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Am J Physiol Endocrinol Metab 260: E897-E904, 1991;
0193-1849/91 $5.00
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AJP - Endocrinology and Metabolism, Vol 260, Issue 6 E897-E904, Copyright © 1991 by American Physiological Society

ARTICLES

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

J. K. Powrie, G. D. Smith, F. Shojaee-Moradie, P. H. Sonksen and R. H. Jones
Department of Endocrinology and Chemical Pathology, United Medical School, Guy's Hospital, London, United Kingdom.

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.


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