Glucose and Insulin Stimulate Heparin-releasable Lipoprotein Lipase Activity in Mouse Islets and INS-1 Cells

Abstract

Lipoprotein lipase (LpL) provides tissues with triglyceride-derived fatty acids. Fatty acids affect ␤-cell function, and LpL overexpression decreases insulin secretion in cell lines, but whether LpL is regulated in ␤-cells is unknown. To test the hypothesis that glucose and insulin regulate LpL activity in ␤-cells, we studied pancreatic islets and INS-1 cells. Acute exposure of ␤-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 ␤-cells. The induction of heparinreleasable 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 ␤-cells independent of insulin secretion. They suggest that hyperglycemia and hyperinsulinemia associated with insulin resistance may contribute to progressive ␤-cell dysfunction by increasing LpL-mediated delivery of lipid to islets.

The common biological basis for common complex diseases: evidence from lipoprotein lipase gene

“…Hypertriglyceridemia prioritizing the utilization of TAG as fuels inhibits the intake and oxidization of glucose; 27 intracellular fatty acid metabolites interfere with propagation of insulin signaling cascade; 28 and delivering more FFA to pancreatic b-cells impairs b-cell function and promote apoptosis. 29 The above findings may be partly responsible for the association between LPL and T2D.…”

“…A recent study found that the reduced LPL delivery in skeletal muscle in skeletal muscle-specific LPL knockout mouse (SMLPLÀ/À) induced increased insulin sensitivity in skeletal muscle but insulin resistance in other metabolic tissues, and ultimately led to obesity and systematic insulin resistance. 29 These results suggested that systematic overexpression of LPL might improve insulin resistance, although the underlying mechanism is not clear. These controversies suggest that the association between the LPL gene and T2D may be tissue specific.…”

“…These controversies suggest that the association between the LPL gene and T2D may be tissue specific. Some results relevant to the underlying mechanisms have been reported as follows: Cruz et al 29 study indicated that more FFA could be delivered to pancreatic b-cells by increasing LPL activity, consequently impairing b-cell function and promoting apoptosis in the patients with hyperglyceridemia, hyperinsulinemia and T2D. Hypertriglyceridemia prioritizing the utilization of TAG as fuels inhibits the intake and oxidization of glucose; 27 intracellular fatty acid metabolites interfere with propagation of insulin signaling cascade; 28 and delivering more FFA to pancreatic b-cells impairs b-cell function and promote apoptosis.…”

Fatty acid metabolism and insulin secretion in pancreatic beta cells

“…For these reasons, extracellular NEFA can be expected to rapidly distribute in the available lipid bilayers and to move rapidly from cell to cell, potentially acting as paracrine mediators. In addition, islets express low-density lipoprotein receptors [71] and lipoprotein lipase [72] and could also obtain fatty acids from circulating lipoproteins.…”

Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets

“…Second, during in vitro experiments, ␤-cells are exposed to stable, constantly elevated levels of fatty acids, a situation clearly different from the cyclical variations of fatty acid levels that occur in vivo during the prandial cycle. Third, the local concentration of biologically active fatty acids (unbound to albumin) in the vicinity of the ␤-cell is essentially unknown and determined by many factors, including the total fatty acid concentration, the molar ratio of fatty acids to albumin, and the activity of lipoprotein lipase (14).…”