Palmitate-induced beta-cell dysfunction is associated with excessive NO production and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms

PLoS One. 2008 May 14;3(5):e2182. doi: 10.1371/journal.pone.0002182.


Background: Type 2 diabetes often displays hyperlipidemia. We examined palmitate effects on pancreatic islet function in relation to FFA receptor GPR40, NO generation, insulin release, and the PPARgamma agonistic thiazolidinedione, rosiglitazone.

Principal findings: Rosiglitazone suppressed acute palmitate-stimulated GPR40-transduced PI hydrolysis in HEK293 cells and insulin release from MIN6c cells and mouse islets. Culturing islets 24 h with palmitate at 5 mmol/l glucose induced beta-cell iNOS expression as revealed by confocal microscopy and increased the activities of ncNOS and iNOS associated with suppression of glucose-stimulated insulin response. Rosiglitazone reversed these effects. The expression of iNOS after high-glucose culturing was unaffected by rosiglitazone. Downregulation of GPR40 by antisense treatment abrogated GPR40 expression and suppressed palmitate-induced iNOS activity and insulin release.

Conclusion: We conclude that, in addition to mediating acute FFA-stimulated insulin release, GPR40 is an important regulator of iNOS expression and dysfunctional insulin release during long-term exposure to FFA. The adverse effects of palmitate were counteracted by rosiglitazone at GPR40, suggesting that thiazolidinediones are beneficial for beta-cell function in hyperlipidemic type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Diazoxide / pharmacology
  • Female
  • Humans
  • Hydrolysis
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiopathology
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase / metabolism
  • Palmitic Acid / pharmacology*
  • Phosphatidylinositols / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Rosiglitazone
  • Signal Transduction / drug effects*
  • Thiazolidinediones / pharmacology*


  • Ffar1 protein, mouse
  • Hypoglycemic Agents
  • Insulin
  • Phosphatidylinositols
  • Receptors, G-Protein-Coupled
  • Thiazolidinediones
  • Rosiglitazone
  • Palmitic Acid
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Diazoxide