Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients.
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) gamma coactivator (PGC)-1alpha, PGC-1beta, PPARdelta, 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.
Karlsson
Håkan K R
HK
Department of Clinical Physiology and Integrative Physiology, Karolinska Institutet, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden.
Ahlsén
Maria
M
Zierath
Juleen R
JR
Wallberg-Henriksson
Harriet
H
Koistinen
Heikki A
HA
D000328:Adult; D015992:Body Mass Index; D049628:Body Size; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005190:Family; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007700:Kinetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D005947:Glucose