Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo R A
Diabetes Division, University of Texas Health Science Center, San Antonio 78284-7886.
Diabetes. 1992 Dec;41(12):1575-86. doi: 10.2337/diab.41.12.1575.
NIDDM patients with overt fasting hyperglycemia are characterized by multiple defects involving both insulin secretion and insulin action. At this point of the natural history of NIDDM, however, it is difficult to establish which defects are primary and which are acquired secondary to insulinopenia and chronic hyperglycemia. To address this question, we have studied the glucose-tolerant offspring (probands) of two Mexican-American NIDDM parents. Such individuals are at high risk for developing NIDDM later in life. The probands are characterized by hyperinsulinemia in the fasting state and in response to both oral and intravenous glucose. Insulin-mediated glucose disposal (insulin clamp technique), measured at two physiological levels of hyperinsulinemia (approximately 240 and 450 pM [approximately 40 and 75 microU/ml]), was reduced by 43 and 33%, respectively. During both the low- and high-dose insulin clamp steps, impaired nonoxidative glucose disposal, which primarily represents glycogen synthesis, was the major defect responsible for the insulin resistance. During the lower dose insulin clamp step only, a small decrease in glucose oxidation was observed. No defect in suppression of HGP by insulin was demonstrable. The ability of insulin to inhibit lipid oxidation (measured by indirect calorimetry) and plasma FFA concentration was impaired at both levels of hyperinsulinemia. These results indicate that the glucose-tolerant offspring of two NIDDM parents are characterized by hyperinsulinemia and manifest all of the metabolic abnormalities that characterize the fully established diabetic state, including insulin resistance, a major impairment in nonoxidative glucose disposal, a quantitatively less important defect in glucose oxidation, and a diminished insulin-mediated suppression of lipid oxidation and plasma FFA concentration.
显性空腹血糖过高的非胰岛素依赖型糖尿病（NIDDM）患者具有涉及胰岛素分泌和胰岛素作用的多种缺陷。然而，在NIDDM自然病程的这一阶段，很难确定哪些缺陷是原发性的，哪些是继发于胰岛素缺乏和慢性高血糖的后天性缺陷。为了解决这个问题，我们研究了两位墨西哥裔美国NIDDM患者的糖耐量正常的后代（先证者）。这些个体在生命后期患NIDDM的风险很高。先证者的特征是空腹状态下以及对口服和静脉注射葡萄糖均有高胰岛素血症。在高胰岛素血症的两个生理水平（约240和450 pM[约40和75微单位/毫升]）下测量的胰岛素介导的葡萄糖处置（胰岛素钳夹技术）分别降低了43%和33%。在低剂量和高剂量胰岛素钳夹步骤中，主要代表糖原合成的非氧化葡萄糖处置受损是导致胰岛素抵抗的主要缺陷。仅在较低剂量胰岛素钳夹步骤中，观察到葡萄糖氧化略有下降。未证实胰岛素对肝糖生成（HGP）的抑制存在缺陷。在两个高胰岛素血症水平下，胰岛素抑制脂质氧化（通过间接量热法测量）和血浆游离脂肪酸（FFA）浓度的能力均受损。这些结果表明，两位NIDDM患者的糖耐量正常的后代具有高胰岛素血症，并表现出已完全确立的糖尿病状态的所有代谢异常，包括胰岛素抵抗、非氧化葡萄糖处置的主要损害、葡萄糖氧化中数量上不太重要的缺陷，以及胰岛素介导的脂质氧化抑制和血浆FFA浓度降低。
