Rosiglitazone prevents the impairment of human islet function induced by fatty-acids. Evidence for a role of PPAR-γ2 in the modulation of insulin secretion. Running Title: PPARγ2 modulation of isolated human islet function

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 γ 1 and γ 2). Recently, the presence of PPARs-γ has been reported in human islets. Whether the other PPARs types can be found in human islets, how islet PPAR-γ mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPAR-γ agonist is not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from non-obese adult donors. The presence of the varying PPARs mRNA was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24h 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 to 1). PPARs-β and, to a greater extent, total-γ and γ-2 mRNAs were expressed in human islets, whereas PPAR-α mRNA was not detected. Compared to human adipose tissue, PPARs-γ mRNA was expressed at lower levels in the islets, and PPARs-β at similar levels. The expression of PPARs γ-2 mRNA was not affected by exposure to 22.2 mmol/l glucose, whereas it decreased markedly and time-dependently after exposure to progressively higher 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-γ agonists rosiglitazone and 15-Deoxy-∆-12,14 prostaglandin J2 (PGJ 2) 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: PPARs-γ mRNA is expressed in human pancreatic islets, with predominance of PPARs γ-2 ; exposure to FFA down-regulates PPAR-γ 2 and insulin mRNA expression and inhibits glucose stimulated insulin secretion; exposure to PPARs-γ agonists can prevent these latter effects.