Amelioration of insulin resistance in diabetic ob/ob mice by a new type of orally active insulin-mimetic vanadyl complex: bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) with VO(S(2)O(2)) coordination mode.

Abstract

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 insulin-mimetic in treating streptozotocin-induced diabetes in rats, with long-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 levels of glucose, insulin and triglyceride in blood. VO(opt)(2) was also effective in ameliorating impaired glucose tolerance in ob/ob mice, when an oral glucose tolerance test was performed after treatment with VO(opt)(2). Tumor necrosis factor-alpha (TNF-alpha) is a key component of obesity-diabetes link, we therefore examined the attenuating effect of VO(opt)(2) on impaired insulin signal transduction induced by TNF-alpha. Elevated expression of TNF-alpha was observed in the epididymal and subcutaneous fat tissues of ob/ob mice. Incubation of 3T3-L1, mouse adipocytes, with TNF-alpha reduced the phosphorylation of insulin receptor substrate-1 (IRS-1), whereas VO(opt)(2) treatment resulted in an enhancement of IRS-1 phosphorylation, irrespective of the presence or absence of TNF-alpha. Overall, the present study demonstrates that VO(opt)(2) exerts an anti-diabetic effect in ob/ob mice by ameliorating impaired glucose tolerance, and furthermore, attenuates the TNF-alpha-induced decrease in IRS-1 phosphorylation in adipocytes. These results suggest that the anti-diabetic action of VO(opt)(2) is derived from an attenuation of a TNF-alpha induced impaired insulin signal transduction via inhibition of protein tyrosine phosphatase, providing a potential clinical utility for VO(opt)(2) in the treatment of NIDDM.

• Authors: S Takeshita, I Kawamura, T Yasuno, C Kimura, T Yamamoto, J Seki, A Tamura, H Sakurai, T Goto
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 85 Issue 2-3 Pg. 179-86 (Jun 2001) ISSN: 0162-0134 [Print] United States
• PMID: 11410238 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Insulin
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Irs1 protein, rat
• Leptin
• Organometallic Compounds
• Phosphoproteins
• Triglycerides
• Tumor Necrosis Factor-alpha
• bis(1-oxy-2-pyridinethiolato)oxovanadium(IV)
• oxovanadium IV
• Vanadates

Topics

• 3T3 Cells
• Adipose Tissue (drug effects, metabolism)
• Administration, Oral
• Animals
• Blood Glucose (drug effects)
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Insulin (blood)
• Insulin Receptor Substrate Proteins
• Insulin Resistance (genetics)
• Kinetics
• Leptin (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Organometallic Compounds (administration & dosage, pharmacology)
• Phosphoproteins (metabolism)
• Phosphorylation (drug effects)
• Triglycerides (blood)
• Tumor Necrosis Factor-alpha (drug effects, metabolism)
• Vanadates (administration & dosage, pharmacology)