Kanoh Y, Bandyopadhyay G, Sajan M P, Standaert M L, Farese R V
J. A. Haley Veterans Hospital Research Service and Department of Internal Medicine, University of South Florida College of Medicine Tampa, Florida 33612, USA.
Endocrinology. 2001 Apr;142(4):1595-605. doi: 10.1210/endo.142.4.8066.
Atypical protein kinases C (PKCs), zeta and lambda, and protein kinase B (PKB) are thought to function downstream of phosphatidylinositol 3-kinase (PI 3-kinase) and regulate glucose transport during insulin action in skeletal muscle and adipocytes. Insulin-stimulated glucose transport is defective in type II diabetes mellitus, and this defect is ameliorated by thiazolidinediones and lowering of blood glucose by chronic insulin therapy or short-term fasting. Presently, we evaluated the effects of these insulin-sensitizing modalities on the activation of insulin receptor substrate-1 (IRS-1)-dependent PI 3-kinase, PKC-zeta/lambda, and PKB in vastus lateralis skeletal muscles and adipocytes of nondiabetic and Goto-Kakizaki (GK) diabetic rats. Insulin provoked rapid increases in the activity of PI 3-kinase, PKC-zeta/lambda, and PKB in muscles and adipocytes of nondiabetic rats, but increases in IRS-1-dependent PI 3-kinase and PKC-zeta/lambda, but not PKB, activity were substantially diminished in GK muscles and adipocytes. Rosiglitazone treatment for 10-14 days, 10-day insulin treatment, and 60-h fasting reversed defects in PKC-zeta/lambda activation in GK muscles and adipocytes and increased glucose transport in GK adipocytes, without necessarily increasing IRS-1-dependent PI 3-kinase or PKB activation. Our findings suggest that insulin-sensitizing modalities, viz. thiazolidinediones, chronic insulin treatment, and short-term fasting, similarly improve defects in insulin-stimulated glucose transport at least partly by correcting defects in insulin-induced activation of PKC-zeta/lambda.
非典型蛋白激酶C（PKC）的ζ和λ亚型以及蛋白激酶B（PKB）被认为在磷脂酰肌醇3激酶（PI 3激酶）下游发挥作用，并在骨骼肌和脂肪细胞的胰岛素作用过程中调节葡萄糖转运。胰岛素刺激的葡萄糖转运在II型糖尿病中存在缺陷，而噻唑烷二酮类药物以及通过长期胰岛素治疗或短期禁食降低血糖可改善这一缺陷。目前，我们评估了这些胰岛素增敏方式对非糖尿病和Goto-Kakizaki（GK）糖尿病大鼠股外侧肌和脂肪细胞中胰岛素受体底物-1（IRS-1）依赖性PI 3激酶、PKC-ζ/λ和PKB激活的影响。胰岛素可使非糖尿病大鼠肌肉和脂肪细胞中PI 3激酶、PKC-ζ/λ和PKB的活性迅速增加，但在GK大鼠的肌肉和脂肪细胞中，IRS-1依赖性PI 3激酶和PKC-ζ/λ的活性增加，而PKB的活性显著降低。罗格列酮治疗10 - 14天、胰岛素治疗10天以及禁食60小时可逆转GK大鼠肌肉和脂肪细胞中PKC-ζ/λ激活的缺陷，并增加GK脂肪细胞中的葡萄糖转运，而不一定增加IRS-1依赖性PI 3激酶或PKB的激活。我们的研究结果表明，胰岛素增敏方式，即噻唑烷二酮类药物、长期胰岛素治疗和短期禁食，至少部分通过纠正胰岛素诱导的PKC-ζ/λ激活缺陷，同样改善了胰岛素刺激的葡萄糖转运缺陷。
