Warram J H, Martin B C, Krolewski A S, Soeldner J S, Kahn C R
Joslin Diabetes Center, Harvard School of Public Health, Boston, Massachusetts.
Ann Intern Med. 1990 Dec 15;113(12):909-15. doi: 10.7326/0003-4819-113-12-909.
To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes.
Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time, 13 years).
Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes.
One hundred and fifty-five normal offspring, ranging in age from 16 to 60 years, of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes.
Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects, even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes, 2.2%/min among offspring who remained nondiabetic, and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498, 354, and 373 pM, respectively, whereas second-phase insulin means were 329, 117, and 87 pM, respectively. In multivariate analysis, low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents.
One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.
确定胰岛素抵抗或胰岛素缺乏在II型糖尿病发病机制中何者为原发性因素。
对糖耐量正常但患II型糖尿病风险高的人群进行队列分析研究（平均随访时间13年）。
门诊患者接受静脉葡萄糖耐量试验，并定期联系以确定糖尿病诊断。
155名年龄在16至60岁之间的正常后代，其父母双方均患有II型糖尿病；以及186名年龄范围相同、无糖尿病家族史的正常对照者。
糖尿病患者后代与对照者有两个表型特征不同。即使在调整肥胖差异后，他们的葡萄糖清除率（Kg）仍低于对照者（P<0.01），胰岛素水平更高（空腹及静脉注射葡萄糖后胰岛素反应的第二阶段；P<0.0001）。16%的后代患II型糖尿病。随后患糖尿病的后代基线时平均Kg为1.7%/分钟，未患糖尿病的后代为2.2%/分钟，对照者为2.3%/分钟。第一阶段胰岛素的相应均值分别为498、354和373 pM，而第二阶段胰岛素均值分别为329、117和87 pM。在多变量分析中，低Kg和高血清胰岛素水平独立增加糖尿病患者后代患糖尿病的风险。
在诊断II型糖尿病前的一到二十年，葡萄糖清除率已降低。这种清除率降低伴随着代偿性高胰岛素血症，而非低胰岛素血症，提示原发性缺陷在于外周组织对胰岛素和葡萄糖的反应，而非胰腺β细胞。
