Enhanced sensitivity of insulin-resistant adipocytes to vanadate is associated with oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4).

作者: Bing Lu , David Ennis , Robert Lai , Elena Bogdanovic , Rinna Nikolov

DOI: 10.1074/JBC.M106783200

关键词:

摘要: Vanadate (sodium orthovanadate), an inhibitor of phosphotyrosine phosphatases (PTPs), mimics many the metabolic actions insulin in vitro and vivo. The potential vanadate to stimulate glucose transport independent early steps signaling prompted us test its effectiveness model resistance. In primary rat adipocytes cultured for 18 h presence high (15 mm) (10(-7) m), sensitivity insulin-stimulated was decreased. contrast, there a paradoxical enhanced insulin-resistant cells (EC(50) control, 325 +/- 7.5 microm; EC(50) insulin-resistant, 171 32 p < 0.002). Enhanced also present stimulation receptor kinase activity autophosphorylation Akt/protein B Ser-473 phosphorylation consistent with more effective PTP inhibition resistant cells. Investigation this phenomenon revealed that 1) depletion GSH buthionine sulfoximine reproduced while preincubation N-acetylcysteine (NAC) prevented it, 2) intracellular decreased normalized by NAC, 3) exposure induced increase reactive oxygen species, which 4) EPR (electron paramagnetic resonance) spectroscopy showed amount vanadyl (+4) sulfoximine-treated cells, correlated increased sensitivity, total vanadium uptake not altered, 5) recombinant PTP1B sensitive (+5) than (+4). conclusion, hyperglycemia-induced is due oxidative stress reduction Thus, regulated cellular redox state.

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