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Pancreatic Islet Adaptation to Fasting Is Dependent on Peroxisome Proliferator-Activated Receptor Transcriptional Up-Regulation of Fatty Acid Oxidation

Center for Integrative Genomics (S.G., B.D., L.M., W.W.), University of Lausanne, CH-1015 Lausanne, Switzerland; the Molecular Nutrition Unit and the Montreal Diabetes Research Center (C.N., R.R., M.-L.P., V.D.-A., M.P.), University of Montreal, Montreal, Quebec, Canada H2L 4M1; Hopital Rangueil (R.B.), 31403 Toulouse, France; and the Division of Medical Genetics (R.R.), Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland

Address all correspondence and requests for reprints to: Dr. Marc Prentki, Centre de Recherche, Centre Hospitalier de l’Université de Montréal, Pavillon de Sève, Y4603, 1560 Sherbrooke East, Montreal, Quebec, Canada H2L 4M1. E-mail: marc.prentki{at}umontreal.ca.

The cellular response to fasting and starvation in tissues such as heart, skeletal muscle, and liver requires peroxisome proliferator-activated receptor- (PPAR)-dependent up-regulation of energy metabolism toward fatty acid oxidation (FAO). PPAR null (PPARKO) mice develop hyperinsulinemic hypoglycemia in the fasting state, and we previously showed that PPAR expression is increased in islets at low glucose. On this basis, we hypothesized that enhanced PPAR expression and FAO, via depletion of lipid-signaling molecule(s) for insulin exocytosis, are also involved in the normal adaptive response of the islet to fasting. Fasted PPARKO mice compared with wild-type mice had supranormal ip glucose tolerance due to increased plasma insulin levels. Isolated islets from the PPAR null mice had a 44% reduction in FAO, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion. In normal rats, fasting for 24 h increased islet PPAR, carnitine palmitoyltransferase 1, and uncoupling protein-2 mRNA expression by 60%, 62%, and 82%, respectively. The data are consistent with the view that PPAR, via transcriptionally up-regulating islet FAO, can reduce insulin secretion, and that this mechanism is involved in the normal physiological response of the pancreatic islet to fasting such that hypoglycemia is avoided.

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