Vanadium is a transitional element and a common constituent of the earth's crust. Two of the oxidative forms of this element, the tetravalent state vanadyl, and the pentavalent state vanadate, have been found to have insulinomimetic properties in experimental animals, isolated tissues and in cell preparations. When given orally, vanadate dramatically improves or normalizes blood glucose in virtually every animal model of diabetes mellitus which has been studied, including the streptozotocin diabetic rat and the BB rat (models of Type I diabetes) and obese hyperglycemic ob/ob and db/db mice (models of Type II diabetes). In a preliminary study of one patient with IDDM, we have found that oral vanadate given for a two week period increased insulin sensitivity by over 50% as assessed by a euglycemic, hyperinsulinernic clamp. Others have shown that vanadate can be administered orally to humans for up to 6 weeks without significant toxicity. The purpose of the present study is to test the efficacy and safety of sodium vanadate and vanadyl sulfate in glycemic control and, more importantly, on insulin sensitivity in insulin-dependent and noninsulin-dependent diabetes mellitus. Specifically, in these two populations we will: (1) Evaluate the effect of vanadate/vanadyl on diabetes control as assessed by daily blood glucose values, insulin requirements, glycosylated hemoglobin and fructosamine levels; (2) Quantitate insulin sensitivity in a two step euglycemic, hyperinsulinemic clamp. In addition, hepatic glucose production, substrate oxidation and energy expenditure will be measured; and the effect non-glucose pathways of insulin action including ion flux, amino acid and lipid metabolism assessed. Changes in insulin secretion will be evaluated with a hyperglycemic clamp; (3) Assess the potential mechanism(s) of vanadyl/vanadate effects by measuring several insulin sensitive enzymes, including phosphotyrosine phosphatases, 56 kinase and MAP kinase, using circulating mononuclear leukocytes; (4) Evaluate potential toxicity including risk of hypoglycemia, depression of appetite, alterations in blood pressure, and measurements of bone marrow, liver, kidney, and thyroid function; and (5) Evaluate the potential toxicity at the molecular level as measured by effects on sodium-proton exchange and mRNA levels of the proto-oncogenes c-myc and c-fos. These studies will provide critical insights into the efficacy and safety of vanadium salts as potential therapeutic agents in the treatment of humans with IDDM and NIDDM.
