Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus

Abstract

Clinical studies have demonstrated that chloroquine and hydroxychloroquine improve glucose metabolism in patients with insulin-resistant diabetes mellitus. The mechanism of action has not been determined. We undertook a randomized double-blind placebo-controlled trial of 3 days of oral chloroquine phosphate, 250 mg four times daily, in 20 patients with non-insulin-dependent diabetes mellitus controlled by diet. Rates of glucose appearance (Ra) and disappearance (Rd) were evaluated by infusion of stable isotopically labeled D-glucose ([6,6-2H2]glucose) during hyperinsulinemic euglycemic clamps before and after treatment with chloroquine or placebo. Chloroquine significantly improved fasting plasma glucose from 199.8 +/- 8.6 to 165.6 +/- 7.6 mg/dl (P less than 0.01). Total exogenous glucose infusion required to maintain euglycemia significantly increased (1,792.6-2,040.1 mg.kg-1.330 min-1, P less than 0.05) due to an increase in Rd (2,348.0-2,618.9 mg.kg-1.330 min-1, P less than 0.01) without change in Ra. Metabolic clearance rate of insulin decreased by 39% from 14.4 +/- 1.3 to 11.0 +/- 0.6 ml.kg-1.min-1 (P less than 0.01) at plasma insulin levels of 150-200 mU/l but not at levels of 2,000-3,000 mU/l. In addition, chloroquine increased fasting C-peptide secretion by 17% and reduced feedback inhibition of C-peptide by 9.1 and 10.6% during low- and high-dose insulin infusions, respectively.