Genetic association studies have implicated that cartilage intermediate layer protein 2 (CILP-2) confers the risk susceptibility for type 2 diabetes (T2DM). However, it is still unknown whether CILP-2 is involved in the regulation of glucose homeostasis and insulin resistance (IR). In the current study, we initially observed that CILP-2 as a secreted protein was detected in both conditioned medium and lysates of cells transfected with an overexpressed vector. We then found that circulating CILP-2 levels had a progressive increase from normal to impaired glucose tolerance (a pre-diabetic status) and then to diabetes, which was correlated positively with waist-to-hip ratio, triglyceride, fasting blood glucose, 2-h blood glucose after glucose overload, HbA1c, fasting insulin, 2-h plasma insulin after glucose overload, and homeostasis model assessment of insulin resistance but negatively with HDL-C. CILP-2 expression was increased in the liver and muscle but decreased in adipose tissues of obese mice or T2DM patients. Furthermore, we demonstrated that CILP-2 circulating levels were affected by OGTT and Exenatide. CILP-2 overexpression resulted in impaired glucose tolerance and hepatic IR in vivo and increased PEPCK expression whereas suppressed phosphorylation of insulin receptor and Akt kinase in vitro. Based on these findings, we have identified a direct interaction between CILP-2 and PEPCK and suggested that CILP-2 plays an important role in the regulation of hepatic glucose production.

中文翻译：

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CILP-2是一种新型的分泌蛋白，与胰岛素抵抗有关。

遗传关联研究表明，软骨中间层蛋白2（CILP-2）具有2型糖尿病（T2DM）的易感性。但是，尚不清楚CILP-2是否参与葡萄糖稳态和胰岛素抵抗（IR）的调节。在当前的研究中，我们最初观察到在条件培养基和用过表达载体转染的细胞的裂解物中均检测到CILP-2作为分泌蛋白。然后，我们发现循环中的CILP-2水平从正常到葡萄糖耐量降低（糖尿病前状态），然后再到糖尿病逐渐升高，这与腰臀比，甘油三酸酯，空腹血糖2呈正相关。葡萄糖超负荷后的-h血糖，HbA1c，空腹胰岛素，葡萄糖超负荷后的2-h血浆胰岛素，和稳态模型评估胰岛素抵抗，但对HDL-C不利。肥胖小鼠或T2DM患者的肝脏和肌肉中CILP-2表达增加，但脂肪组织中CILP-2表达减少。此外，我们证明了CIG-2循环水平受OGTT和艾塞那肽的影响。CILP-2过表达导致体内葡萄糖耐量降低和肝IR降低，PEPCK表达增加，而体外胰岛素受体和Akt激酶的磷酸化受到抑制。基于这些发现，我们已经确定了CILP-2和PEPCK之间的直接相互作用，并建议CILP-2在调节肝葡萄糖产生中起重要作用。此外，我们证明了CIG-2循环水平受OGTT和艾塞那肽的影响。CILP-2过表达导致体内葡萄糖耐量降低和肝IR降低，PEPCK表达增加，而体外胰岛素受体和Akt激酶的磷酸化受到抑制。基于这些发现，我们已经确定了CILP-2和PEPCK之间的直接相互作用，并建议CILP-2在调节肝葡萄糖产生中起重要作用。此外，我们证明了CIG-2循环水平受OGTT和艾塞那肽的影响。CILP-2过表达导致体内葡萄糖耐量降低和肝IR降低，PEPCK表达增加，而体外胰岛素受体和Akt激酶的磷酸化受到抑制。基于这些发现，我们已经确定了CILP-2和PEPCK之间的直接相互作用，并建议CILP-2在调节肝葡萄糖产生中起重要作用。