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J. Biol. Chem., Vol. 280, Issue 10, 9023-9029, March 11, 2005

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Pancreatic -Cell Lipoprotein Lipase Independently Regulates Islet Glucose Metabolism and Normal Insulin Secretion^*

Kirk L. Pappan, Zhijun Pan¶, Guim Kwon, Connie A. Marshall, Trey Coleman¶, Ira J. Goldberg||, Michael L. McDaniel, and Clay F. Semenkovich¶**

From the Department of Pathology and Immunology, ^¶Departments of Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, and ^||Department of Medicine, Columbia University, New York, New York 10032

Lipid and glucose metabolism are adversely affected by diabetes, a disease characterized by pancreatic -cell dysfunction. To clarify the role of lipids in insulin secretion, we generated mice with -cell-specific overexpression (LPL-TG) or inactivation (LPL-KO) of lipoprotein lipase (LPL), a physiologic provider of fatty acids. LPL enzyme activity and triglyceride content were increased in LPL-TG islets; decreased LPL enzyme activity in LPL-KO islets did not affect islet triglyceride content. Surprisingly, both LPL-TG and LPL-KO mice were strikingly hyperglycemic during glucose tolerance testing. Impaired glucose tolerance in LPL-KO mice was present at one month of age, whereas LPL-TG mice did not develop defective glucose homeostasis until approximately five months of age. Glucose-simulated insulin secretion was impaired in islets isolated from both mouse models. Glucose oxidation, critical for ATP production and triggering of insulin secretion mediated by the ATP-sensitive potassium (K_ATP) channel, was decreased in LPL-TG islets but increased in LPL-KO islets. Islet ATP content was not decreased in either model. Insulin secretion was defective in both LPL-TG and LPL-KO islets under conditions causing calcium-dependent insulin secretion independent of the K_ATP channel. These results show that -cell-derived LPL has two physiologically relevant effects in islets, the inverse regulation of glucose metabolism and the independent mediation of insulin secretion through effects distal to membrane depolarization.

Received for publication, August 24, 2004 , and in revised form, December 15, 2004.

^* This study was supported by National Institutes of Health Grants DK06181, HL58427, and HL45095, an American Diabetes Association mentor-based postdoctoral fellowship (to M. L. M.), and the Washington University Diabetes Research and Training Center (DK20579) and Clinical Nutrition Research Unit (DK56341). 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.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: Washington University, Campus Box 8127, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-7617; Fax: 314-362-7641; E-mail: csemenko{at}im.wustl.edu.

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