Journal Article

Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats

Y Kawano, R A Roth, A Krook, S Efendic, J R Zierath, J W Ryder, H Wallberg-Henriksson, X M Song

1999

Overview

Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats. X M Song , Y Kawano , A Krook , J W Ryder , S Efendic , R A Roth , H Wallberg-Henriksson and J R Zierath Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden. Abstract To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.

• Publisher: American Diabetes Association
• Subject: 3-O-Methylglucose - pharmacokinetics / Analysis / Animals / Biological and medical sciences / Biological transport / Biological Transport - drug effects / Body Weight / Diabetes / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - physiopathology / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Gene Expression Regulation - drug effects / Glucose / Glucose - metabolism / Glucose Transporter Type 4 / Glycogen Synthase - genetics / Hyperglycemia / Insulin / Insulin - physiology / Insulin Receptor Substrate Proteins / Insulin resistance / Kinases / Medical sciences / Metabolism / Monosaccharide Transport Proteins - genetics / Muscle Fibers, Skeletal - drug effects / Muscle Fibers, Skeletal - metabolism / Muscle Proteins / Muscle, Skeletal - drug effects / Muscle, Skeletal - metabolism / Musculoskeletal system / Phlorhizin - pharmacology / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Phosphoproteins - genetics / Phosphoproteins - metabolism / Phosphorylation / Physiological transport / Protein-Serine-Threonine Kinases / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-akt / Rats / Rats, Inbred Strains / Rats, Wistar / Rodents / Signal transduction / Signal Transduction - physiology / Species Specificity