Krook A, Björnholm M, Galuska D, Jiang X J, Fahlman R, Myers M G, Wallberg-Henriksson H, Zierath J R
Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.
Diabetes. 2000 Feb;49(2):284-92. doi: 10.2337/diabetes.49.2.284.
We characterized metabolic and mitogenic signaling pathways in isolated skeletal muscle from well-matched type 2 diabetic and control subjects. Time course studies of the insulin receptor, insulin receptor substrate (IRS)-1/2, and phosphatidylinositol (PI) 3-kinase revealed that signal transduction through this pathway was engaged between 4 and 40 min. Insulin-stimulated (0.6-60 nmol/l) tyrosine phosphorylation of the insulin receptor beta-subunit, mitogen-activated protein (MAP) kinase phosphorylation, and glycogen synthase activity were not altered in type 2 diabetic subjects. In contrast, insulin-stimulated tyrosine phosphorylation of IRS-1 and anti-phosphotyrosine-associated PI 3-kinase activity were reduced 40-55% in type 2 diabetic subjects at high insulin concentrations (2.4 and 60 nmol/l, respectively). Impaired glucose transport activity was noted at all insulin concentrations (0.6-60 nmol/l). Aberrant protein expression cannot account for these insulin-signaling defects because expression of insulin receptor, IRS-1, IRS-2, MAP kinase, or glycogen synthase was similar between type 2 diabetic and control subjects. In skeletal muscle from type 2 diabetic subjects, IRS-1 phosphorylation, PI 3-kinase activity, and glucose transport activity were impaired, whereas insulin receptor tyrosine phosphorylation, MAP kinase phosphorylation, and glycogen synthase activity were normal. Impaired insulin signal transduction in skeletal muscle from type 2 diabetic patients may partly account for reduced insulin-stimulated glucose transport; however, additional defects are likely to play a role.
我们对匹配良好的2型糖尿病患者和对照受试者的分离骨骼肌中的代谢和有丝分裂信号通路进行了表征。对胰岛素受体、胰岛素受体底物（IRS）-1/2和磷脂酰肌醇（PI）3激酶的时间进程研究表明，通过该途径的信号转导在4至40分钟之间启动。2型糖尿病患者中，胰岛素刺激（0.6 - 60 nmol/l）的胰岛素受体β亚基酪氨酸磷酸化、丝裂原活化蛋白（MAP）激酶磷酸化和糖原合酶活性未改变。相比之下，在高胰岛素浓度（分别为2.4和60 nmol/l）下，2型糖尿病患者中胰岛素刺激的IRS-1酪氨酸磷酸化和抗磷酸酪氨酸相关的PI 3激酶活性降低了40 - 55%。在所有胰岛素浓度（0.6 - 60 nmol/l）下均观察到葡萄糖转运活性受损。异常的蛋白质表达不能解释这些胰岛素信号缺陷，因为2型糖尿病患者和对照受试者之间胰岛素受体、IRS-1、IRS-2、MAP激酶或糖原合酶的表达相似。在2型糖尿病患者的骨骼肌中，IRS-1磷酸化、PI 3激酶活性和葡萄糖转运活性受损，而胰岛素受体酪氨酸磷酸化、MAP激酶磷酸化和糖原合酶活性正常。2型糖尿病患者骨骼肌中胰岛素信号转导受损可能部分解释了胰岛素刺激的葡萄糖转运减少；然而，其他缺陷可能也起作用。
