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1 Department of Medicine, Lund University, Malmö, SE-205 02 Sweden; and 2 Department of Nutrition, University of California, Davis, California 95616
The effect of leptin on insulin secretion is controversial due to conflicting results in the literature. In the present study, we incubated insulin-producing 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-1-methylxanthine (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-O-tetradecanoylphorbol 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.
glucagon-like peptide-1; pituitary adenylate cyclase activating polypeptide-38; forskolin; adenosine 3',5'-cyclic monophosphate; 3-isobutyl-1-methylxanthine; carbachol; protein kinase C; calcium
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