Nyomba B L, Ossowski V M, Bogardus C, Mott D M
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016.
Am J Physiol. 1990 Jun;258(6 Pt 1):E964-74. doi: 10.1152/ajpendo.1990.258.6.E964.
To investigate the relationship of insulin receptor kinase with insulin resistance in humans, we studied insulin-sensitive tyrosine kinase activity in muscle biopsies taken from 20 Pima Indians [14 nondiabetics, 6 with non-insulin-dependent mellitus (NIDDM)] during euglycemic clamps, at insulin concentrations of approximately 68 microU/ml (low dose) and approximately 1,170 microU/ml (high dose). In the nondiabetics, the low dose, insulin-induced kinase activation in vivo was 1.5-fold the activity in the fasting state (P less than 0.05), whereas in the diabetics, the kinase activity actually decreased by 40% relative to fasting (P less than 0.05). The difference in delta-kinase in vivo was significant (P less than 0.01) between the two groups. Similarly, the kinase activation in vitro in response to 1 nM insulin was lower in diabetic subjects compared with nondiabetics (P less than 0.01). These data indicate that, in NIDDM, both in vitro and in vivo insulin-stimulated tyrosine kinase activity is impaired. Among nondiabetics, the kinase sensitivity to insulin, calculated as the ratio of the kinase activity at 1 nM insulin in vitro to the kinase activity at 100 nM insulin, was positively correlated with plasma insulin concentrations 2 h after an oral glucose load (r = 0.69, P less than 0.01). Thus, in nondiabetic subjects with insulin resistance, insulin activation of the kinase is not reduced, but the kinase sensitivity to insulin increases with increasing plasma insulin levels. Therefore, the site of insulin resistance in nondiabetic subjects is distal to the insulin receptor kinase. Furthermore, it is possible that circulating insulin, by increasing the kinase sensitivity to insulin, is a determinant of the receptor kinase activity.
为研究胰岛素受体激酶与人类胰岛素抵抗的关系，我们在正常血糖钳夹期间，对20名皮马印第安人（14名非糖尿病患者，6名非胰岛素依赖型糖尿病患者）的肌肉活检样本进行了研究，胰岛素浓度分别为约68微单位/毫升（低剂量）和约1170微单位/毫升（高剂量）。在非糖尿病患者中，低剂量胰岛素诱导的体内激酶激活是空腹状态下活性的1.5倍（P<0.05），而在糖尿病患者中，激酶活性相对于空腹状态实际上下降了40%（P<0.05）。两组之间体内激酶变化的差异具有显著性（P<0.01）。同样，与非糖尿病患者相比，糖尿病患者体外对1 nM胰岛素的激酶激活较低（P<0.01）。这些数据表明，在非胰岛素依赖型糖尿病中，体外和体内胰岛素刺激的酪氨酸激酶活性均受损。在非糖尿病患者中，激酶对胰岛素的敏感性（以体外1 nM胰岛素时的激酶活性与100 nM胰岛素时的激酶活性之比计算）与口服葡萄糖负荷后2小时的血浆胰岛素浓度呈正相关（r = 0.69，P<0.01）。因此，在有胰岛素抵抗的非糖尿病患者中，胰岛素对激酶的激活并未降低，但激酶对胰岛素的敏感性随血浆胰岛素水平升高而增加。所以，非糖尿病患者胰岛素抵抗的部位在胰岛素受体激酶的下游。此外，循环胰岛素可能通过增加激酶对胰岛素的敏感性，从而成为受体激酶活性的一个决定因素。
