Insulin resistance differentially affects the PI3-kinase- and MAP kinase-mediated signaling in human muscle
Insulin resistance differentially affects the PI3-kinase- and MAP kinase-mediated signaling in human muscle
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DOI：
10.1172/jci7535
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发表时间：
2000-02-01
影响因子：
15.9
通讯作者：
Mandarino, LJ
中科院分区：
文献类型：
--
作者：
Cusi, K;Maezono, K;Mandarino, LJ
2型糖尿病患者骨骼肌中胰岛素抵抗葡萄糖代谢的广泛性表明胰岛素信号网络近端部分存在缺陷。我们试图确定胰岛素抵抗中受损的途径，并测试适度运动对全身和细胞胰岛素作用的影响。我们对2型糖尿病患者、肥胖非糖尿病患者和瘦对照组进行了正葡萄糖钳夹和肌肉活检，并进行了一次运动和一次运动。胰岛素刺激磷脂酰肌醇3-激酶（PI 3-激酶）途径，通过胰岛素受体和IRS-1的磷酸化和IRS蛋白与p85和PI 3-激酶的结合来测量，在肥胖非糖尿病患者中显著降低，在2型糖尿病患者中几乎不存在。胰岛素刺激MAP激酶通路在肥胖和糖尿病受试者中是正常的。胰岛素刺激葡萄糖处置与p85和IRS-1的关联相关。正常血糖钳夹前24小时的运动增加了肥胖和糖尿病受试者中胰岛素受体和IRS-1的磷酸化，但在胰岛素刺激后并没有增加葡萄糖摄取或IRS-1与PIS-激酶的相关性。因此，胰岛素抵抗不同地影响PI 3-激酶和MAP激酶信号传导途径，并且胰岛素刺激的IRS-1与PI 3-激酶的缔合定义了胰岛素抵抗中的关键步骤。
The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI S-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-l-association with PI 3-kinase defines a key step in insulin resistance.