Journal Article

Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients

M Björnholm, A Krook, D Galuska, J R Zierath, M G Myers, Jr, H Wallberg-Henriksson, X J Jiang, R Fahlman

2000

Overview

Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. A Krook , M Björnholm , D Galuska , X J Jiang , R Fahlman , M G Myers, Jr , H Wallberg-Henriksson and J R Zierath Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden. Abstract 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.

• Publisher: American Diabetes Association
• Subject: Biological and medical sciences / Biological Transport / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - physiopathology / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Glucose / Glucose - metabolism / Glucose synthesis / Glycogen Synthase - metabolism / Humans / Insulin / Insulin - physiology / Insulin Receptor Substrate Proteins / Insulin resistance / Male / Medical sciences / Middle Aged / Mitogen-Activated Protein Kinases - metabolism / Muscle, Skeletal - metabolism / Phosphatidylinositol 3-Kinases - metabolism / Phosphoproteins - metabolism / Phosphorylation - drug effects / Phosphotyrosine - metabolism / Physiological aspects / Physiological transport / Receptor, Insulin - metabolism / Signal Transduction / Synthesis / Time Factors / Type 2 diabetes / Tyrosine - metabolism