Henriksen Erik J, Dokken Betsy B
Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA.
Curr Drug Targets. 2006 Nov;7(11):1435-41. doi: 10.2174/1389450110607011435.
A reduced ability of insulin to activate glucose transport in skeletal muscle, termed insulin resistance, is a primary defect leading to the development of impaired glucose tolerance and type 2 diabetes. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with important roles in the regulation of glycogen synthesis, protein synthesis, gene transcription, and cell differentiation in various cell types. An emerging body of evidence has implicated GSK-3 in the multifactorial etiology of skeletal muscle insulin resistance in obese animal models and in obese human type 2 diabetic subjects. Overexpression and overactivity of GSK-3 in skeletal muscle of rodent models of obesity and obese type 2 diabetic humans are associated with an impaired ability of insulin to activate glucose disposal and glycogen synthase. New insights into the importance of GSK-3 as a regulator of insulin action on glucose transport activity in muscle have come from studies utilizing selective and sensitive inhibitors of GSK-3. These studies have demonstrated that selective inhibition of GSK-3 in insulin-resistant skeletal muscle causes improvements in insulin-stimulated glucose transport activity that are likely caused by enhanced post-insulin receptor insulin signaling and GLUT-4 glucose transporter translocation. An additional important action of these GSK-3 inhibitors in the context of obese-associated type 2 diabetes is a reduction of hepatic glucose production, likely via downregulation of genes associated with gluconeogensis. It is clear from these studies that selectively targeting GSK-3 in skeletal muscle may be an important new strategy for the treatment of obesity-associated insulin-resistant states characterized by GSK-3 overactivity in insulin-sensitive tissues.
胰岛素激活骨骼肌中葡萄糖转运的能力降低，即胰岛素抵抗，是导致糖耐量受损和2型糖尿病发生的主要缺陷。糖原合酶激酶-3（GSK-3）是一种丝氨酸/苏氨酸激酶，在多种细胞类型的糖原合成、蛋白质合成、基因转录和细胞分化调节中发挥重要作用。越来越多的证据表明，在肥胖动物模型和肥胖的2型糖尿病患者中，GSK-3与骨骼肌胰岛素抵抗的多因素病因有关。在肥胖和肥胖的2型糖尿病人类的啮齿动物模型的骨骼肌中，GSK-3的过表达和过度活性与胰岛素激活葡萄糖处理和糖原合酶的能力受损有关。利用GSK-3的选择性和敏感抑制剂进行的研究，为GSK-3作为肌肉中胰岛素对葡萄糖转运活性作用的调节剂的重要性提供了新的见解。这些研究表明，在胰岛素抵抗的骨骼肌中选择性抑制GSK-3可改善胰岛素刺激的葡萄糖转运活性，这可能是由胰岛素受体后胰岛素信号增强和GLUT-4葡萄糖转运体易位引起的。在肥胖相关的2型糖尿病背景下，这些GSK-3抑制剂的另一个重要作用是降低肝脏葡萄糖生成，可能是通过下调与糖异生相关的基因来实现的。从这些研究中可以清楚地看出，在骨骼肌中选择性靶向GSK-3可能是治疗以胰岛素敏感组织中GSK-3过度活性为特征的肥胖相关胰岛素抵抗状态的重要新策略。
