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J. Biol. Chem., Vol. 279, Issue 49, 51049-51056, December 3, 2004
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Free Fatty Acid-induced 
-Cell Defects Are Dependent on Uncoupling Protein 2 Expression*
¶
From the
Departments of Medicine and Physiology, University of Toronto, Ontario M5S 1A8, Canada, **Divisions of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52246, ||Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Prince Edward Island C1A4P3, Canada, and Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215
Chronic exposure to elevated free fatty acids (lipotoxicity) induces uncoupling protein (UCP2) in the pancreatic 
-cell, and therefore a causal link between UCP2 and -cell defects associated with obesity may exist. Recently, we showed that lipid treatment in vivo and in vitro in UCP2(–/–) mice/islets does not result in any loss in -cell glucose sensitivity. We have now assessed the mechanism of maintained -cell function in UCP2(–/–) mice by exposing islets to 0.4 mM palmitate for 48 h. Palmitate treatment increased triglyceride concentrations in wild type (WT) but not UCP2(–/–) islets because of higher palmitate oxidation rates in the UCP2(–/–) islets. Dispersed -cells from the palmitate-exposed WT islets had reduced glucose-stimulated hyperpolarization of the mitochondrial membrane potential compared with both control WT and palmitate-exposed UCP2(–/–) -cells. The glucose-stimulated increases in the ATP/ADP ratio and cytosolic Ca2+ are attenuated in palmitate-treated WT but not UCP2(–/–) -cells. Exposure to palmitate reduced glucose-stimulated insulin secretion (GSIS) in WT islets, whereas UCP2(–/–) islets had enhanced GSIS. Overexpression of recombinant UCP2 but not enhanced green fluorescent protein in -cells resulted in a loss of glucose-stimulated hyperpolarization of the mitochondrial membrane potential and GSIS similar to that seen in WT islets exposed to palmitate. Reactive oxygen species (ROS) are known to increase the activity of UCP2. We showed that ROS levels were elevated in control UCP2(–/–) islets as compared with WT and UCP2(–/–) islets overexpressing UCP2 and that palmitate increased ROS in WT and UCP2(–/–) islets overexpressing UCP2 but not in UCP2(–/–) islets. Thus, UCP2(–/–) islets resisted the toxic effects of palmitate by maintaining glucose-dependent metabolism-secretion coupling. We propose that higher free fatty acid oxidation rates prevent accumulation of triglyceride in UCP2(–/–) islets, such accumulation being a phenomenon associated with lipotoxicity.
Received for publication, August 11, 2004 , and in revised form, September 17, 2004.
* This work was supported in part by Operating Grant MOP-12898 from the Canadian Institutes of Health Research (CIHR) (to M. B. W. and C. B. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a CIHR doctoral award.
¶ Supported by a New Emerging Teams Grant in Diabetes Complications from CIHR.
Supported by a CIHR investigator award. To whom correspondence should be addressed: University of Toronto, Dept. of Physiology, 1 Kings College Circle, Rm. 3352, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-6737; Fax: 416-978-4940; E-mail: michael.wheeler{at}utoronto.ca.
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