The expression of hormone-sensitive lipase in clonal beta-cells and rat islets is induced by long-term exposure to high glucose

Hormone-sensitive lipase (HSL) is expressed and enzymatically active in bet a -cells and has been proposed to be involved in the generation of the lipi d-derived signal that seems to be necessary for glucose-stimulated insulin secretion. In this study, we investigated whether the expression of HSL in INS-I cells and in rat islets is affected by exposure to high glucose conce ntrations. Incubation of INS-1 cells in 25 mmol/l glucose for 16 and 32 h i nduced HSL protein expression twofold, whereas no effect was observed after 4 and 8 It of incubation. The HSL activity, defined as the diglyceride lip ase activity inhibited by anti-rat HSL antibodies, constituted similar to 2 5% of total diglyceride lipase activity and was induced to a similar extent as HSL protein levels. The glucose effect at 16 It on HSL protein expressi on level was confirmed in freshly isolated rat islets. Exposure of INS-1 ce lls to different glucose concentrations for 16 It showed that the inductive effect on HSL protein levels was maximum at 20 mmol/l glucose (2- to 2.5-f old). Northern blot analysis demonstrated a more than threefold elevation o f HSL mRNA levels. The induction was blocked by actinomycin D, and the half -life of the transcript seemed to be unchanged by high glucose, suggesting a transcriptional nature of the glucose effect on HSL gene expression. The nonmetabolizable glucose analog 2-deoxyglucose, which has no mitogenic effe ct, induced HSL similar to1.3-fold, whereas mannose was similar to glucose, stimulating HSL expression 1.7- to 2-fold. The results suggest that HSL is involved in the beta -cell responses to hyperglycemia and also in generati ng the lipid signal that is needed in stimulus-secretion coupling.