title: Palmitate-induced beta-cell dysfunction is associated with excessive NO production and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Science, Division of Endocrine Pharmacology, the Malmö University Hospital (UMAS), Malmö, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meidute Abaraviciene
authors.forename: Ingmar
authors.initials: I
authors.lastname: Lundquist
authors.forename: Juris
authors.initials: J
authors.lastname: Galvanovskis
authors.forename: Erik
authors.initials: E
authors.lastname: Flodgren
authors.forename: Björn
authors.initials: B
authors.lastname: Olde
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
mesh_terms: D000818:Animals; D002460:Cell Line; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C473036:Ffar1 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D010716:Phosphatidylinositols; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019308:Palmitic Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D003981:Diazoxide