Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia, Spain.
PLoS One. 2013;8(2):e56928. doi: 10.1371/journal.pone.0056928. Epub 2013 Feb 28.
Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20-37 kg/m(2)). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min(-1).m(-2).), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.
胰岛素抵抗（IR）是一种细胞、组织和全身对胰岛素反应受损的病症，是 2 型糖尿病的主要病理生理缺陷。尽管 IR 与肥胖密切相关，但肥胖引起的骨骼肌胰岛素抵抗的分子缺陷的本质仍存在争议；先前已经涉及胰岛素受体底物 1（IRS1）衔接蛋白的受体后信号转导减少和下游效应物，如蛋白激酶 B（PKB）。我们检查了 22 名健康年轻男性（BMI 范围 20-37 kg/m(2)）的骨骼肌中胰岛素信号级联的许多成分的表达和/或激活。通过高胰岛素（40 mU.min(-1).m(-2)），正葡萄糖钳夹和双能 X 射线吸收仪（DEXA）分别测定全身胰岛素敏感性（M 值）和身体成分。在一小时高胰岛素血症前后，从股外侧肌（vastus lateralis）活检，并通过 Western blot 和免疫沉淀分析检查肌肉胰岛素信号蛋白。M 值与 BMI 呈强负相关。最显著的异常是胰岛素敏感性差的志愿者中，通过特定的测定，p42/44 MAP 激酶的激活显著降低。然而，在个体的 BMI 或 M 值与 IRS1、PKB 或 p42/44 MAP 激酶蛋白的基础或高胰岛素血症条件下的表达/磷酸化之间没有关系。在少数胰岛素敏感性差但保留 p42/44 MAP 激酶激活的个体中，存在其他信号缺陷。这些发现表明，在非糖尿病人群中，p42/44 MAP 激酶信号的缺陷可能是肥胖相关的 IR 的一个潜在原因，尽管肥胖相关的 IR 显然是由多种信号缺陷引起的。
