Powrie J K, Smith G D, Shojaee-Moradie F, Sönksen P H, Jones R H
Department of Endocrinology and Chemical Pathology, United Medical School, Guy's Hospital, London, United Kingdom.
Am J Physiol. 1991 Jun;260(6 Pt 1):E897-904. doi: 10.1152/ajpendo.1991.260.6.E897.
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.
临床研究表明，氯喹和羟氯喹可改善胰岛素抵抗型糖尿病患者的葡萄糖代谢。其作用机制尚未明确。我们进行了一项随机双盲安慰剂对照试验，对20名通过饮食控制的非胰岛素依赖型糖尿病患者口服磷酸氯喹3天，剂量为每日4次，每次250毫克。在使用氯喹或安慰剂治疗前后，通过在高胰岛素正常血糖钳夹期间输注稳定同位素标记的D-葡萄糖（[6,6-2H2]葡萄糖）来评估葡萄糖出现率（Ra）和消失率（Rd）。氯喹显著改善了空腹血糖，从199.8±8.6毫克/分升降至165.6±7.6毫克/分升（P<0.01）。由于Rd增加（从2,348.0-2,618.9毫克·千克-1·330分钟-1，P<0.01）而Ra不变，维持正常血糖所需的总外源性葡萄糖输注量显著增加（从1,792.6-2,040.1毫克·千克-1·330分钟-1，P<0.05）。在血浆胰岛素水平为150-200毫国际单位/升时，胰岛素的代谢清除率从14.4±1.3毫升·千克-1·分钟-1降至11.0±0.6毫升·千克-1·分钟-1，下降了39%（P<0.01），但在2,000-3,000毫国际单位/升水平时未出现此情况。此外，氯喹使空腹C肽分泌增加了17%，并分别在低剂量和高剂量胰岛素输注期间使C肽的反馈抑制降低了9.1%和10.6%。
