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.