Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes

Vanadyl sulfate (VOSO4) is an oxidative form of vanadium that in vitro and in animal models of diabetes has been shown to reduce hyperglycemia and ins ulin resistance. Small clinical studies of 2- to 4-week duration in type 2 diabetes (T2DM) have led to inconsistent results. To define its efficacy an d mechanism of action, 11 type 2 diabetic patients were treated with VOSO4 at a higher dose (150 mg/day) and for a longer period of time (6 weeks) tha n in previous studies. Before and after treatment we measured insulin secre tion during an oral glucose tolerance test, and endogenous glucose producti on (EGP) and whole body insulin-mediated glucose disposal using the euglyce mic insulin clamp technique combined [3-H-3]glucose infusion. Treatment sig nificantly improved glycemic control: fasting plasma glucose (FPG) decrease d 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 mu mol/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 a bout 20% (P < 0.01), and the decline in EGP was correlated with the reducti on in FPG (r = 0.60; P < 0.05). Vanadyl sulfate also caused a modest increa se in insulin-mediated glucose disposal (from 4.3 +/- 0.4 to 5.1 +/- 0.6 mg /kg lean body mass min; P < 0.03), although the improvement in insulin sens itivity did not correlate with the decline in FPG after treatment (r = -0.1 6; P = NS). Vanadyl sulfate treatment lowered the plasma total cholesterol (223 +/- 14 vs. 202 +/- 16 mg/dL; P < 0.01) and low density lipoprotein cho lesterol(141 +/- 14 vs. 129 +/- 14 mg/dL; P < 0.05), whereas 24-h ambulator y blood pressure was unaltered. We conclude that VOSO4 at maximal tolerated doses for 6 weeks improves hepatic and muscle insulin sensitivity in T2DM. The glucose-lowering effect of VOSO4 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 VOSO4 action at therapeutic doses in T2DM.