Insulin Signaling and Glucose Transport in Skeletal Muscle From First-Degree Relatives of Type 2 Diabetic Patients

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 5; pp. 1283 - 1288
• Main Authors: KARLSSON, Hakan K. R, AHLSEN, Maria, ZIERATH, Juleen R, WALLBERG-HENRIKSSON, Harriet, KOISTINEN, Heikki A
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2006
• Subjects: Adult; Biological and medical sciences; Body Mass Index; Body Size; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes research; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Family; Fundamental and applied biological sciences. Psychology; Genetic aspects; Glucose - metabolism; Glucose Tolerance Test; Humans; Insulin - physiology; Kinetics; Medical sciences; Medicin och hälsovetenskap; Metabolic diseases; Morbidity; Muscle, Skeletal - metabolism; Reference Values; Risk factors; Signal Transduction - physiology; Striated muscle. Tendons; Type 2 diabetes; Vertebrates: osteoarticular system, musculoskeletal system; Endocrinopathy; Type 2 diabetes; Human; Signal transduction; Pancreatic hormone; Biological transport; Metabolic diseases; Glucose; Striated muscle; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db05-0853

Insulin Signaling and Glucose Transport in Skeletal Muscle From First-Degree Relatives of Type 2 Diabetic Patients Håkan K.R. Karlsson 1 , Maria Ahlsén 2 , Juleen R. Zierath 1 , Harriet Wallberg-Henriksson 1 2 and Heikki A. Koistinen 1 2 3 1 Department of Molecular Medicine and Surgery, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden 2 Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden 3 Division of Cardiology, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland Address correspondence and reprint requests to Harriet Wallberg-Henriksson, MD, PhD, Professor of Physiology, Department of Clinical PhysiologyIntegrative Physiology, Karolinska Institutet, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden. E-mail: harriet.wallberg-henriksson{at}fyfa.ki.se Abstract Aberrant insulin signaling and glucose metabolism in skeletal muscle from type 2 diabetic patients may arise from genetic defects and an altered metabolic milieu. We determined insulin action on signal transduction and glucose transport in isolated vastus lateralis skeletal muscle from normal glucose-tolerant first-degree relatives of type 2 diabetic patients ( n = 8, 41 ± 3 years, BMI 25.1 ± 0.8 kg/m 2 ) and healthy control subjects ( n = 9, 40 ± 2 years, BMI 23.4 ± 0.7 kg/m 2 ) with no family history of diabetes. Basal and submaximal insulin-stimulated (0.6 and 1.2 nmol/l) glucose transport was comparable between groups, whereas the maximal response (120 nmol/l) was 38% lower ( P < 0.05) in the relatives. Insulin increased phosphorylation of Akt and Akt substrate of 160 kDa (AS160) in a dose-dependent manner, with comparable responses between groups. AS160 phosphorylation and glucose transport were positively correlated in control subjects ( R 2 = 0.97, P = 0.01) but not relatives ( R 2 = 0.46, P = 0.32). mRNA of key transcriptional factors and coregulators of mitochondrial biogenesis were also determined. Skeletal muscle mRNA expression of peroxisome proliferator–activated receptor (PPAR) γ coactivator (PGC)-1α, PGC-1β, PPARδ, nuclear respiratory factor-1, and uncoupling protein-3 was comparable between first-degree relatives and control subjects. In conclusion, the uncoupling of insulin action on Akt/AS160 signaling and glucose transport implicates defective GLUT4 trafficking as an early event in the pathogenesis of type 2 diabetes. IRS-1, insulin receptor substrate-1 KHB, Krebs-Henseleit buffer NRF-1, nuclear respiratory factor-1 PGC, peroxisome proliferator–activated receptor γ coactivator PPAR, peroxisome proliferator–activated receptor UCP-3, uncoupling protein-3 Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 24, 2006. Received July 6, 2005. DIABETES