Journal Article

Obesity-Induced Insulin Resistance in Human Skeletal Muscle Is Characterised by Defective Activation of p42/p44 MAP Kinase

Petrie, John R., Murphy, Michael J., Ruiz-Alcaraz, Antonio J., Lipina, Christopher, Cuthbertson, Daniel J., Morris, Andrew D., Sutherland, Calum

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Adult / AKT protein / Biology / Blood Glucose / Body Composition / Body mass / Body mass index / Body size / Defects / Diabetes mellitus / Dual energy X-ray absorptiometry / Enzyme Activation / Glucose / Humans / Immunoprecipitation / Insulin / Insulin receptor substrate 1 / Insulin Receptor Substrate Proteins - metabolism / Insulin Resistance / Kinases / Male / MAP kinase / Medicine / Mitogen-Activated Protein Kinase 1 - metabolism / Mitogen-Activated Protein Kinase 3 - metabolism / Muscle, Skeletal - metabolism / Muscles / Obesity / Obesity - metabolism / Phosphorylation / Polycystic ovary syndrome / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Sensitivity / Signal Transduction / Signaling / Skeletal muscle / Substrates / Young Adult