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

J Clin Endocrinol Metab. 2005 Dec;90(12):6678-86. doi: 10.1210/jc.2005-0079. Epub 2005 Oct 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / poisoning*
  • Cytoprotection*
  • Gene Expression
  • Genes, Dominant
  • Glucose / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • In Vitro Techniques
  • Insulin / metabolism
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / drug effects*
  • NF-kappa B / metabolism
  • PPAR gamma / drug effects*
  • PPAR gamma / genetics
  • PPAR gamma / physiology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rosiglitazone
  • Signal Transduction
  • Thiazolidinediones / pharmacology*


  • Amyloid
  • Hypoglycemic Agents
  • Insulin
  • Islet Amyloid Polypeptide
  • NF-kappa B
  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose