-Oncogene Proteins c-akt - metabolism; Rosiglitazone; Signal Transduction; Thiazolidinediones; Thiazolidinediones - pharmacology; Toxicity; Vertebrates: endocrinology; Human; Enzyme; Toxicity; Transferases; Amylin; Langerhans islet; Peroxisome proliferator activated receptor gamma; Thiazolidinedione derivatives; Activation; 1-Phosphatidylinositol 3-kinase; Rosiglitazone; Endocrinology; Endocrine pancreas
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2005-0079

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.