A role for hormone-sensitive lipase in glucose-stimulated insulin secretion - A study in hormone-sensitive lipase-deficient mice

Endogenous lipid stores are thought to be involved in the mechanism whereby the beta -cell adapts its secretory capacity in obesity and diabetes. In a ddition, hormone-sensitive lipase (HSL) is expressed in beta -cells and may provide fatty acids necessary for the generation of coupling factors linki ng glucose metabolism to insulin release. We have recently created HSL-defi cient mice that were used to directly assess the role of HSL in insulin sec retion and action. HSL-/- mice were normoglycemic and normoinsulinemic unde r basal conditions, but showed an similar to 30% reduction of circulating f ree fatty acids (FFAs) with respect to control and heterozygous animals aft er an overnight fast. An intraperitoneal glucose tolerance test revealed th at HSL-null mice were glucose-intolerant and displayed a lack of a rise in plasma insulin after a glucose challenge. Examination of plasma glucose dur ing an insulin tolerance test suggested that HSL-null mice were insulin-res istant, because plasma glucose was barely lowered after the injection of in sulin. Freshly isolated islets from HSL-deficient mice displayed elevated s ecretion at low (3 mmol/l) glucose, failed to release insulin in response t o high (20 mmol/l) glucose, but had a normal secretion when challenged with elevated KCI. The phenotype of heterozygous mice with respect to the measu red parameters in vitro was similar to that of wild type. Finally, the isle t triglyceride content of HSL-/- mice was 2-2.5 fold that in HSL-/+ and HSL +/+ animals. The results demonstrate an important role of HSL and endogenou s beta -cell lipolysis in the coupling mechanism of glucose-stimulated insu lin secretion. The data also provide direct support for the concept that so me lipid molecule(s), such as FFAs, fatty acyl-CoA or their derivatives, ar e implicated in beta -cell glucose signaling.