Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPARγ2 in the modulation of insulin secretion

Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: α, β and γ (subdivided into γ1 and γ2). Recently, the presence of PPARγ has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPARγ mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPARγ 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). PPARβ and, to a greater extent, total PPARγ and PPARγ2 mRNAs were expressed in human islets, whereas PPARα mRNA was not detected. Compared with human adipose tissue, PPARγ mRNA was expressed at lower levels in the islets, and PPARβ at similar levels. The expression of PPARγ2 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 PPARγ agonists rosiglitazone and 15-deoxy-Δ-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 PPARγ mRNA is expressed in human pancreatic islets, with predominance of PPARγ2; exposure to FFA downregulates PPARγ2 and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPARγ agonists can prevent these effects.