Sevillano Julio, de Castro Javier, Bocos Carlos, Herrera Emilio, Ramos M Pilar
Facultad de Farmacia, Universidad CEU-San Pablo, Crta. Boadilla Km 5, 3, Madrid, Spain.
Endocrinology. 2007 Dec;148(12):5933-42. doi: 10.1210/en.2007-0352. Epub 2007 Sep 6.
Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and phosphatase and tensin homolog (PTEN) did not change at late pregnancy. However, insulin-stimulated tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at serine 307 and a decrease in adiponectin levels. To corroborate the role of IRS-1 in adipose tissue insulin resistance during pregnancy, we treated pregnant rats with the antidiabetic drug englitazone. Englitazone improved glucose tolerance, and this pharmacological reversal of insulin resistance was paralleled by an increase of adiponectin levels in adipose tissue as well as by a reduction of IRS-1 serine phosphorylation. Furthermore, the impaired insulin-stimulated tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with adiponectin. Together, our findings support a role for adiponectin and serine phosphorylation of IRS-1 in the modulation of insulin resistance in adipose tissue at late pregnancy.
胰岛素抵抗是人类和大鼠妊娠晚期的一个标志。脂肪组织是对这种胰岛素敏感性降低贡献最大的组织之一。本研究的目的是阐明妊娠晚期脂肪组织中胰岛素抵抗的分子机制。为此，我们分析了未怀孕和怀孕（第20天）大鼠在基础状态和胰岛素刺激条件下腰椎脂肪组织中的胰岛素信号级联反应。我们发现，在妊娠晚期，胰岛素受体（IR）、胰岛素受体底物-1（IRS-1）、磷脂酰肌醇3激酶、3-磷酸肌醇依赖性蛋白激酶-1、细胞外信号调节激酶1/2（ERK1/2）和磷酸酶及张力蛋白同源物（PTEN）等相关信号蛋白的水平没有变化。然而，胰岛素刺激的IR和IRS-1的酪氨酸磷酸化显著降低，同时IRS-1/p85结合减少，AKR小鼠胸腺瘤病毒原癌基因（Akt）和ERK1/2的磷酸化受损。IRS-1的这种激活受损伴随着丝氨酸307处IRS-1磷酸化的增加和脂联素水平的降低。为了证实IRS-1在妊娠期间脂肪组织胰岛素抵抗中的作用，我们用抗糖尿病药物恩格列净治疗怀孕大鼠。恩格列净改善了葡萄糖耐量，这种胰岛素抵抗的药理学逆转伴随着脂肪组织中脂联素水平的增加以及IRS-1丝氨酸磷酸化的减少。此外，通过用脂联素处理分离的脂肪细胞，可在体外恢复怀孕动物脂肪组织中胰岛素刺激的IRS-1酪氨酸磷酸化受损的情况。总之，我们的研究结果支持脂联素和IRS-1的丝氨酸磷酸化在调节妊娠晚期脂肪组织胰岛素抵抗中的作用。
