Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110β protein levels in skeletal muscle of type 2 diabetic subjects
Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110β protein levels in skeletal muscle of type 2 diabetic subjects
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DOI：
10.2337/diabetes.51.2.443
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发表时间：
2002-02-01
期刊：
影响因子：
7.7
通讯作者：
Kahn, BB
中科院分区：
文献类型：
--
作者：
Kim, YB;Ciaraldi, TP;Kahn, BB
胰岛素刺激磷脂酰肌醇（PI）3-激酶活性在2型糖尿病患者骨骼肌中存在缺陷。我们研究了降糖治疗对格列本脲治疗失败的2型糖尿病受试者的这种缺陷的影响，这些受试者通过添加曲格列酮（600 mg/天）或二甲双胍（2，550 mg/天）治疗3-4个月。两组血糖控制的改善相似，如空腹血糖和HbA（1c）水平的变化所示。胰岛素对全身葡萄糖处置率（GDR）的作用在治疗前后使用高胰岛素血症（300 MU（.）m（-2）（.）min（-1））正葡萄糖（5.0-5.5 nmol/L）钳夹技术。在每次3小时胰岛素输注之前和之后获得股外侧肌的针活检。曲格列酮治疗导致GDR改善35 +/- 9%（P < 0.01），大于二甲双胍治疗后的22.13%（P <0.05）。两种治疗均对肌肉中基础胰岛素受体底物-1（IRS-1）相关的PI 3-激酶活性没有任何影响。然而，在曲格列酮治疗后，胰岛素对PI 3-激酶活性的刺激增加了近3倍（从基础治疗前的67 +/- 22%刺激增加到治疗后的211 +/- 62%，P < 0.05），而二甲双胍没有影响。曲格列酮对PI 3-激酶活性的影响与PI 3-激酶的p110 β催化亚基的量增加46 +/- 22%（P < 0.05）有关。胰岛素刺激的Akt活性在曲格列酮治疗后也增加（从32 +/- 8至107 +/- 32%刺激，P +/- 0.05），但在二甲双胍治疗后无变化。其他关键胰岛素信号分子（IRS-1，PI 3-激酶的p85亚基和Akt）的蛋白表达在两种治疗后均未改变。我们的结论是，曲格列酮的胰岛素增敏作用的机制，而不是二甲双胍，涉及增强PI 3-激酶途径激活肥胖2型糖尿病患者的骨骼肌。
Insulin stimulation of phosphatidylinositol (PI) 3-kinase activity is defective in skeletal muscle of type 2 diabetic individuals. We studied the impact of antidiabetic therapy on this defect in type 2 diabetic subjects who failed glyburide treatment by the addition of troglitazone (600 mg/day) or metformin (2,550 mg/day) therapy for 3-4 months. Improvement in glycemic control was similar for the two groups, as indicated by changes in fasting glucose and HbA(1c) levels. Insulin action on whole-body glucose disposal rate (GDR) was determined before and after treatment using the hyper-insulinemic (300 MU (.) m(-2) (.) min(-1)) euglycemic (5.0-5.5 nmol/l) clamp technique. Needle biopsies of vastus lateralis muscle were obtained before and after each 3-h insulin infusion. Troglitazone treatment resulted in a 35 +/- 9% improvement in GDR (P < 0.01), which was greater than (P < 0.05) the 22 13% increase (P < 0.05) after metformin treatment. Neither treatment had any effect on basal insulin receptor substrate-1 (IRS-1)-associated PI 3-kinase activity in muscle. However, insulin stimulation of PI 3-kinase activity was augmented nearly threefold after troglitazone treatment (from 67 +/- 22% stimulation over basal pre-treatment to 211 +/- 62% post-treatment, P < 0.05), whereas metformin had no effect. The troglitazone effect on PI 3-kinase activity was associated with a 46 +/- 22% increase (P < 0.05) in the amount of the p110beta catalytic subunit of PI 3-kinase. Insulin-stimulated Akt activity also increased after troglitazone treatment (from 32 +/- 8 to 107 +/- 32% stimulation, P +/- 0.05) but was unchanged after metformin therapy. Protein expression of other key insulin signaling molecules (IRS-1, the p85 subunit of PI 3-kinase, and Akt) was unaltered after either treatment. We conclude that the mechanism for the insulin-sensitizing effect of troglitazone, but not metformin, involves enhanced PI 3-kinase pathway activation in skeletal muscle of obese type 2 diabetic subjects.