Amelioration of insulin resistance in diabetic ob/ob mice by a new type oforally active insulin-mimetic vanadyl complex: Bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) with VO(S2O2) coordination mode

Recently, we have shown that a newly synthesized vanadyl complex, bis(1-oxy -2-pyridinethiolato)oxovanadium(IV) VO(opt)(2), is a potent orally active i nsulin-mimetic in treating streptozotocin-induced diabetes in rats, with lo ng-term action. In the present study, the anti-diabetic effect of VO(opt)(2 ) and its mechanism in ob/ob mice, an obese non-insulin-dependent diabetes mellitus (NIDDM) animal model, was investigated. In ob/ob mice, 15-day oral treatment with VO(opt)(2) resulted in a dose-dependent decrease in the lev els of glucose, insulin and triglyceride in blood. VO(opt)(2) was also effe ctive in ameliorating impaired glucose tolerance in ob/ob mice, when an ora l glucose tolerance test was performed after treatment with VO(opt)(2). Tum or necrosis factor-alpha (TNF-alpha) is a key component of obesity-diabetes link, we therefore examined the attenuating effect of VO(opt)(2) on impair ed insulin signal transduction induced by TNF-alpha. Elevated expression of TNF-alpha was observed in the epididymal and subcutaneous fat tissues of o b/ob mice. Incubation of 3T3-L1, mouse adipocytes, with TNF-alpha reduced t he phosphorylation of insulin receptor substrate-1 (IRS-1), whereas VO(opt) (2) treatment resulted in an enhancement of IRS-1 phosphorylation, irrespec tive of the presence or absence of TNF-alpha. Overall, the present study de monstrates that VO(opt)(2) exerts an anti-diabetic effect in ob/ob mice by ameliorating impaired glucose tolerance, and furthermore, attenuates the TN F-alpha -induced decrease in IRS-1 phosphorylation in adipocytes. These res ults suggest that the anti-diabetic action of VO(opt)(2) is derived from an attenuation of a TNF-alpha induced impaired insulin signal transduction vi a inhibition of protein tyrosine phosphatase, providing a potential clinica l utility for VO(opt)(2) in the treatment of NIDDM. (C) 2001 Elsevier Scien ce B.V. All rights reserved.