Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes
Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes
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DOI：
10.2337/diabetes.48.9.1807
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发表时间：
1999-09-01
期刊：
影响因子：
7.7
通讯作者：
Catalano, P
中科院分区：
文献类型：
--
作者：
Friedman, JE;Ishizuka, T;Catalano, P
妊娠期糖尿病（GDM）的妇女有严重的胰岛素抵抗，并显着增加的风险，发展为2型糖尿病。本研究采用离体培养的方法，观察妊娠和妊娠期糖尿病对人骨骼肌纤维条葡萄糖转运活性、胰岛素受体和胰岛素受体底物（IRS）-1表达和磷酸化的影响。（妊娠对照组）、7名患有GDM的妊娠妇女和11名接受择期手术的非妊娠妇女（非妊娠对照组）。在妊娠对照组中，胰岛素（10（-7）mol/l）刺激的最大2-脱氧葡萄糖转运率降低了32%（P < 0.05），而在GDM患者中则进一步降低了54%（P < 0.05）。胰岛素对胰岛素受体酪氨酸磷酸化的最大作用降低了37%（P < 0.05），且与胰岛素受体丰度的变化无关。与非妊娠对照组相比，最大胰岛素刺激IRS-1酪氨酸磷酸化显著降低59 +/- 24%（平均值+/- SD）（P < 0.05）和62 +/- 28%（P < 0.05）。妊娠对照组和GDM受试者肌肉中IRS-1蛋白水平分别降低了23%（P < 0.05）和44%（P < 0.002）。妊娠对照组和GDM受试者的IRS-2和PI 3-激酶p85 α调节亚基水平均升高1.5- 2倍（P <0.01），尽管葡萄糖转运活性降低。这些数据表明，妊娠期间胰岛素抵抗葡萄糖转运是唯一与IRS-1酪氨酸磷酸化的减少，主要是由于IRS-1蛋白的表达减少。然而，在GDM受试者中，胰岛素受体P-亚基酪氨酸磷酸化的减少与葡萄糖转运活性的进一步降低相关。因此，受损的胰岛素受体自身磷酸化是GDM年轻女性肌肉胰岛素抵抗的一个重要早期区别，它可能是未来发展为2型糖尿病的风险的基础。
Women who develop gestational diabetes mellitus (GDM) have severe insulin resistance and markedly increased risk to develop subsequent type 2 diabetes. We investigated the effects of pregnancy and GDM on glucose transport activity and the expression and phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1 in human skeletal muscle fiber strips in vitro, Rectus abdominis muscle biopsies were obtained at the time of cesarean section from 11 pregnant women with normal glucose tolerance (pregnant control), 7 pregnant women with GDM, and 11 non-pregnant women undergoing elective surgery (nonpregnant control), Subjects were matched for age and similar degree of obesity. The rate of maximal insulin (10(-7) mol/l)-stimulated 2-deoxyglucose transport was reduced by 32% (P < 0.05) in muscle strips from the pregnant control group and even further in GDM subjects by 54% (P < 0.05 vs, pregnant control). The maximal effect of insulin on tyrosine phosphorylation of the insulin receptor was 37% lower (P < 0.05) in GDM subjects than in pregnant control subjects and was not related to changes in the abundance of the insulin receptor, Compared with nonpregnant control subjects, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significantly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. This was reflected by a 23% (P < 0.05) and 44% (P < 0.002) reduction in IRS-1 protein levels in muscle from pregnant control and GDM subjects. Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0.01) and p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0,05), despite reduced glucose transport activity. These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-I protein. However, in GDM subjects, a decrease in tyrosine phosphorylation of the insulin receptor P-subunit is associated with further decreases in glucose transport activity. Thus, impaired insulin receptor autophosphorylation is an important early distinction underlying muscle insulin resistance in young women with GDM, and it may underlie future risk for the development of type 2 diabetes.