Diabetes-altered gene expression in rat skeletal muscle corrected by oral administration of vanadyl sulfate

Abstract

with vanadium, a representative of a class of antidiabetic compounds, alleviates diabetic hyperglycemia and hyperlipidemia. Oral administration of vanadium compounds in animal models and humans does not cause clinical symptoms of hypoglycemia, a common problem for diabetic patients with insulin treatment. Gene expression, using Affymetrix arrays, was examined in muscle from streptozotocin-induced diabetic and normal rats in the presence or absence of oral vanadyl sulfate treatment. This treatment affected normal rats differently from diabetic rats, as demonstrated by two-way ANOVA of the full array data. Diabetes altered the expression of 133 genes, and the expression of 30% of these genes dysregulated in diabetes was normalized by vanadyl sulfate treatment. For those genes, the ratio of expression in normal animals to the expression in diabetic animals showed a strong negative correlation with the ratio of expression in diabetic animals to the expression in diabetic animals treated with vanadyl sulfate (P ϭ Ϫ0.85). The genes identified belong to six major metabolic functional groups: lipid metabolism, oxidative stress, muscle structure, protein breakdown and biosynthesis, the complement system, and signal transduction. The identification of oxidative stress genes, coupled with the known oxidative chemistry of vanadium, implicates reactive oxygen species in the action of this class of compounds. These results imply that early transition metals or compounds formed from their chemical interactions with other metabolites may act as general transcription modulators, a role not usually associated with this class of compounds. vanadium; microarray; streptozotocin EARLY TRANSITION METALS and their complexes represent a unique class of antidiabetic agents. Specific lowering of diabetic hyperglycemia has been obtained by treatment with chromium (1, 13), tungsten (17), molybdenum (36, 50), and vanadium (V) compounds, with the later the most extensively studied. Although V was first used to treat diabetic patients in 1899 (33), the detailed mechanism of its antidiabetic action remains unclear. Inhibition of phosphotyrosine phosphatase (PTP)-1B is one mechanism by which V compounds may alleviate diabetic symptoms (16); however, alternative mechanisms could also be important contributors. Oral administration of V alleviates symptoms of diabetes in humans (9,14,15,23) and rodents (25, 35) without causing any clinical symptoms of hypoglycemia, although blood glucose levels are slightly lowered in normal animals by V treatment. This differential effect on normal (N) and diabetic (D) animals is seen with many other metabolic processes. For example, diabetic hyperlipidemia is significantly lowered by vanadyl sulfate (VS) treatment, whereas serum lipid levels in N animals are not substantially reduced by VS treatment (35). Given the importance of tight control of blood glucose levels in the diabetic patient, this class of compounds is a promising alternative for the treatment of diabetes.Various strategies are being explored to lo...

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