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Submitted on November 1, 2004
Accepted on April 5, 2005
potentiates whereas PPAR
attenuates Glucose-Stimulated Insulin Secretion in Pancreatic 
-cells
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.; Department of Cell Physiology and Metabolism, University Medical Center, CH-1211 Geneva 4, Switzerland
* To whom correspondence should be addressed. E-mail: s.mandrup{at}bmb.sdu.dk.
Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic 
-cells. FA-CoA esters have been shown to directly stimulate the secretion process, whereas long-term exposure of -cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms so far unknown. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family, via an induction of uncoupling protein 2 (UCP2). Here we show that adenoviral co-expression of PPAR
and retinoid-X-receptor (RXR) in INS-1E -cells synergistically and in a dose- and ligand-dependent manner increases expression of known PPAR target genes and enhances FA uptake and -oxidation. In contrast, ectopic expression of PPAR
/RXR increases FA uptake and deposition as triacylglycerides. Although expression of PPAR/RXR leads to induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarisation of the mitochondrial membrane, indicating that, under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPAR/RXR attenuates GSIS, expression of PPAR/RXR potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes and on lipid partitioning and insulin secretion when systematically compared in a -cell context.
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