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.
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.
Takeshita
S
S
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
Kawamura
I
I
Yasuno
T
T
Kimura
C
C
Yamamoto
T
T
Seki
J
J
Tamura
A
A
Sakurai
H
H
Goto
T
T
D016475:3T3 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D007700:Kinetics; D020738:Leptin / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014638:Vanadates / Q000008:administration & dosage / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D020738:Leptin; D009942:Organometallic Compounds; D010750:Phosphoproteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C438939:bis(1-oxy-2-pyridinethiolato)oxovanadium(IV); C075743:oxovanadium IV; D014638:Vanadates