Add time:09/02/2019         Source:sciencedirect.com

We used MK-912, a potent new selective α2-adrenergic receptor antagonist that is active orally, to study the effect of short-term, selective α2-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 α2-adrenergic blockade was apparently achieved, as there were substantial increases of plasma norepinephrine (NE) (P < .01) and both systolic blood pressure (SBP) (P < .01) and diastolic blood pressure (DBP) (P < .05) after treatment with MK-912, but not after placebo. MK-912 caused a significant (P < .05) although modest decrease of FPG that was associated with a small increase of fasting plasma insulin (P < 0.01), C-peptide (P < .05), and glucagon (P < .01). FPG and hormone levels remained unchanged after placebo. MK-912 tended to increase the AIR (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 < .05, ANOVA). These studies indicate that MK-912 causes (1) sympathetic activation consistent with effective α2-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 α2-adrenergic tone may contribute, although to a small extent, to the impaired B-cell function in NIDDM. If an α2-blocker becomes available that does not increase BP, studies would be warranted to evaluate its potential impact on glucose regulation in patients with NIDDM.

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