Increased interaction with insulin receptor substrate 1, a novel abnormality in insulin resistance and type 2 diabetes.
Increased interaction with insulin receptor substrate 1, a novel abnormality in insulin resistance and type 2 diabetes.
复制标题
作者：
Caruso M;Ma D;Msallaty Z;Lewis M;Seyoum B;Al-janabi W;Diamond M;Abou-Samra AB;Højlund K;Tagett R;Draghici S;Zhang X;Horowitz JF;Yi Z
胰岛素受体底物1（Insulin receptor substrate 1，IRS 1）是胰岛素信号转导的关键介质。涉及IRS 1复合物的扰动可能导致胰岛素抵抗和2型糖尿病（T2 D）的发展。令人惊讶的是，人们对健康和疾病条件下与IRS 1相互作用的蛋白质知之甚少。我们使用蛋白质组学方法评估了瘦健康对照受试者（LC）、肥胖胰岛素抵抗非糖尿病对照受试者（OC）以及胰岛素输注前后T2 D受试者骨骼肌中的IRS 1相互作用伙伴。我们确定了113种新的内源性IRS 1相互作用伴侣，这代表了人类最大的IRS 1相互作用组，并为各种疾病中IRS 1复合物的研究提供了新的靶点。此外，我们生成了LC中IRS 1相互作用伙伴的第一个全球图片，以及它们在OC和T2 D患者中的差异。有趣的是，与基础和/或胰岛素刺激条件下的LC相比，OC和/或T2 D患者中的数十种蛋白质与IRS 1的相关性增加，揭示了OC和T2 D患者中多种新的功能失调的IRS 1途径。这种新的异常，在肥胖症和T2 D中多种蛋白质与IRS 1的相互作用增加，为胰岛素抵抗的分子机制提供了新的见解，并为T2 D药物开发确定了新的靶点。
Insulin receptor substrate 1 (IRS1) is a key mediator of insulin signal transduction. Perturbations involving IRS1 complexes may lead to the development of insulin resistance and type 2 diabetes (T2D). Surprisingly little is known about the proteins that interact with IRS1 in humans under health and disease conditions. We used a proteomic approach to assess IRS1 interaction partners in skeletal muscle from lean healthy control subjects (LCs), obese insulin-resistant nondiabetic control subjects (OCs), and participants with T2D before and after insulin infusion. We identified 113 novel endogenous IRS1 interaction partners, which represents the largest IRS1 interactome in humans and provides new targets for studies of IRS1 complexes in various diseases. Furthermore, we generated the first global picture of IRS1 interaction partners in LCs, and how they differ in OCs and T2D patients. Interestingly, dozens of proteins in OCs and/or T2D patients exhibited increased associations with IRS1 compared with LCs under the basal and/or insulin-stimulated conditions, revealing multiple new dysfunctional IRS1 pathways in OCs and T2D patients. This novel abnormality, increased interaction of multiple proteins with IRS1 in obesity and T2D in humans, provides new insights into the molecular mechanism of insulin resistance and identifies new targets for T2D drug development.
登录
查看更多内容
影响因子：
15.9
作者：
Cusi, K;Maezono, K;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
7.7
作者：
Chen XW;Wang H;Bajaj K;Zhang P;Meng ZX;Ma D;Bai Y;Liu HH;Adams E;Baines A;Yu G;Sartor MA;Zhang B;Yi Z;Lin J;Young SG;Schekman R;Ginsburg D
通讯作者：
Ginsburg D
影响因子：
7
作者：
Donato M;Xu Z;Tomoiaga A;Granneman JG;Mackenzie RG;Bao R;Than NG;Westfall PH;Romero R;Draghici S
通讯作者：
Draghici S
影响因子：
--
作者：
Abdul-Ghani MA;DeFronzo RA
通讯作者：
DeFronzo RA
影响因子：
4
作者：
Grimmsmann, T;Levin, K;Klein, HH
通讯作者：
Klein, HH