Effect of an oral [alpha]2-adrenergic blocker (MK-912) on pancreatic islet function in non-insulin-dependent diabetes mellitus

Abstract

We used MK-912, a potent new selective [alpha]2-adrenergic receptor antagonist that is active orally, to study the effect of short-term, selective [alpha]2-blockade on fasting plasma glucose (FPG) and pancreatic islet function in non-insulin-dependent diabetes (NIDDM). Ten asymptomatic patients with NIDDM received either a single oral dose of MK-912 (2 mg) or placebo in a double-blind, cross-over study. B-cell function was measured by the acute insulin response (AIR) to glucose (1.66 mmol/kg intravenously [IV]) and by the AIR to arginine (5 g IV) during a hyperglycemic glucose clamp at a mean glucose level of 32.1 mmol/L to provide an estimation of maximal B-cell secretory capacity. A-cell function was estimated by the acute glucagon response (AGR) to arginine during the glucose clamp. Effective [alpha]2-adrenergic blockade was apparently achieved, as there were substantial increases of plasma norepinephrine (NE) (P P P P P P P P = .06) and the C-peptide response (P = .07) to glucose compared with placebo. There was a small, but significant, overall treatment effect for both the AIR and AGR to arginine with MK-912 (both P 2-adrenergic blockade; (2) a small decrease of FPG and a small increase of fasting plasma insulin; (3) a small improvement of B-cell function due to an increase in maximal B-cell secretory capacity; and (4) a small increase in basal and stimulated glucagon. These findings suggest that endogenous [alpha]2-adrenergic tone may contribute, although to a small extent, to the impaired B-cell function in NIDDM. If an [alpha]2-blocker becomes available that does not increase BP, studies would be warranted to evaluate its potential impact on glucose regulation in patients with NIDDM.