L-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide.
The mechanism of L-arginine stimulation of glucose-induced insulin secretion from mouse pancreatic islets was studied. At 16.7 mmol/l glucose, L-arginine (10 mmol/l) potentiated both phases 1 and 2 of glucose-induced insulin secretion. This potentiation of glucose-induced insulin secretion was mimicked by the membrane depolarizing agents tetraethylammonium (TEA, 20 mmol/l) and K+ (60 mmol/l), which at 16.7 mmol/l glucose obliterated L-arginine (10 mmol/l) modulation of insulin secretion. Thus L-arginine may potentiate glucose-induced insulin secretion by stimulation of membrane depolarization. At 3.3 mmol/l glucose, L-arginine (10 mmol/l) failed to stimulate insulin secretion. In accordance with membrane depolarization by the electrogenic transport of L-arginine, however, L-arginine (10 mmol/l) stimulation of insulin secretion was enabled by the K+ channel inhibitor TEA (20 mmol/l), which potentiates membrane depolarization by L-arginine. Furthermore, L-arginine (10 mmol/l) stimulation of insulin secretion was permitted by forskolin (10 micromol/l) or tetradecanoylphorbol 13-acetate (0.16 micromol/l), which, by activation of protein kinases A and C respectively sensitize the exocytotic machinery to L-arginine-induced Ca2+ influx. Thus glucose may sensitize L-arginine stimulation of insulin secretion by potentiation of membrane depolarization and by activation of protein kinase A or protein kinase C. Finally, L-arginine stimulation of glucose-induced insulin secretion was mimicked by NG-nitro-L-arginine methyl ester (10 mmol/l), which stimulates membrane depolarization but inhibits nitric oxide synthase, suggesting that L-arginine-derived nitric oxide neither inhibits nor stimulates insulin secretion. In conclusion, it is suggested that L-arginine potentiation of glucose-induced insulin secretion occurs independently of nitric oxide, but is mediated by membrane depolarization, which stimulates insulin secretion through protein kinase A- and C-sensitive mechanisms.
Department of Medical Biochemistry and Genetics, Biochemistry Laboratory A, The Panum Institute, University of Copenhagen, Denmark.
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D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D010084:Oxidation-Reduction; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D019789:Tetraethylammonium; D013997:Time Factors
D007328:Insulin; D009569:Nitric Oxide; D019789:Tetraethylammonium; D001120:Arginine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D005947:Glucose; D003981:Diazoxide; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester