Shafrir E, Spielman S, Nachliel I, Khamaisi M, Bar-On H, Ziv E
Department of Biochemistry and Diabetes Research Unit, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):55-66. doi: 10.1002/1520-7560(2000)9999:9999<::aid-dmrr165>3.0.co;2-j.
Numerous investigations have demonstrated the beneficial effect of vanadium salts on diabetes in streptozotocin (STZ)-diabetic rats, in rodents with genetically determined diabetes and in human subjects. The amelioration of diabetes included the abolition of hyperglycemia, preservation of insulin secretion, reduction in hepatic glucose production, enhanced glycolysis and lipogenesis and improved muscle glucose uptake through GLUT4 elevation and translocation. The molecular basis of vanadium salt action is not yet fully elucidated. Although evidence has been provided that the insulin receptor is activated, the possibility exists that cytosolic non-receptor tyrosine kinase, direct phosphorylation of IRS-1 and activation of PI3-K, leading to GLUT4 translocation, are involved. The raised phosphorylation of proteins in the insulin signaling pathway appears to be related to the inhibition of protein tyrosine phosphatase (PTPase) activity by vanadium salts.
The model utilized in our study was Psammomys obesus (sand rat), a desert gerbil which becomes hyperglycemic and hyperinsulinemic on an ad libitum high energy (HE) diet. In contrast to the previously investigated insulin deficient models, vanadyl sulphate was used to correct insulin resistance and hyperinsulinemia, which led to beta-cell loss. Administration of 5 mg/kg vanadyl sulfate for 5 days resulted in prolonged restoration of normoglycemia and normoinsulinemia in most animals, return of glucose tolerance to normal, and a reduction of hepatic phosphoenolpyruvate carboxykinase activity. There was no change in food consumption and in regular growth during or after the vanadyl treatment. Pretreatment with vanadyl sulfate, followed by transfer to a HE diet, significantly delayed the onset of hyperglycemia. Hyperinsulinemic-euglycemic clamp of vanadyl sulfate treated Psammomys demonstrated an improvement in glucose utilization. However, vanadyl sulfate was ineffective when administered to animals which lost their insulin secretion capacity on protracted HE diet, but substantially reduced the hyperglycemia when given together with exogenous insulin. The in vitro insulin activation of liver and muscle insulin receptors isolated from vanadyl treated Psammomys was ineffective. The in vivo vanadyl treatment restored muscle GLUT4 total protein and mRNA contents in addition to membrane GLUT4 protein, in accordance with the increased glucose utilization during the clamp study. These results indicate that short-term vanadyl sulfate treatment corrects the nutritionally induced, insulin resistant diabetes. This action requires the presence of insulin for its beneficial effect. Thus, vanadyl action in P. obesus appears to be the result of insulin potentiation rather than mimicking, with activation of the signaling pathway proteins leading to GLUT4 translocation, probably distal to the insulin receptor.
大量研究已证实钒盐对链脲佐菌素（STZ）诱导的糖尿病大鼠、遗传性糖尿病啮齿动物及人类受试者的糖尿病具有有益作用。糖尿病的改善包括消除高血糖、保留胰岛素分泌、减少肝脏葡萄糖生成、增强糖酵解和脂肪生成，以及通过提高和转运葡萄糖转运蛋白4（GLUT4）改善肌肉对葡萄糖的摄取。钒盐作用的分子基础尚未完全阐明。尽管已有证据表明胰岛素受体被激活，但仍有可能涉及胞质非受体酪氨酸激酶、IRS-1的直接磷酸化和PI3-K的激活，从而导致GLUT4转运。胰岛素信号通路中蛋白质磷酸化水平的升高似乎与钒盐对蛋白质酪氨酸磷酸酶（PTPase）活性的抑制有关。
我们研究中使用的模型是肥尾沙鼠，一种沙漠沙鼠，在随意摄入高能量（HE）饮食时会出现高血糖和高胰岛素血症。与先前研究的胰岛素缺乏模型不同，硫酸氧钒用于纠正胰岛素抵抗和高胰岛素血症，后者会导致β细胞丢失。给予5mg/kg硫酸氧钒，持续5天，可使大多数动物的正常血糖和正常胰岛素血症得到长期恢复，葡萄糖耐量恢复正常，并降低肝脏磷酸烯醇式丙酮酸羧激酶活性。在硫酸氧钒治疗期间或之后，食物摄入量和正常生长均无变化。用硫酸氧钒预处理，然后改为HE饮食，可显著延迟高血糖的发生。对硫酸氧钒治疗的肥尾沙鼠进行高胰岛素-正常血糖钳夹实验，结果显示葡萄糖利用率有所提高。然而，当给因长期HE饮食而丧失胰岛素分泌能力的动物注射硫酸氧钒时，其无效，但与外源性胰岛素一起给药时，可显著降低高血糖。从硫酸氧钒处理的肥尾沙鼠分离的肝脏和肌肉胰岛素受体的体外胰岛素激活实验无效。体内硫酸氧钒治疗除了恢复膜GLUT4蛋白外，还恢复了肌肉GLUT4总蛋白和mRNA含量，这与钳夹实验期间葡萄糖利用率的增加一致。这些结果表明，短期硫酸氧钒治疗可纠正营养诱导的胰岛素抵抗性糖尿病。这种作用需要胰岛素的存在才能产生有益效果。因此，硫酸氧钒在肥尾沙鼠中的作用似乎是胰岛素增强的结果，而非模拟胰岛素，其通过激活信号通路蛋白导致GLUT4转运，可能在胰岛素受体的下游。
