Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.

中文翻译：

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可溶性 SorCS1 结合胰岛素受体以增强胰岛素敏感性

2 型糖尿病已达到流行程度，对受影响的患者和社会来说是一个沉重的负担。除了生活方式因素外，还发现了一些易患 2 型糖尿病的基因位点，包括SORCS1编码跨膜受体 SorCS1。SorCS1 (sol-SorCS1) 的胞外域从质膜脱落，但该片段的生物学功能尚不清楚。在这里，我们显示 sol-SorCS1 作为胰岛素受体的高亲和力结合伙伴，以稳定受体并增加胰岛素亲和力、蛋白激酶 B 激活和肌细胞中的葡萄糖摄取。Sol-SorCS1 从脂肪细胞中释放出来，在糖尿病患者中，血浆浓度与体重指数正相关，但与血糖成反比。在胰岛素抵抗的小鼠模型中，外源性 sol-SorCS1 恢复了胰岛素敏感性。我们得出结论，sol-SorCS1 增加了外周胰岛素敏感性，并提出 sol-SorCS1 作为一种新型胰岛素增敏脂肪因子和潜在的抗糖尿病药物。