AREGU October 46/4

Ahrén, Bo, and Peter J. Havel. Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells). Am. J. Physiol. 277 (Regulatory Integrative Comp. Physiol. 46): R959–R966, 1999.—The effect of leptin on insulin secretion is controversial due to conflicting results in the literature. In the present study, we incubated insulinproducing rat insulinoma INS-1 cells for 60 min and examined the effects of recombinant murine leptin (20 nmol/l). We found that leptin (0.1–100 nmol/l) did not affect the insulin response to glucose (1–20 mmol/l). However, when cells were incubated with agents that increase the intracellular content of cAMP, i.e., glucagon-like peptide-1 (100 nmol/l), pituitary adenylate cyclase activating polypeptide (100 nmol/l), forskolin (2.5 μmol/l), dibutyryl-cAMP (1 mmol/l), or 3-isobutyl-1methylxanthine (100 μmol/l), leptin significantly reduced insulin secretion (by 34–58%, P , 0.05–0.001). In contrast, when insulin secretion was stimulated by the cholinergic agonist carbachol (100 μmol/l) or the phorbol ester 12-Otetradecanoylphorbol 13-acetate (1 μmol/l), both of which activate protein kinase C, leptin was without effect. We conclude that leptin inhibits insulin secretion from INS-1 cells under conditions in which intracellular cAMP is increased. This suggests that the cAMP-protein kinase A signal transduction pathway is a target for leptin to inhibit insulin secretion in insulin-producing cells.