Turnbow M A, Smith L K, Garner C W
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock 79430.
Endocrinology. 1995 Apr;136(4):1450-8. doi: 10.1210/endo.136.4.7895655.
Oxazolidinediones are a class of oral antidiabetic agents that are closely related structurally and pharmacologically to thiazolidinediones. The thiazolidinediones have been shown to partially reverse the loss in insulin-responsive glucose uptake caused by chronic treatment with dexamethasone. This study was conducted to determine certain aspects of the mechanism of thiazolidinedione and oxazolidinedione action. We selected the oxazolidinedione CP-92,768-2 (5-[2-[(5-methyl2-phenyl-4-oxazolyl)methyl]5-benzofuranyl methyl]2,4- oxazolidinedione) to determine whether these agents could reverse the dexamethasone-induced down-regulation of IRS-1, the insulin receptor substrate-1. In 3T3-L1 adipocytes, dexamethasone treatment resulted in down-regulation of IRS-1 to 60% of control values. Simultaneous treatment with CP-92,768-2 significantly increased IRS-1 to 78% of the control value (EC50, < 10 nM), although it did not completely reverse the dexamethasone effect at any concentration tested. CP-92,768-2 alone did not have any effect on IRS-1. CP-92,768-2 did not affect the stability of IRS-1 protein in the presence or absence of dexamethasone, as measured by [35S]methionine pulse-chase labeling. Dexamethasone decreased messenger RNA (mRNA) for IRS-1 after 24 h of treatment to 40% of the control value. CP-92,768-2 partially reversed this decrease in IRS-1 mRNA to 65% of the control value after 24 h of treatment, but had no effect on IRS-1 mRNA in the absence of dexamethasone. Dexamethasone down-regulated the insulin stimulation of [3H]thymidine incorporation to 68% of the control value. Dexamethasone in the presence of CP-92,768-2 down-regulated insulin stimulation of thymidine incorporation by only 9%. Dexamethasone also down-regulated the expression of phosphoenolpyruvate carboxykinase (PEPCK) protein by 50%. CP-92,768-2 partially protected PEPCK from the dexamethasone down-regulation. Conversely, the up-regulation of expression of PEPCK and IRS-1 produced by dexamethasone in KRC-7 hepatoma cells was not affected by CP-92,768-2. One contribution of oxazolidinediones to an increase in insulin responsiveness in the presence of glucocorticoids may be the up-regulation of IRS-1 in adipose cells.
恶唑烷二酮类是一类口服抗糖尿病药物，在结构和药理上与噻唑烷二酮类密切相关。已证明噻唑烷二酮类可部分逆转因长期用地塞米松治疗而导致的胰岛素反应性葡萄糖摄取减少。进行本研究以确定噻唑烷二酮类和恶唑烷二酮类作用机制的某些方面。我们选择恶唑烷二酮CP-92,768-2（5-[2-[(5-甲基-2-苯基-4-恶唑基)甲基]-5-苯并呋喃基甲基]-2,4-恶唑烷二酮）来确定这些药物是否能逆转地塞米松诱导的胰岛素受体底物-1（IRS-1）下调。在3T3-L1脂肪细胞中，地塞米松处理导致IRS-1下调至对照值的60%。同时用CP-92,768-2处理可使IRS-1显著增加至对照值的78%（半数有效浓度，<10 nM），尽管在任何测试浓度下它都未完全逆转地塞米松的作用。单独使用CP-92,768-2对IRS-1没有任何影响。通过[35S]甲硫氨酸脉冲追踪标记法测定，CP-92,768-2在有或没有地塞米松存在的情况下均不影响IRS-1蛋白的稳定性。地塞米松处理24小时后，IRS-1的信使核糖核酸（mRNA）降至对照值的40%。CP-92,768-2处理24小时后可部分将IRS-1 mRNA的这种降低逆转至对照值的65%，但在没有地塞米松的情况下对IRS-1 mRNA没有影响。地塞米松将胰岛素刺激的[3H]胸苷掺入下调至对照值的68%。在有CP-92,768-2存在的情况下，地塞米松仅将胰岛素刺激的胸苷掺入下调了9%。地塞米松还使磷酸烯醇式丙酮酸羧激酶（PEPCK）蛋白的表达下调了50%。CP-92,768-2部分保护PEPCK免受地塞米松的下调作用。相反，地塞米松在KRC-7肝癌细胞中诱导的PEPCK和IRS-1表达上调不受CP-92,768-2影响。在存在糖皮质激素的情况下，恶唑烷二酮类对胰岛素反应性增加的一个作用可能是上调脂肪细胞中的IRS-1。
