Diazoxide and D600 Inhibition of Insulin Release: Distinct Mechanisms Explain the Specificity for Different Stimuli

Abstract

The mechanisms by which diazoxide and D600 affect insulin release have been compared in experiments using isolated rat islets. Diazoxide (20-400 (JLM) and D600 (1-50 /xM) produced a dose-dependent inhibition of glucose-stimulated release. Diazoxide also inhibited the insulinotropic effect of leucine and related substances (ketoisocaproate and BCH), but not that of potassium or of arginine and other cationic amino acids. Diazoxide suppressed glucose and leucine stimulation of Ca uptake in islet cells, but had no effect on the stimulation by potassium and arginine. By contrast, D600 suppressed the effect of all these agents on both Ca uptake and insulin release. Theophylline partially antagonized the inhibitory effect of D600 on release, in the presence of diazoxide, theophylline was much less effective, except when combined with cationic amino acids. Diazoxide inhibition of glucose-induced release was prevented by phentolamine, but hot by dihydroergotamine and yohimbine, two other blpckers of a-adrenergic receptors. Epinephrine abolished the insulinotropic effect of arginine alone or with theophylline. Diazoxide increased 86 Rb + efflux from islet cells, whereas D600 and epinephrine decreased it. The acceleration of efflux by diazoxide was inhibited by D600 and phentolamine, but not by epinephrine or dihydroergotamine. It thus appears that the effects of diazoxide on B-cells are not due to activation of a-adrenergic receptors. The results suggest that, in contrast to the direct blockade of Ca channels by D600, the blockade of these channels by diazoxide is secondary to the hyperpolarization of the B-cell membrane. Since the latter results from an increase in K permeability, the inhibitory effects of diazoxide are restricted to stimulators that depolarize the B-cell membrane by decreasing its K permeability (glucose, leucine, and related substances) and do not affect the stimulation by K and cationic amino acids, which depolarize by other mechanisms. DIABETES 37:776-783, September 1982. D iazoxide remains the drug of choice for medical treatment of chronic hypoglycemia due to hyperinsulinemia. 1 ' 2 A stimulation of epinephrine release and mainly an inhibition of insulin release account for its hyperglycemic action. 3 -4 The direct inhibitory effect of the drug on the pancreatic B-cell has been demonstrated in vitro, 5 " 7 but its mechanisms have long remained elusive. The latest experimental evidence 8 has ascribed the inhibition of glucose-stimulated release to the ability of diazoxide to hyperpolarize the B-cell membrane by increasing its potassium permeability. Nevertheless, certain aspects of its mode of action are still unclear. It has been suggested that diazoxide directly activates a-adrenergic receptors in B-ceils, 9~12 but such a mechanism appears difficult to reconcile with the clinically useful relaxation of vascular smooth muscles that the drug, also produces. 13 Furthermore, diazoxide inhibition of insulin release shows a certain stimulus selectivity in vitro 14 and in vivo. 15 Iri particular, the int...

Inhibitors of phosphatidylinositol 3-kinase amplify insulin release from islets of lean but not obese mice

“…Blocking calcium influx into the -cell abolishes glucoseinduced insulin secretion (Henquin et al 1982). In the next series of experiments, islets were perifused and Figure 2 Effect of wortmannin on 10 mM glucose-induced insulin release from mouse islets.…”

Stimulation of the KATP channel by ADP and diazoxide requires nucleotide hydrolysis in mouse pancreatic beta‐cells.

“…The hyperglyeaemic sulphonamide diazoxide inhibits glucose-stimulated insulin secretion and electrical activity (Henquin, Charles, Nenquin, Mathot & Tamagawa, 1982;Henquin & Meissner, 1982). Patch-clamp experiments have shown that diazoxide antagonizes the inhibitory effect of ATP on the KATP channel (Trube, Rorsman & Ohno-Shosaku, 1986;Dunne, Illot & Petersen, 1987;Gillis, Gee, Hammoud, McDaniel, Falke & Misler, 1989;Kozlowski, Hales & Ashford, 1989).…”

Magnesium uptake by pancreatic islet cells is modulated by stimulators and inhibitors of the B‐cell function

“…First, the relative increase in 45Ca2+ uptake induced by various concentrations of glucose is larger than the stimulation of 2*Mg2+ uptake [25, 30, 311. This difference is even more pronounced for tolbutamide or KC1 stimulation [21, 271. Second, diazoxide and D600 inhibited glucose-induced 28Mg2+ uptake only slightly, whereas they practically blocked the stimulation of 45Ca2 + uptake under similar conditions [21]. Third, cationic amino acids inhibited "Mgz + uptake, whereas they stimulate 45Ca2f uptake [21, 26, 291. In summary, though they bear several similarities, the changes in "Mg2+ and 45Ca2+ uptake, brought about by glucose and other modifyers of the B-cell function, are far from identical.…”

“…Second, all agents which increased 28Mg2+ uptake have been reported to increase 45Ca2+ uptake [21,[25][26][27][28][29]. Third, except for glucosamine, all agents which inhibited basal or glucose-induced 28Mg2+ uptake have been reported to inhibit basal or glucose-induced 45Ca2 + uptake [15,21,25,271. There are, however, several marked differences between 28Mg2+ and 45CaZ+ uptake by islet cells.…”