Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle
Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle
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DOI：
10.2337/diabetes.54.8.2351
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发表时间：
2005-08-01
期刊：
影响因子：
7.7
通讯作者：
Olefsky, JM
中科院分区：
文献类型：
--
作者：
Bandyopadhyay, GK;Yu, JG;Olefsky, JM
胰岛素抵抗的主要特征是骨骼肌中胰岛素刺激的葡萄糖摄取减少。在当前的研究中，我们评估了从正常、肥胖非糖尿病和 2 型糖尿病受试者输注 5 小时胰岛素之前和之后获得的骨骼肌活检中磷脂酰肌醇 (PI) 3 激酶途径的各个方面。我们发现体内胰岛素敏感性（通过葡萄糖输注速率测量）与 p85/55/50 蛋白表达增加、蛋白激酶 C (PKC)-theta 活性、pSer(307) 胰岛素受体底物 (IRS)-1 和 p-Jun NH2 末端激酶 (JNK)-1 水平以及肌球蛋白重链 IIx 纤维水平之间存在高度显着的负相关。肥胖和 2 型糖尿病受试者中 Ser(307) IRS-1 基础磷酸化的增加与胰岛素刺激的 IRS-1 酪氨酸磷酸化、PI 3-激酶活性和胰岛素诱导的 Akt 激活以及更显着的 PKC-zeta/A 的降低相对应。总之，PI 3-激酶接头亚基 p85/55/50 表达的增加，以及促炎激酶 JNK-1、PKC-theta 的活性增加，以及较小程度的 kappa B 激酶-β 抑制剂的活性增加，与基础 Ser(307) IRS-1 磷酸化的增加和 PI 3-激酶活性的降低有关，并且可能遵循共同的途径来减弱体内胰岛素敏感性。胰岛素抵抗受试者。这些发现表明，相互作用的机制可能导致肥胖和 2 型糖尿病受试者骨骼肌中胰岛素刺激的 PI 3 激酶活性受损。
Insulin resistance is predominantly characterized by decreased insulin-stimulated glucose uptake into skeletal muscle. In the current study, we have assessed various aspects of the phosphatidylinositol (PI) 3-kinase pathway in skeletal muscle biopsies obtained from normal, obese nondiabetic, and type 2 diabetic subjects, before and after a 5-h insulin infusion. We found a highly significant inverse correlation between in vivo insulin sensitivity (as measured by the glucose infusion rate) and increased protein expression of p85/55/50, protein kinase C (PKC)-theta activity, levels of pSer(307) insulin receptor substrate (IRS)-1 and p-Jun NH2-terminal kinase (JNK)-1, and myosin heavy chain IIx fibers. Increased basal phosphorylation of Ser(307) IRS-1 in the obese and type 2 diabetic subjects corresponds with decrease in insulin-stimulated IRS-1 tyrosine phosphorylation, PI 3-kinase activity, and insulin-induced activation of Akt and, more prominently, PKC-zeta/A. In summary, increased expression of the PI 3-kinase adaptor subunits p85/55/50, as well as increased activity of the proinflammatory kinases JNK-1, PKC-theta, and, to a lesser extent, inhibitor of kappa B kinase-beta, are associated with increased basal Ser(307) IRS-1 phosphorylation and decreased PI 3-kinase activity and may follow a common pathway to attenuate in vivo insulin sensitivity in insulin-resistant subjects. These findings demonstrate interacting mechanisms that can lead to impaired insulin-stimulated PI 3-kinase activity in skeletal muscle from obese and type 2 diabetic subjects.