Folli F, Saad M J, Backer J M, Kahn C R
Research Division, Joslin Diabetes Center, Boston, MA 02215.
J Clin Invest. 1993 Oct;92(4):1787-94. doi: 10.1172/JCI116768.
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 PI 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.
胰岛素刺激胰岛素受体底物1（IRS-1）的酪氨酸磷酸化，而IRS-1反过来又与磷脂酰肌醇3激酶（PI 3激酶）结合并激活它。在本研究中，我们在胰岛素抵抗和胰岛素缺乏型糖尿病动物模型中研究了这些过程。在体内胰岛素刺激后，ob/ob小鼠肝脏和肌肉中IRS-1磷酸化降低了60%-80%。没有胰岛素刺激PI 3激酶（85 kD亚基）与IRS-1结合，并且与IRS-1相关的PI 3激酶活性降低了90%。ob/ob小鼠的这两种组织中也都不存在胰岛素刺激的总PI 3激酶活性。相比之下，在链脲佐菌素诱导的糖尿病大鼠中，肌肉中IRS-1磷酸化增加了50%，肝脏和肌肉中与IRS-1相关的PI 3激酶活性增加了2至3倍，并且胰岛素刺激后肌肉中与IRS-1相关的p85增加了50%。总之，（a）在高胰岛素血症和低胰岛素血症糖尿病状态下，与IRS-1相关的PI 3激酶活性受到不同调节；（b）PI 3激酶激活与IRS-1磷酸化密切相关；（c）PI 3激酶活性降低可能在胰岛素抵抗性糖尿病状态（如ob/ob小鼠中所见）的病理生理学中起作用。
