Insulin-mimetic effects of vanadate. Possible implications for future treatment of diabetes.
Vanadate ions, low-molecular-weight phosphate analogues, mimic most of the rapid actions of insulin in various cell types. When administered orally to diabetic hyperglycemic rats, vanadate reaches the circulation, mimics insulin stimulation of glucose uptake and metabolism, and leads to normoglycemic and partial anabolic states. In addition, vanadate restores tissue responsiveness to insulin and hepatic glycogen levels and activates new synthesis of key enzymes for carbohydrate metabolism. This suggests that correcting hyperglycemia is sufficient to correct the typical metabolic alterations found in streptozocin-induced diabetic rats. Several weeks of oral administration of vanadate to diabetic rats has not produced detectable liver or kidney toxicity. The mechanism by which vanadate mimics the actions of insulin is still obscure. Unlike insulin, vanadate does not seem to stimulate the autophosphorylation and endogenous tyrosine phosphorylation of insulin-receptor kinase or other intracellular proteins either directly or by virtue of its known inhibitory effect on protein phosphotyrosine phosphatase. Results from many studies support a model in which vanadate activates glucose metabolism by either utilizing an alternative (insulin-independent) cascade or bypassing the early events of the insulin-dependent cascade. Either of these possibilities is of clinical importance, because early insulin events may become defective, as a result of severe hyperinsulinemia, and may contribute to insulin resistance. Alternative pathways by which vanadate may stimulate glucose metabolism, e.g., by increasing intracellular Ca2+ levels and/or regulating intracellular and intravesicular pH, are discussed. From a clinical perspective, studies should be continued in evaluating the level of vanadate toxicity after prolonged treatment and searching for agents that potentiate its insulin mimetic actions in vitro and in vivo.
Department of Hormone Research, Weizmann Institute of Science, Rehovot, Israel.
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Shechter
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D006801:Humans; D007328:Insulin / Q000502:physiology* / Q000627:therapeutic use; D009004:Monosaccharide Transport Proteins / Q000502:physiology; D014638:Vanadates / Q000627:therapeutic use* / Q000633:toxicity
D007328:Insulin; D009004:Monosaccharide Transport Proteins; D014638:Vanadates