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...
The similarities between the effects of acetylcholine and glucose on phospholipid metabolism in pancreatic islet cells prompted the comparison of their effects on ionic fluxes. Acetylcholine (1 PM) consistently increased 45Ca2+ efflux from mouse islets, whereas glucose increased it in the presence, but decreased it in the absence of extracellular Ca 2+. Acetylcholine consistently accelerated *6Rb+ emux, and this effect was augmented by Ca2+ omission. On the other hand, glucose markedly inhibited *6Rb+ eftlux, except when its concentration was raised from 10 to 15 mM in the presence of Ca 2+. Unlike their effects on phospholipid metabolism, the ionic effects of the two insulin-secretagogues are thus very different.
Pancreatic islet Acetylcholine Glucose
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