PMID- 16204373 OWN - NLM STAT- MEDLINE DCOM- 20060110 LR - 20181203 IS - 0021-972X (Print) IS - 0021-972X (Linking) VI - 90 IP - 12 DP - 2005 Dec TI - Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3'-kinase-dependent pathway. PG - 6678-86 AB - 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 microM) 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 microM) 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. FAU - Lin, Chia-Yu AU - Lin CY AD - 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, USA. FAU - Gurlo, Tatyana AU - Gurlo T FAU - Haataja, Leena AU - Haataja L FAU - Hsueh, Willa A AU - Hsueh WA FAU - Butler, Peter C AU - Butler PC LA - eng GR - DK-61539/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20051004 PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (Amyloid) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Islet Amyloid Polypeptide) RN - 0 (NF-kappa B) RN - 0 (PPAR gamma) RN - 0 (Thiazolidinediones) RN - 05V02F2KDG (Rosiglitazone) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Amyloid/*poisoning MH - *Cytoprotection MH - Gene Expression MH - Genes, Dominant MH - Glucose/pharmacology MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - In Vitro Techniques MH - Insulin/metabolism MH - Islet Amyloid Polypeptide MH - Islets of Langerhans/*drug effects MH - NF-kappa B/metabolism MH - PPAR gamma/*drug effects/genetics/physiology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rosiglitazone MH - Signal Transduction MH - Thiazolidinediones/*pharmacology EDAT- 2005/10/06 09:00 MHDA- 2006/01/13 09:00 CRDT- 2005/10/06 09:00 PHST- 2005/10/06 09:00 [pubmed] PHST- 2006/01/13 09:00 [medline] PHST- 2005/10/06 09:00 [entrez] AID - jc.2005-0079 [pii] AID - 10.1210/jc.2005-0079 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2005 Dec;90(12):6678-86. doi: 10.1210/jc.2005-0079. Epub 2005 Oct 4.