The early phase of glucose-stimulated insulin secretion requires nitric oxide

Abstract

Nitric oxide (nitrogen monoxide; NO) is an important messenger molecule in various cell types, e. g. endothelial cells [1], neurons [2], or T lymphocytes [3]. However, when produced in large amounts and over prolonged periods of time, e. g. by macrophages [4], NO is cytotoxic.In pancreatic beta cells NO produced upon activation of the inducible isoform of NO synthase by cytokines causes beta-cell destruction [5]. There is also evidence that NO could function as signal transmitter in beta cells. However, results obtained in pursuit of a possible involvement of NO in the signalling pathway of insulin secretion are controversial. Some investigations provided evidence that NO, presumably produced by a calcium/calmodulin-dependent constitutive NO synthase (NOS), participates in the signal transduction pathway mediating insulin secretion [6], and that L-arginine-derived NO mediates insulin secretion via stimulation of guanylate cyclase and cGMP formation [7]. Others found no evidence for endogenously produced NO being involved in the initiation of secretagogue-induced insulin release [8] or reported that L-arginine-derived NO may even inhibit insulin release [9].Recently, Willmott et al. [10] showed that beta cells preloaded with tryptamine, which accumulates in insulin-containing granules and is co-secreted with insulin, respond to NO by mobilizing Ca 2+ from the endoplasmic reticulum accompanied by a release of tryptamine from the cells. These data corroborate our previous finding that exogenously added NO Diabetologia (1998) Summary Nitric oxide (nitrogen monoxide, NO) acts as a signal transducer in a variety of cells. In the present study rat pancreatic islets were perifused with physiologically relevant glucose concentrations in the presence or absence of various NO-modulating agents. Perifusion in the presence of 0.1±1 mmol/l of the NO synthase inhibitor, N G -monomethyl-L-arginine or of 10 mmol/l of the NO-scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), resulted in an inhibition of the early phase of glucose-stimulated insulin secretion by 60±65 % and 46 %, respectively. Light-and electron-microscopic studies revealed that pancreatic islets constitutively express NO-synthase in alpha and delta cells, where it is confined to the secretory granules. Therefore, these data indicate that NO may be important in the signal transduction pathway of the early phase of glucose-stimulated insulin secretion.[ Diabetologia (1998) 41: 292±299]

Exogenous Nitric Oxide and Endogenous Glucose-Stimulated β-Cell Nitric Oxide Augment Insulin Release

“…Our demonstration of a stimulatory effect of NO on insulin release is in agreement with previously published reports (5,(13)(14)(15)21,22); however, a number of studies argue against a stimulatory role for NO (6,9,16 -18,23-27). Since we used the intracellular NO donor HA to simulate physiological endogenous NO production (and demonstrated this production using Daf2) and because we used a ␤-cell line, we produced an experimental model in which we were able to observe the effect of NO produced within the ␤-cell acting on the ␤-cell.…”

“…However, several reports in which cNOS activity was manipulated or exogenous NO was applied have yielded seemingly conflicting results. NOS inhibition has been reported to produce an inhibitory effect (5,(13)(14)(15), a stimulatory effect (6,9,16 -18), and no effect at all (19,20) on insulin release. Similarly, exogenously applied NO has been reported to exert a stimulatory (5,13,14,21,22) and an inhibitory effect (6,18,(23)(24)(25)(26)(27) on insulin release.…”

Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes.

“…Total ginsenosides have also been shown to modulate nitric oxide synthesis, the enhancement of which has been linked to ginseng' s effects (38). The former 3 systems affect glucose metabolism in vivo (39), and nitric oxide has been noticed to increase insulin-stimulated glucose uptake in rat skeletal muscles and adipose tissue (40) and to stimulate glucose-dependent secretion of insulin in rat islet cells (41). It is therefore possible that these ginsenosides contributed to the postprandial hypoglycemic effects we observed.…”

Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-).

“…A possible reason for these conflicting observations is the use of relatively nonspecific pharmacological blockers of iNOS activity. Indeed, pancreatic ␤-cells also express a constitutive isoform of NOS (nNOS), which may participate in ␤-cell physiology (14,15). Thus, it is conceivable that pharmacological NO synthase inhibitors will affect both isoforms of the enzyme, confounding the experimental data obtained.…”