Metabolic effects of vanadyl sulfate in humans with non-insulin-dependent diabetes mellitus: In vivo and in vitro studies

To investigate the efficacy and mechanism of action of vanadium salts as or al hypoglycemic agents, 16 type 2 diabetic patients were studied before and after 6 weeks of vanadyl sulfate (VOSO4) treatment at three doses. Glucose metabolism during a euglycemic insulin clamp did not increase at 75 mg/d, but improved in 3 of 5 subjects receiving 150 mg VOSO4 and 4 of 8 subjects receiving 300 mg VOSO4. Basal hepatic glucose production (HGP) and suppress ion of HGP by insulin were unchanged at all doses. Pasting glucose and hemo globin A(1c) (HbA(1c)) decreased significantly in the 150- and 300-mg VOSO4 groups. At the highest dose, total cholesterol decreased, associated with a decrease in high-density lipoprotein (HDL). There was no change in systol ic, diastolic, or mean arterial blood pressure on 24-hour ambulatory monito rs at any dose. There was no apparent correlation between the clinical resp onse and peak serum level of vanadium, the 150- and 300-mg vanadyl doses ca used some gastrointestinal intolerance but did not increase tissue oxidativ e stress as assessed by thiobarbituric acid-reactive substances (TBARS). In muscle obtained during clamp studies prior to vanadium therapy, insulin st imulated the tyrosine phosphorylation of the insulin receptor, insulin rece ptor substrate-1 (IRS-1), and Shc proteins by 2- to 3-fold, while phosphati dylinositol 3-kinase (PI B-kinase) activity associated with IRS-1 increased 4.7-fold during insulin stimulation (P = .02). Following vanadium, there w as a consistent trend for increased basal levels of insulin receptor, Shc, and IRS-1 protein tyrosine phosphorylation and IRS-l-associated PI 3-kinase , but no further increase with insulin, there was no discernible correlatio n between tyrosine phosphorylation patterns and glucose disposal responses to vanadyl. While glycogen synthase fractional activity increased 1.5-fold following insulin infusion, there was no change in basal or insulin-stimula ted activity after vanadyl. There was no increase in the protein phosphatas e activity of muscle homogenates to exogenous substrate after vanadyl. Vana dyl sulfate appears safe at these doses for 6 weeks, but at the tolerated d oses, it does not dramatically improve insulin sensitivity or glycemic cont rol. Vanadyl modifies proteins in human skeletal muscle involved in early i nsulin signaling, including basal insulin receptor and substrate tyrosine p hosphorylation and activation of PI 3-kinase, and is not additive or synerg istic with insulin at these steps. Vanadyl sulfate does not modify the acti on of insulin to stimulate glycogen synthesis. Since glucose utilization is improved in some patients, vanadyl must also act at other steps of insulin action. Copyright (C) 2000 by W.B. Saunders Company.