New insights into serum/extracellular thioredoxin in regulating hepatic insulin receptor activation.

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.

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