This is a revised version of a competitive renewal of a two year pilot grant (R01-DK47462) to explore the potential utility of oral vanadium salts as an insulin sensitizing nutritional supplement in diabetes mellitus and other insulin resistant states. Vanadium is a transitional element. When given orally, vanadium salts can dramatically improve or normalize blood glucose in virtually every animal model of diabetes mellitus, and can also lower insulin and blood pressure in animal models of hypertension. In our preliminary studies oral sodium metavanadate (NaVO3) or vanadyl sulfate (VOSO4) treatment resulted in improved insulin sensitivity in humans with NIDDM and in some subjects with IDDM due primarily to increase non- oxidative metabolism. Increased basal activity of the insulin-sensitive S6 and MAP kinases in circulating mononuclear leukocytes was also demonstrated. NaVO3 lowered serum cholesterol levels in both groups. The purpose of the renewal is to perform longer term studies to test the efficacy and safety of vanadyl sulfate in glycemic control, insulin sensitivity, blood pressure and cholesterol in humans with NIDDM and other states of insulin resistance, including impaired glucose tolerance and hypertension, and controls. Specifically, we will evaluate the effect of oral vanadyl sulfate on: (1) diabetes control and insulin sensitivity, as assessed by a two step euglycemic, hyperinsulinemic clamp; (2) blood pressure, by use of 24 hour blood pressure monitoring and investigate potential mechanisms at the molecular level as effects on sodium-proton exchange and Na+/Li+ countertransport; (3) potential mechanism(s) of action by measuring several insulin sensitive cellular enzymes, including phosphotyrosine proteins, phosphotyrosine phosphatases, S6 kinase and MAP kinase using skeletal muscle biopsies: (4) potential toxicity at the clinical level, and at the molecular level as potential for tissue oxidative stress as well s mitogenic potential, assessed by mRNA levels of key proto-oncogenes; and (5) investigate the pharmacokinetics of oral vanadyl sulfate in human blood, serum and urine samples. These studies will provide critical insights into the efficacy and safety of vanadium salts as potential therapeutic agents ina the treatment of humans with a variety of insulin resistant states including NIDDM, impaired glucose tolerance, and hypertension.
