L-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide

Abstract

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, Larginine (10 mmol/l) stimulation of insulin secretion was permitted by forskolin (10 mmol/l) or tetradecanoylphorbol 13-acetate (0.16 mmol/l), which, by activation of protein kinases A and C respectively sensitize the exocytotic machinery to L-arginine-induced Ca 2+ 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 N G -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 Csensitive mechanisms.

Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans

“…First, we did not show an absolute NEFA-mediated reduction in insulin secretion in acute response to arginine, as we have previously shown for GSIS [11]. Because arginine is believed to stimulate insulin secretion distal in the insulin secretion cascade of events, primarily by inducing depolarisation of the beta-cell membrane (22,23,40), the absence of a significant effect at normoglycaemia, combined with our previous observation of a NEFA-induced reduction of GSIS, would suggest that prolonged NEFA exposure could alter glucose-mediated insulin secretion and glucose potentiation of arginine-stimulated insulin secretion primarily by interfering with the metabolism of glucose, leaving the exocytotic machinery relatively intact. The stimulatory effect of arginine on acute insulin secretion at hyperglycaemia and glucose potentiation were also not affected in our present study, which suggest an absence of interaction between glucose and a prolonged increase of plasma NEFA on arginine-stimulated acute insulin secretion.…”

Nuclear Factor-κB Activity in β-Cells Is Required for Glucose-Stimulated Insulin Secretion

“…Arginine stimulates insulin secretion largely independent of glucose by directly depolarizing the ␤-cell membrane, but it still depends on a fully functional pathway of insulin exocytosis (38,(41)(42)(43). Arginine administration to endocrine clusters (A and B).…”

Reduction of Plasma Leptin Concentrations by Arginine but Not Lipid Infusion in Humans

“…Arginine was particularly chosen for the evaluation of ␤-cell function because of its superior ability over glucose to stimulate endogenous insulin release in type 2 diabetes (45,46) and because of the excellent reproducibility of this test (47). Arginine stimulates insulin secretion mainly by directly entering the cell through cationic amino acid transporters inducing depolarization of the ␤-cell membrane (48,49). Few data are available at present on the impact of arginine or other amino acids on production and/or secretion of leptin.…”