Glucose lowering activity by oral administration of bis(allixinato)oxidovanadium(iv) complex in streptozotocin-induced diabetic mice and gene expression profiling in their skeletal muscles

Abstract

Vanadyl(iv) complexes are anti-diabetogenic agents. Intra-peritoneal administration of bis(allixinato)oxidovanadium(iv) [VO(alx)2] lowers high blood glucose levels in animal models of type 1 and type 2 diabetes. We have examined whether oral administration of VO(alx)2 restores impaired activation in signaling cascades related to glucose metabolism and insulin action, and alters gene expression in the skeletal muscles of streptozotocin (STZ)-induced diabetic mice (STZ-diabetic mice). We report here that daily oral administration of VO(alx)2 lowered high blood glucose levels in the STZ-diabetic mice. The oral administration of VO(alx)2 enhanced phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), located downstream of the insulin receptor cascade in the skeletal muscles. We analyzed gene expression in the muscles of the diabetic mice before and after insulin or VO(alx)2 treatment. Treating the diabetic mice with insulin or VO(alx)2 normalized the gene expression levels of 152 down-regulated and 11 up-regulated genes, and especially the up-regulation of Cyp2E1 and FoxO1 in the muscles of the diabetic mice. The insulin-mimetic effects of VO(alx)2 in the STZ-induced diabetic mice may be due to the enhancement of protein phosphorylation leading to the activation or inactivation of the transcriptional machinery. Our findings suggest that the insulin-mimetic effects of VO(alx)2 in diabetes may be due to changes in the protein phosphorylations and their gene expression levels. Orally administered VO(alx)2 complex exhibited blood glucose lowering effect in type 1-like diabetic mice and improved the impaired gene expression levels in diabetic states.