Ryan E A, O'Sullivan M J, Skyler J S
Diabetes. 1985 Apr;34(4):380-9. doi: 10.2337/diab.34.4.380.
To assess the mechanisms responsible for the insulin resistance associated with both normal human pregnancy and gestational-onset diabetes, we have measured exogenous glucose disposal using sequential insulin infusions with the euglycemic glucose clamp technique and erythrocyte insulin binding. Three groups of women were studied: nonpregnant women with normal glucose tolerance (N = 7, mean age 32.9 +/- 2.1 yr), pregnant women with normal glucose tolerance (N = 5, mean age 24.8 +/- 3.5 yr), and pregnant women with gestational-onset diabetes (N = 5, mean age 34.6 +/- 2.6 yr). Despite normal plasma glucose levels obtained during a 100-g oral glucose tolerance test, plasma insulin levels were significantly elevated in the pregnant women compared with the nonpregnant control subjects, suggesting a state of insulin resistance. Insulin binding to erythrocytes was similar in all three groups (maximum specific binding being 5.0 +/- 0.6%, 5.5 +/- 1.1%, and 6.0 +/- 0.7% in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively). In vivo peripheral insulin action was measured using the euglycemic glucose clamp technique during an insulin infusion of 40 mU/m2 X min, with blood glucose clamped at a concentration of 75 mg/dl using a variable glucose infusion. Glucose infusion rates were 213 +/- 11 mg/m2 X min, 143 +/- 23 mg/m2 X min, and 57 +/- 18 mg/m2 X min in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates that pregnant subjects display a state of insulin resistance, and that this appears to be more marked in gestational-onset diabetic subjects. To further define the possible mechanism of insulin resistance during pregnancy, the insulin infusion rate was increased to 240 mU/m2 X min and further euglycemic clamp measurements performed. Glucose infusion rates were 372 +/- 11 mg/m2 X min, 270 +/- 31 mg/m2 X min, and 157 +/- 26 mg/m2 X min, in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates a shift to the right of the dose-response curve of insulin action and suggests that the insulin resistance of pregnancy may include a decrease in presumed "maximum" insulin responsivity. In four subjects, studies were repeated in the postpartum period, and these demonstrated that the insulin resistance of pregnancy is ameliorated shortly after delivery. These studies suggest that the insulin resistance of pregnancy results from a target cell defect in insulin action beyond the initial step of insulin binding to cellular receptors, a postreceptor (or postbinding) defect in insulin action.
为评估与正常妊娠及妊娠期糖尿病相关的胰岛素抵抗机制，我们采用正常血糖葡萄糖钳夹技术序贯输注胰岛素及测定红细胞胰岛素结合情况，来检测外源性葡萄糖处置。研究了三组女性：糖耐量正常的非孕女性（N = 7，平均年龄32.9±2.1岁）、糖耐量正常的孕妇（N = 5，平均年龄24.8±3.5岁）及妊娠期糖尿病孕妇（N = 5，平均年龄34.6±2.6岁）。尽管在100克口服葡萄糖耐量试验中血浆葡萄糖水平正常，但与非孕对照受试者相比，孕妇的血浆胰岛素水平显著升高，提示存在胰岛素抵抗状态。三组红细胞胰岛素结合情况相似（非孕、非糖尿病孕妇及妊娠期糖尿病孕妇的最大特异性结合分别为5.0±0.6%、5.5±1.1%和6.0±0.7%）。采用正常血糖葡萄糖钳夹技术，在以40 mU/m²·min的速率输注胰岛素期间，将血糖浓度钳夹在75 mg/dl，通过可变葡萄糖输注来测定体内外周胰岛素作用。非孕、非糖尿病孕妇及妊娠期糖尿病孕妇的葡萄糖输注速率分别为213±11 mg/m²·min、143±23 mg/m²·min和57±18 mg/m²·min。这表明孕妇存在胰岛素抵抗状态，且在妊娠期糖尿病患者中似乎更为明显。为进一步明确孕期胰岛素抵抗的可能机制，将胰岛素输注速率增至240 mU/m²·min，并再次进行正常血糖钳夹测量。非孕、非糖尿病孕妇及妊娠期糖尿病孕妇的葡萄糖输注速率分别为372±11 mg/m²·min、270±31 mg/m²·min和157±26 mg/m²·min。这表明胰岛素作用的剂量 - 反应曲线向右移位，提示孕期胰岛素抵抗可能包括假定的“最大”胰岛素反应性降低。在四名受试者中，产后重复了研究，结果表明产后不久孕期的胰岛素抵抗有所改善。这些研究提示，孕期胰岛素抵抗是由胰岛素作用的靶细胞缺陷所致，该缺陷发生在胰岛素与细胞受体结合的初始步骤之后，即胰岛素作用的受体后（或结合后）缺陷。
