Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells).
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 micromol/l), dibutyryl-cAMP (1 mmol/l), or 3-isobutyl-1-methylxanthine (100 micromol/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 micromol/l) or the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (1 micromol/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.
Ahrén
B
B
Department of Medicine, Lund University, Malmö, SE-205 02 Sweden. bo.ahren@medforsk.mas.lu.se
Havel
P J
PJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000494:pharmacology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured
C495403:Adcyap1 protein, rat; D004791:Enzyme Inhibitors; D007328:Insulin; D007329:Insulin Antagonists; D020738:Leptin; D009479:Neuropeptides; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011498:Protein Precursors; D005576:Colforsin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium