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Originally published In Press as doi:10.1074/jbc.M010707200 on January 11, 2001

J. Biol. Chem., Vol. 276, Issue 15, 12162-12168, April 13, 2001
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Glucose and Insulin Stimulate Heparin-releasable Lipoprotein Lipase Activity in Mouse Islets and INS-1 Cells
A POTENTIAL LINK BETWEEN INSULIN RESISTANCE AND beta -CELL DYSFUNCTION*

Wilhelm S. CruzDagger §, Guim Kwon§, Connie A. Marshall§, Michael L. McDaniel§, and Clay F. SemenkovichDagger ||**

From the Departments of Dagger  Medicine, § Pathology and Immunology, and  Cell Biology and Physiology and the || Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110

Lipoprotein lipase (LpL) provides tissues with triglyceride-derived fatty acids. Fatty acids affect beta -cell function, and LpL overexpression decreases insulin secretion in cell lines, but whether LpL is regulated in beta -cells is unknown. To test the hypothesis that glucose and insulin regulate LpL activity in beta -cells, we studied pancreatic islets and INS-1 cells. Acute exposure of beta -cells to physiological concentrations of glucose stimulated both total cellular LpL activity and heparin-releasable LpL activity. Glucose had no effect on total LpL protein mass but instead promoted the appearance of LpL protein in a heparin-releasable fraction, suggesting that glucose stimulates the translocation of LpL from intracellular to extracellular sites in beta -cells. The induction of heparin-releasable LpL activity was unaffected by treatment with diazoxide, an inhibitor of insulin exocytosis that does not alter glucose metabolism but was blocked by conditions that inhibit glucose metabolism. In vitro hyperinsulinemia had no effect on LpL activity in the presence of low concentrations of glucose but increased LpL activity in the presence of 20 mM glucose. Using dual-laser confocal microscopy, we detected intracellular LpL in vesicles distinct from those containing insulin. LpL was also detected at the cell surface and was displaced from this site by heparin in dispersed islets and INS-1 cells. These results show that glucose metabolism controls the trafficking of LpL activity in beta -cells independent of insulin secretion. They suggest that hyperglycemia and hyperinsulinemia associated with insulin resistance may contribute to progressive beta -cell dysfunction by increasing LpL-mediated delivery of lipid to islets.

* This study was supported by National Institutes of Health Grants DK06181, HL58427, DK53198, and T32 DK07296, by Washington University Clinical Nutrition Research Unit Grant DK56341, by Washington University Diabetes Research and Training Center Grant DK20579, and by an American Diabetes Association Mentor-based Fellowship.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Clay F. Semenkovich, Division of Atherosclerosis, Nutrition, and Lipid Research, Washington University School of Medicine, Campus Box 8046, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-4454; Fax: 314-747-4477; E-mail: semenkov@im.wustl.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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