title: 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.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gurlo
authors.forename: Leena
authors.initials: L
authors.lastname: Haataja
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000682:Amyloid / Q000506:poisoning*; D019610:Cytoprotection; D015870:Gene Expression; D005799:Genes, Dominant; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose