Diazoxide-mediated insulin suppression in obese men: a dose-response study

Area of Science:

• Pharmacology
• Endocrinology
• Metabolic Disorders

Background:

• Diazoxide (DZX) is investigated for its potential to suppress insulin and promote weight loss in obese individuals.
• Hyperinsulinemia in obese subjects necessitates exploring effective insulin-suppressing agents.

Purpose of the Study:

• To determine a safe and effective dose range of diazoxide (DZX) for obese, hyperinsulinemic men.
• To compare the efficacy and safety of DZX in obese versus non-obese individuals.

Main Methods:

• Open-label study in non-obese men to assess DZX efficacy.
• Double-blind, placebo-controlled trial in obese men using DZX doses of 50, 75, and 100 mg thrice daily for 6 days.
• Evaluation of plasma glucose and insulin responses to a standardized breakfast on day 6 of treatment.

Main Results:

• In non-obese men, DZX (50-100 mg) dose-dependently reduced peak insulin levels and increased peak glucose levels.
• In obese men, DZX doses of 50 and 75 mg showed no significant effects on glucose or insulin.
• DZX 100 mg reduced peak insulin by ~20% in obese men, but fasting/postprandial glucose remained unaffected. Obese subjects exhibited ~30% lower plasma DZX levels than non-obese subjects at comparable doses, attributed to weight-dependent distribution.
• Plasma DZX levels were significantly correlated with dose (p < 0.001) and body weight (p < 0.001).

Conclusions:

• Diazoxide-mediated insulin suppression is dose-dependent but significantly less effective in obese individuals compared to non-obese individuals.
• Lower plasma DZX levels in obese subjects, due to increased distribution volume, limit its efficacy.
• Weight-adjusted DZX doses, estimated at 3.2-4.2 mg/kg daily, are required to achieve effective insulin suppression in obese men.