Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes
Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes
复制标题
DOI：
10.1172/jci119552
复制
发表时间：
1997-07-15
影响因子：
15.9
通讯作者：
Goldstein, BJ
中科院分区：
文献类型：
--
作者：
Ahmad, F;Azevedo, JL;Goldstein, BJ
肥胖受试者脂肪组织中蛋白酪氨酸磷酸酶（PTK）活性增加，其可以使胰岛素受体激酶脱磷酸化和活化。为了将这些发现扩展到骨骼肌，我们测量了一系列瘦对照、胰岛素抵抗肥胖和肥胖症患者骨骼肌颗粒部分和细胞质中的PTK活性。（体重指数> 30）非糖尿病受试者和患有非胰岛素依赖性糖尿病的肥胖个体。非糖尿病肥胖受试者的亚细胞组分中PTB活性增加到瘦对照组水平的140- 170而非胰岛素依赖型糖尿病肥胖组两种组分中的PTB活性均显著降低，仅为对照组的39免疫印迹分析显示，白细胞抗原相关蛋白（LAR）和蛋白酪氨酸磷酸酶1B（PTP 1B）的表达最高（三倍）在来自肥胖、非糖尿病受试者的颗粒部分中，与对照受试者的活性相比，使用针对白细胞抗原相关细胞质结构域的亲和纯化抗体对该级分进行免疫耗竭，使PTPase活性正常化，这些发现进一步支持了在人类肥胖的胰岛素抵抗的发病机制中通过特异性PTPases负调节胰岛素作用，而其他调节机制可能在糖尿病状态下起作用。
Obese human subjects have increased protein-tyrosine phosphatase (PTPase) activity in adipose tissue that can dephosphorylate and inactivate the insulin receptor kinase, To extend these findings to skeletal muscle, we measured PTPase activity in the skeletal muscle particulate fraction and cytosol from a series of lean controls, insulin-resistant obese (body mass index > 30) nondiabetic subjects, and obese individuals with non-insulin-dependent diabetes. PTPase activities in subcellular fractions from the nondiabetic obese subjects were increased to 140-170% of the level in lean controls (P < 0.05), In contrast, PTPase activity in both fractions from the obese subjects with non-insulin-dependent diabetes was significantly decreased to 39% of the level in controls (P < 0.05), By immunoblot analysis, leukocyte antigen related (LAR) and protein-tyrosine phosphatase 1B had the greatest increase (threefold) in the particulate fraction from obese, nondiabetic subjects, and immunodepletion of this fraction using an affinity-purified antibody directed at the cytoplasmic domain of leukocyte antigen related normalized the PTPase activity when compared to the activity from control subjects, These findings provide further support for negative regulation of insulin action by specific PTPases in the pathogenesis of insulin resistance in human obesity, while other regulatory mechanisms may be operative in the diabetic state.