BACKGROUND Serum thioredoxin of type-2 diabetic patients is significantly higher than that of healthy people. Pathophysiological significance is unclear. METHODS Effects of serum/extracellular thioredoxin on phosphorylation (activation) of hepatic insulin receptor (IR) were investigated by using methods in biochemistry, cell/molecular biology and mass spectrometry. RESULTS In human serum, thioredoxin and insulin may interact. Their mixture contains a mixed disulfide between insulin B-chain and thioredoxin-Cys73, which limits their activities. In contrast, free form of serum/extracellular thioredoxin is active, and can regulate phosphorylation of insulin receptor β-subunits (IRβ) via direct/indirect mechanisms. The direct mechanism associates with positive regulation. Serum/extracellular thioredoxin increases insulin binding to IR, facilitating insulin-induced phosphorylation of IRβ and downstream AKT. The indirect mechanism is involved in negative regulation. Entry of extracellular thioredoxin into hepatic cells via IR enhances the expression and activity of cellular protein-tyrosine phosphatase 1B (PTP1B), which negatively regulates IRβ phosphorylation. After coordination between these two mechanisms, the positive impact of serum/extracellular thioredoxin overwhelms its negative impact on IRβ phosphorylation, which subsequently accelerates hepatic glucose uptake. In hepatic cells with thioredoxin deficiency, insulin-induced IRβ phosphorylation is decreased, which could be restored by extracellular thioredoxin entry. Moreover, the results from assaying 475 serum samples demonstrate a discriminating value of serum thioredoxin activity in diagnosing type-2 diabetes. CONCLUSION Serum/extracellular thioredoxin plays a critical role in regulating hepatic IRβ phosphorylation. GENERAL SIGNIFICANCE In case of insulin resistance/type-2 diabetes, hepatic IRβ is at low phosphorylation level, thereby the improvement effect of serum/extracellular thioredoxin on insulin-induced IRβ phosphorylation seems particularly important.

中文翻译：

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血清/细胞外硫氧还蛋白在调节肝胰岛素受体激活中的新见解。

背景技术2型糖尿病患者的血清硫氧还蛋白明显高于健康人。病理生理学意义尚不清楚。方法采用生物化学，细胞/分子生物学和质谱等方法研究血清/细胞外硫氧还蛋白对肝胰岛素受体（IR）磷酸化（活化）的影响。结果在人血清中，硫氧还蛋白和胰岛素可能相互作用。它们的混合物在胰岛素B链和硫氧还蛋白-Cys73之间含有混合的二硫键，这限制了它们的活性。相反，游离形式的血清/细胞外硫氧还蛋白具有活性，并且可以通过直接/间接机制调节胰岛素受体β亚基（IRβ）的磷酸化。直接机制与积极监管相关。血清/细胞外硫氧还蛋白增加了胰岛素与IR的结合，促进胰岛素诱导的IRβ和下游AKT的磷酸化。间接机制涉及负面调节。胞外硫氧还蛋白通过IR进入肝细胞可增强细胞蛋白酪氨酸磷酸酶1B（PTP1B）的表达和活性，从而负调控IRβ磷酸化。在这两种机制之间进行协调之后，血清/细胞外硫氧还蛋白的正向作用抵消了其对IRβ磷酸化的负向影响，继而加速了肝脏对葡萄糖的摄取。在硫氧还蛋白缺乏症的肝细胞中，胰岛素诱导的IRβ磷酸化减少，这可以通过细胞外硫氧还蛋白的进入来恢复。此外，从475个血清样品中检测的结果证明了血清硫氧还蛋白活性在诊断2型糖尿病方面具有鉴别价值。结论血清/细胞外硫氧还蛋白在调节肝IRβ磷酸化中起关键作用。一般意义在胰岛素抵抗/ 2型糖尿病的情况下，肝IRβ处于低磷酸化水平，因此改善血清/细胞外硫氧还蛋白对胰岛素诱导的IRβ磷酸化的改善作用显得尤为重要。