Cusi K, Cukier S, DeFronzo R A, Torres M, Puchulu F M, Redondo J C
University of Texas Health Science Center, San Antonio, Texas 78284, USA.
J Clin Endocrinol Metab. 2001 Mar;86(3):1410-7. doi: 10.1210/jcem.86.3.7337.
Vanadyl sulfate (VOSO(4)) is an oxidative form of vanadium that in vitro and in animal models of diabetes has been shown to reduce hyperglycemia and insulin resistance. Small clinical studies of 2- to 4-week duration in type 2 diabetes (T2DM) have led to inconsistent results. To define its efficacy and mechanism of action, 11 type 2 diabetic patients were treated with VOSO(4) at a higher dose (150 mg/day) and for a longer period of time (6 weeks) than in previous studies. Before and after treatment we measured insulin secretion during an oral glucose tolerance test, and endogenous glucose production (EGP) and whole body insulin-mediated glucose disposal using the euglycemic insulin clamp technique combined [3-(3)H]glucose infusion. Treatment significantly improved glycemic control: fasting plasma glucose (FPG) decreased from 194 +/- 16 to 155 +/- 15 mg/dL, hemoglobin A(1c) decreased from 8.1 +/- 0.4 to 7.6 +/- 0.4%, and fructosamine decreased from 348 +/- 26 to 293 +/- 12 micromol/L (all P < 0.01) without any change in body weight. Diabetics had an increased rate of EGP compared with nondiabetic controls (4.1 +/- 0.2 vs. 2.7 +/- 0.2 mg/kg lean body mass.min; P< 0.001), which was closely correlated with FPG (r = 0.56; P< 0.006). Vanadyl sulfate reduced EGP by about 20% (P< 0.01), and the decline in EGP was correlated with the reduction in FPG (r = 0.60; P< 0.05). Vanadyl sulfate also caused a modest increase in insulin-mediated glucose disposal (from 4.3 +/- 0.4 to 5.1 +/- 0.6 mg/kg lean body mass x min; P< 0.03), although the improvement in insulin sensitivity did not correlate with the decline in FPG after treatment (r = -0.16; P = NS). Vanadyl sulfate treatment lowered the plasma total cholesterol (223 +/- 14 vs. 202 +/- 16 mg/dL; P < 0.01) and low density lipoprotein cholesterol (141 +/- 14 vs. 129 +/- 14 mg/dL; P < 0.05), whereas 24-h ambulatory blood pressure was unaltered. We conclude that VOSO(4) at maximal tolerated doses for 6 weeks improves hepatic and muscle insulin sensitivity in T2DM. The glucose-lowering effect of VOSO(4) correlated well with the reduction in EGP, but not with insulin-mediated glucose disposal, suggesting that liver, rather than muscle, is the primary target of VOSO(4) action at therapeutic doses in T2DM.
硫酸氧钒（VOSO₄）是钒的一种氧化形式，在糖尿病的体外及动物模型研究中已显示其可降低高血糖和胰岛素抵抗。在2型糖尿病（T2DM）患者中进行的为期2至4周的小型临床研究结果并不一致。为明确其疗效及作用机制，我们对11例2型糖尿病患者采用了比以往研究更高的剂量（150毫克/天）和更长的疗程（6周）进行硫酸氧钒治疗。治疗前后，我们通过口服葡萄糖耐量试验测量胰岛素分泌，并采用正常血糖胰岛素钳夹技术结合[³H]葡萄糖输注来测量内源性葡萄糖生成（EGP）及全身胰岛素介导的葡萄糖处置。治疗显著改善了血糖控制：空腹血糖（FPG）从194±16降至155±15毫克/分升，糖化血红蛋白A₁c从8.1±0.4降至7.6±0.4%，果糖胺从348±26降至293±12微摩尔/升（均P<0.01），且体重未发生任何变化。与非糖尿病对照组相比，糖尿病患者的EGP速率升高（4.1±0.2对2.7±0.2毫克/千克去脂体重·分钟；P<0.001），这与FPG密切相关（r = 0.56；P<0.006）。硫酸氧钒使EGP降低约20%（P<0.01），EGP的下降与FPG的降低相关（r = 0.60；P<0.05）。硫酸氧钒还使胰岛素介导的葡萄糖处置略有增加（从4.3±0.4增至5.1±0.6毫克/千克去脂体重×分钟；P<0.03），尽管治疗后胰岛素敏感性的改善与FPG的下降不相关（r = -0.16；P = 无显著性差异）。硫酸氧钒治疗降低了血浆总胆固醇（223±14对202±16毫克/分升；P < 0.01）和低密度脂蛋白胆固醇（141±14对129±14毫克/分升；P < 0.05），而24小时动态血压未改变。我们得出结论，在最大耐受剂量下给予硫酸氧钒6周可改善T2DM患者肝脏和肌肉的胰岛素敏感性。硫酸氧钒的降糖作用与EGP的降低密切相关，但与胰岛素介导的葡萄糖处置无关，这表明在T2DM治疗剂量下，肝脏而非肌肉是硫酸氧钒作用的主要靶点。
