REGULATION OF PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY IN LIVER AND MUSCLE OF ANIMAL-MODELS OF INSULIN-RESISTANT AND INSULIN-DEFICIENT DIABETES-MELLITUS
REGULATION OF PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY IN LIVER AND MUSCLE OF ANIMAL-MODELS OF INSULIN-RESISTANT AND INSULIN-DEFICIENT DIABETES-MELLITUS
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DOI：
10.1172/jci116768
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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：
FOLLI, F;SAAD, MJA;KAHN, CR
胰岛素刺激胰岛素受体底物1（IRS-1）的酪氨酸磷酸化，IRS-1进而结合并激活磷脂酰肌醇3-激酶（PI 3-激酶）。在本研究中，我们已经研究了这些过程中的动物模型的胰岛素抵抗和胰岛素缺乏型糖尿病。在体内胰岛素刺激后，ob / ob小鼠肝脏和肌肉中IRS-1磷酸化降低60- 80%。与IRS-1结合的PI 3-激酶（85 kD亚基）无胰岛素刺激作用，IRS-1结合的PI 3-激酶活性降低90%。胰岛素刺激的总PI 3-激酶活性也不存在于ob/ob小鼠的两个组织中。相比之下，在链脲佐菌素糖尿病大鼠中，肌肉中IRS-1磷酸化增加50%，肝脏和肌肉中IRS-1相关的Pt 3-激酶活性增加2至3倍，并且肌肉中胰岛素刺激后与IRS-1相关的p85增加50%。（a）IRS-1相关的PI 3-激酶活性在高胰岛素血症和低胰岛素血症糖尿病状态中受到不同调节;（B）PI 3-激酶活化与IRS-1磷酸化密切相关;和（c）PI 3-激酶活性降低可能在胰岛素抵抗性糖尿病状态的病理生理学中起作用，例如在ob/ob小鼠中所见。
Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1 ), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). In the present study, we have examined these processes in animal models of insulin-resistant and insulin-deficient diabetes mellitus. After in vivo insulin stimulation, there was a 60-80%, decrease in IRS-1 phosphorylation in liver and muscle of the ob / ob mouse. There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. Insulin-stimulated total PI 3-kinase activity was also absent in both tissues of the ob/ob mouse. By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated Pt 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle.In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resistant diabetic states, such as that seen in the ob/ob mouse.