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

Lipoprotein lipase (LpL) provides tissues with triglyceride-derived fatty a cids. Fatty acids affect beta -cell function, and LpL overexpression decrea ses 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 st imulated both total cellular LpL activity and heparin-releasable LpL activi ty. Glucose had no effect on total LpL protein mass but instead promoted th e appearance of LpL protein in a heparin-releasable fraction, suggesting th at glucose stimulates the translocation of LpL hom intracellular to extrace llular sites in beta -cells. The induction of heparin-releasable LpL activi ty was unaffected by treatment with diazoxide, an inhibitor of insulin exoc ytosis 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 increa sed LpL activity in the presence of 20 mM glucose. Using dual-laser confoca l microscopy, we detected intracellular LpL in vesicles distinct from those containing insulin. LpL was also detected at the cell surface and was disp laced from this site by heparin in dispersed islets and INS-1 cells. These results show that glucose metabolism controls the trafficking of LpL activi ty in beta -cells independent of insulin secretion. They suggest that hyper glycemia and hyperinsulinemia associated with insulin resistance may contri bute to progressive beta -cell dysfunction by increasing LpL-mediated deliv ery of lipid to islets.