Groop L C, Saloranta C, Shank M, Bonadonna R C, Ferrannini E, DeFronzo R A
Fourth Department of Medicine, Helsinki University Hospital, Finland.
J Clin Endocrinol Metab. 1991 Jan;72(1):96-107. doi: 10.1210/jcem-72-1-96.
To investigate the mechanisms of insulin resistance in obesity and noninsulin-dependent diabetes mellitus (NIDDM), we examined oxidative and nonoxidative pathways of free fatty acid (FFA) and glucose metabolism in 14 lean and 17 obese (with normal oral glucose tolerance) nondiabetic subjects and in 8 lean and 8 obese subjects with NIDDM. FFA and glucose metabolism were measured using the sequential insulin clamp technique in combination with indirect calorimetry and infusion of [3-3H]glucose and [1-14C]palmitate. Obesity was characterized by enlarged fat mass, which correlated positively with the plasma FFA concentration (r = 0.62; P less than 0.01). FFA metabolism was less sensitive to insulin in obese than in lean nondiabetic subjects, but this defect could be overcome by increasing the plasma insulin concentration. NIDDM patients showed normal sensitivity to the inhibitory action of insulin on FFA metabolism; however, maximal suppression by insulin was impaired. The combination of obesity and NIDDM was associated with a further enhancement of reesterification of FFA than observed in either condition alone. In both obesity and NIDDM, the dose-response curve for suppression of hepatic glucose production by insulin was impaired. While obesity was primarily characterized by reduced sensitivity to the stimulatory action of insulin on oxidative and nonoxidative pathways of glucose metabolism, resistance to the effect of insulin on glucose metabolism in NIDDM was characterized by a reduced maximal response. The combination of obesity and NIDDM further impaired the sensitivity of liver glucose output and glucose oxidation to insulin. The hypothesis is advanced that in uncomplicated obesity, increased availability and oxidation of FFA leads, by the FFA/glucose cycle, to the impairment in glucose utilization. In NIDDM, on the other hand, the defect in glucose utilization is primary, and the enhanced rate of FFA oxidation may represent a compensatory phenomenon.
为研究肥胖症和非胰岛素依赖型糖尿病（NIDDM）中胰岛素抵抗的机制，我们检测了14名体重正常的非糖尿病受试者、17名肥胖（口服葡萄糖耐量正常）的非糖尿病受试者以及8名体重正常的NIDDM受试者和8名肥胖的NIDDM受试者的游离脂肪酸（FFA）氧化和非氧化途径以及葡萄糖代谢情况。采用连续胰岛素钳夹技术结合间接测热法，并输注[3-³H]葡萄糖和[1-¹⁴C]棕榈酸来测定FFA和葡萄糖代谢。肥胖症的特征是脂肪量增加，且与血浆FFA浓度呈正相关（r = 0.62；P < 0.01）。与体重正常的非糖尿病受试者相比，肥胖受试者的FFA代谢对胰岛素的敏感性较低，但通过提高血浆胰岛素浓度可克服这一缺陷。NIDDM患者对胰岛素抑制FFA代谢的作用表现出正常的敏感性；然而，胰岛素的最大抑制作用受损。肥胖与NIDDM并存时，FFA再酯化作用比单独存在这两种情况时进一步增强。在肥胖症和NIDDM中，胰岛素抑制肝葡萄糖生成的剂量-反应曲线均受损。肥胖症主要表现为对胰岛素刺激葡萄糖代谢氧化和非氧化途径的敏感性降低，而NIDDM中对胰岛素葡萄糖代谢作用的抵抗则表现为最大反应降低。肥胖与NIDDM并存进一步损害了肝脏葡萄糖输出和葡萄糖氧化对胰岛素的敏感性。我们提出假说：在单纯性肥胖症中，FFA可用性和氧化增加通过FFA/葡萄糖循环导致葡萄糖利用受损。另一方面，在NIDDM中，葡萄糖利用缺陷是原发性的，FFA氧化速率增加可能是一种代偿现象。
