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Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR₂ in the modulation of insulin secretion

¹Department of Endocrinology and Metabolism, Metabolic Unit, and ²Department of Oncology, Surgical Unit, University of Pisa, 56100 Pisa, Italy

Submitted 23 December 2002 ; accepted in final form 12 November 2003

Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: , and (subdivided into ₁ and ₂). Recently, the presence of PPAR has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPAR mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPAR agonist are not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from nonobese adult donors. The presence of PPAR mRNAs was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24 h to either 22.2 mmol/l glucose and/or 0.25, 0.5, or 1.0 mmol/l long-chain fatty acid mixture (oleate to palmitate, 2:1). PPAR and, to a greater extent, total PPAR and PPAR₂ mRNAs were expressed in human islets, whereas PPAR mRNA was not detected. Compared with human adipose tissue, PPAR mRNA was expressed at lower levels in the islets, and PPAR at similar levels. The expression of PPAR₂ mRNA was not affected by exposure to 22.2 mmol/l glucose, whereas it decreased markedly and time dependently after exposure to progressively higher free fatty acids (FFA). This latter effect was not affected by the concomitant presence of high glucose. Exposure to FFA caused inhibition of insulin mRNA expression, glucose-stimulated insulin release, and reduction of islet insulin content. The PPAR agonists rosiglitazone and 15-deoxy--^12,14prostaglandin J₂ prevented the cytostatic effect of FFA as well as the FFA-induced changes of PPAR and insulin mRNA expression. In conclusion, this study shows that PPAR mRNA is expressed in human pancreatic islets, with predominance of PPAR₂; exposure to FFA downregulates PPAR₂ and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPAR agonists can prevent these effects.

pancreatic islets; peroxisome proliferator-activated receptors; polymerase chain reaction; messenger ribonucleic acid; lipotoxicity; glucotoxicity; prostaglandin; free fatty acids

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