VANADATE NORMALIZES HYPERGLYCEMIA IN 2 MOUSE MODELS OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS
VANADATE NORMALIZES HYPERGLYCEMIA IN 2 MOUSE MODELS OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS
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DOI：
10.1172/jci115131
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发表时间：
1991-04-01
影响因子：
15.9
通讯作者：
KAHN, CR
中科院分区：
文献类型：
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作者：
MEYEROVITCH, J;ROTHENBERG, P;KAHN, CR
我们研究了在两种非胰岛素依赖型糖尿病（NIDDM）高胰岛素啮齿动物模型中，口服vanadate（一种胰岛素抑制剂和一种有效的磷酸酪氨酸蛋白磷酸酶（PTPase）抑制剂）对血糖和PTPase作用的影响。口服钒酸盐（饮用水中0.25 mg/ml）给ob/ob小鼠3周后，血糖水平从236 +/- 4降至143 +/- 2 mg/dl，对体重没有影响。给db/db小鼠服用钒酸盐也产生了类似的效果。治疗47 d后，电镜检查未见肝毒性迹象。在体内刺激后，用抗磷酸酪氨酸抗体进行免疫印迹检测，胰岛素受体自身磷酸化水平略有降低，ob/ob小鼠胰岛素受体内源性底物pp185的磷酸化水平明显降低。通过对胰岛素受体自磷酸化主要位点对应的P-32标记肽的去磷酸化测量，ob/ob小鼠肝脏的胞浆和颗粒PTPase活性均下降了约50% （P < 0.01）。在db/db糖尿病小鼠中，胞浆部分PTPase活性降低至对照组的53% (P < 0.02)，颗粒PTPase活性无显著差异。在ob/ob小鼠中，尽管钒酸盐对血糖有显著影响，但在体外实验中，它并没有改变肝脏PTPase活性，也没有改变体内实验中受体和底物磷酸化。这些数据表明，在NIDDM状态下，钒酸盐是一种有效的口服降糖药物，并表明其主要作用发生在远端胰岛素受体酪氨酸激酶。
We have studied the effects of oral administration of vanadate, an insulinometic agent and a potent inhibitor of phosphotyrosyl protein phosphatase (PTPase) in vitro, on blood glucose and PTPase action, in two hyperinsulinemic rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Oral administration of vanadate (0.25 mg/ml in the drinking water) to ob/ob mice for 3 wk lowered blood glucose level from 236 +/- 4 to 143 +/- 2 mg/dl without effect on body weight. Administration of vanadate to db/db mice produced a similar effect. Electron microscopic examination revealed no signs of hepatotoxicity after 47 d of treatment.There was a slight reduction in insulin receptor autophosphorylation when tested by immunoblotting with antiphosphotyrosine antibody after in vivo stimulation, and the phosphorylation of the endogenous substrate of the insulin receptor, pp185, was markedly decreased in the ob/ob mice. Both cytosolic and particulate PTPase activities in liver of ob/ob mice measured by dephosphorylation of a P-32-labeled peptide corresponding to the major site of insulin receptor autophosphorylation were decreased by approximately 50% (P < 0.01). In db/db diabetic mice, PTPase activity in the cytosolic fraction was decreased to 53% of control values (P < 0.02) with no significant difference in the particulate PTPase activity. Treatment with vanadate did not alter hepatic PTPase activity as assayed in vitro, or receptor and substrate phosphorylation as assayed in vivo, in ob/ob mice despite its substantial effect on blood glucose. These data indicate that vanadate is an effective oral hypoglycemic treatment in NIDDM states and suggest that its major effects occurs distal to the insulin receptor tyrosine kinase.