Leptin constrains phospholipase C-protein kinase C-induced insulin secretion via a phosphatidylinositol 3-kinase-dependent pathway.
Leptin-deficient Lep(ob)/Lep(ob)mice hypersecrete insulin in response to acetylcholine stimulation of the phospholipase C-protein kinase C (PLC-PKC) pathway, and leptin constrains this hypersecretion. Leptin has been reported to activate phosphatidylinositol 3-kinase (PI 3-K) and subsequently phosphodiesterase (PDE) to impair protein kinase A (PKA)-induced insulin secretion from cultured islets of neonatal rats. We determined if PKA-induced insulin secretion was also hyperresponsive in islets from Lep(ob)/Lep(ob)mice, and if leptin impaired this pathway in islets from these mice. Additionally, the possible role for PI 3-K and PDE in leptin-induced control of acetylcholine-induced insulin secretion was examined. Stimulation of insulin secretion with GLP-1, forskolin (an activator of adenylyl cyclase), or IBMX (an inhibitor of PDE) did not cause hypersecretion of insulin from islets of young Lep(ob)/Lep(ob)mice, and leptin did not inhibit GLP-1-induced insulin secretion from islets of these mice. Inhibition of PDE with IBMX also did not block leptin-induced inhibition of acetylcholine-mediated insulin secretion from islets of Lep(ob)/Lep(ob)mice. But, preincubation of islets with wortmannin, an inhibitor of PI 3-K activity, blocked the ability of leptin to constrain acetylcholine-induced insulin secretion from islets of Lep(ob)/Lep(ob)mice. We conclude that the capacity of the PKA pathway to stimulate insulin secretion is not increased in islets from young Lep(ob)/Lep(ob)mice, and that leptin does not regulate this pathway in islets from mice. Leptin may stimulate PI 3-K to constrain PLC-PKC-induced insulin secretion from islets of Lep(ob)/Lep(ob)mice.
Lee
Joo-Won
JW
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA.
Swick
Andrew G
AG
Romsos
Dale R
DR
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000378:metabolism*; D011498:Protein Precursors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism*; D000077191:Wortmannin
D015056:1-Methyl-3-isobutylxanthine; D000109:Acetylcholine; D000730:Androstadienes; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D007328:Insulin; D020738:Leptin; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011498:Protein Precursors; D010738:Type C Phospholipases; D000077191:Wortmannin