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¹ Instituto Bioingeniería, Universidad Miguel Hernández de Elche, Elche 03202, Alicante, Spain² CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Universidad Miguel Hernández de Elche, Elche 03202, Alicante, Spain³ Laboratorio de Medicina Regenerativa and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Hospital Carlos Haya, Fundación IMABIS, Málaga 29010, Spain

(Correspondence should be addressed to A Nadal at Institute of Bioengineering, Miguel Hernández University, 03202 Elche, Alicante, Spain; Email: nadal{at}umh.es)

^* (A Rafacho is now at Department of Physiology and Biophysics, Institute of Biology, State University of Campinas, Campinas, SP, Brazil)

PPAR is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPAR is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPAR ligands on the intracellular calcium concentration ([Ca²⁺]_i), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPAR agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-D. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPAR is present in β-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPAR ligand effects in mice bearing a disrupted Ppar gene raises the possibility that the rapid effects of the agonists in pancreatic β-cells are independent of the receptor. We conclude that PPAR agonists produce a decrease in glucose-induced [Ca²⁺]_i signals and insulin secretion in β-cells through a rapid, non-genomic mechanism.