title: 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.
authors.affiliation: Department of Endocrinology and Chemical Pathology, United Medical School, Guy's Hospital, London, United Kingdom.
authors.forename: J K
authors.initials: JK
authors.lastname: Powrie
authors.forename: G D
authors.initials: GD
authors.lastname: Smith
authors.forename: F
authors.initials: F
authors.lastname: Shojaee-Moradie
authors.forename: P H
authors.initials: PH
authors.lastname: Sönksen
authors.forename: R H
authors.initials: RH
authors.lastname: Jones
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D002738:Chloroquine / Q000494:pharmacology*; D003903:Deuterium; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000378:metabolism; D005215:Fasting; D005260:Female; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011865:Radioisotope Dilution Technique
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D002738:Chloroquine; D003903:Deuterium; D005947:Glucose