Karlsson Håkan K R, Ahlsén Maria, Zierath Juleen R, Wallberg-Henriksson Harriet, Koistinen Heikki A
Department of Clinical Physiology and Integrative Physiology, Karolinska Institutet, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden.
Diabetes. 2006 May;55(5):1283-8. doi: 10.2337/db05-0853.
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.
2型糖尿病患者骨骼肌中异常的胰岛素信号传导和葡萄糖代谢可能源于遗传缺陷和代谢环境改变。我们测定了2型糖尿病患者糖耐量正常的一级亲属（n = 8，41±3岁，体重指数25.1±0.8kg/m²）和无糖尿病家族史的健康对照者（n = 9，40±2岁，体重指数23.4±0.7kg/m²）分离的股外侧肌中胰岛素对信号转导和葡萄糖转运的作用。两组之间基础和次最大胰岛素刺激（0.6和1.2nmol/L）的葡萄糖转运相当，而亲属组的最大反应（120nmol/L）低38%（P<0.05）。胰岛素以剂量依赖性方式增加Akt和160kDa的Akt底物（AS160）的磷酸化，两组反应相当。在对照者中AS160磷酸化与葡萄糖转运呈正相关（R² = 0.97，P = 0.01），而在亲属中无相关性（R² = 0.46，P = 0.32）。还测定了线粒体生物发生关键转录因子和共调节因子的mRNA。一级亲属和对照者之间过氧化物酶体增殖物激活受体（PPAR）γ共激活因子（PGC）-1α、PGC-1β及PPARδ、核呼吸因子-1和解偶联蛋白-3的骨骼肌mRNA表达相当。总之，胰岛素对Akt/AS160信号传导和葡萄糖转运作用的解偶联表明GLUT4转运缺陷是2型糖尿病发病机制中的早期事件。
