MODULATION OF INSULIN-RECEPTOR, INSULIN-RECEPTOR SUBSTRATE-1, AND PHOSPHATIDYLINOSITOL 3-KINASE IN LIVER AND MUSCLE OF DEXAMETHASONE-TREATED RATS
MODULATION OF INSULIN-RECEPTOR, INSULIN-RECEPTOR SUBSTRATE-1, AND PHOSPHATIDYLINOSITOL 3-KINASE IN LIVER AND MUSCLE OF DEXAMETHASONE-TREATED RATS
复制标题
DOI：
10.1172/jci116803
复制
发表时间：
1993-10-01
影响因子：
15.9
通讯作者：
KAHN, CR
中科院分区：
文献类型：
--
作者：
SAAD, MJA;FOLLI, F;KAHN, CR
胰岛素迅速刺激其受体的酪氨酸激酶活性，导致其胞质底物胰岛素受体底物-1 （IRS-1）磷酸化，而胰岛素受体底物-1又与磷脂酰肌醇3-激酶（PI 3-激酶）结合，从而激活酶。已知糖皮质激素治疗可产生胰岛素抵抗，但确切的分子机制尚不清楚。在本研究中，我们检测了地塞米松治疗大鼠肝脏和肌肉中胰岛素受体和IRS-1的水平和磷酸化状态，以及IRS-1和PI - 3激酶之间的关联/激活。地塞米松治疗（1 mg/kg / d，连用5 d）后，通过免疫印迹检测胰岛素受体cooh末端抗体，大鼠肝脏中胰岛素受体浓度无变化。然而，通过抗磷酸酪氨酸抗体免疫印迹检测，胰岛素对受体自磷酸化的刺激减少了46.7+/-9.1%。地塞米松组小鼠肝脏IRS-1和PI 3-激酶蛋白水平分别升高了73%和25% （P < 0.05）。相比之下，胰岛素刺激后的IRS-1磷酸化水平降低了31.3+/-10.9% (P < 0.05)，抗IRS-1免疫沉淀物中PI 3-激酶活性降低了79.5+/-11.2% （P < 0.02）。在肌肉中，这种变化不那么剧烈，而且往往与肝脏的变化方向相反。因此，地塞米松治疗后胰岛素受体水平和磷酸化没有明显变化。IRS-1和PI 3-激酶水平分别降至38.6%和65.6% （P < 0.01和P < 0.05）。IRS-1磷酸化在肌肉中没有明显变化，但胰岛素刺激的IRS-1相关PI - 3激酶降低了41%。因此，地塞米松对肝脏和肌肉中参与胰岛素作用早期步骤的蛋白质有不同的影响。在这两种组织中，地塞米松治疗导致胰岛素刺激的irs -1相关PI - 3激酶的减少，这可能在这些动物的细胞水平上胰岛素抵抗的发病机制中起作用。
Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1 ), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. Glucocorticoid treatment is known to produce insulin resistance, but the exact molecular mechanism is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association / activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone.After dexamethasone treatment (1 mg/kg per d for 5 d), there was no change in insulin receptor concentration in liver of rats as determined by immunoblotting with antibody to the COOH-terminus of the receptor. However, insulin stimulation of receptor autophosphorylation determined by immunoblotting with antiphosphotyrosine antibody was reduced by 46.7+/-9.1%. IRS-1 and PI 3-kinase protein levels increased in liver of dexamethasone-treated animals by 73 and 25%, respectively (P < 0.05). By contrast, IRS-1 phosphorylation was decreased by 31.3+/-10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5+/-11.2% (P < 0.02).In muscle, the changes were less dramatic, and often in opposite direction of those observed in liver. Thus, there was no significant change in insulin receptor level or phosphorylation after dexamethasone treatment. IRS-1 and PI 3-kinase levels were decreased to 38.6 and 65.6%, respectively (P < 0.01 and P < 0.05). IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. Thus, dexamethasone has differential effects on the proteins involved in the early steps in insulin action in liver and muscle. In both tissues, dexamethasone treatment results in a reduction in insulin-stimulated IRS-1-associated PI 3-kinase, which may play a role in the pathogenesis of insulin resistance at the cellular level in these animals.