THE ROLE OF FREE FATTY-ACID METABOLISM IN THE PATHOGENESIS OF INSULIN RESISTANCE IN OBESITY AND NONINSULIN-DEPENDENT DIABETES-MELLITUS
THE ROLE OF FREE FATTY-ACID METABOLISM IN THE PATHOGENESIS OF INSULIN RESISTANCE IN OBESITY AND NONINSULIN-DEPENDENT DIABETES-MELLITUS
复制标题
DOI：
10.1210/jcem-72-1-96
复制
发表时间：
1991-01-01
影响因子：
5.8
通讯作者：
DEFRONZO, RA
中科院分区：
文献类型：
--
作者：
GROOP, LC;SALORANTA, C;DEFRONZO, RA
为了研究肥胖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名消瘦的非糖尿病受试者、17名肥胖（口服葡萄糖耐量正常）的非糖尿病受试者以及8名消瘦的和8名肥胖的NIDDM患者体内游离脂肪酸（FFA）和葡萄糖代谢的氧化及非氧化途径。采用序贯胰岛素钳夹技术，结合间接测热法以及输注[3 - H - 3]葡萄糖和[1 - C - 14]棕榈酸来测定FFA和葡萄糖代谢。肥胖的特征是脂肪量增加，这与血浆FFA浓度呈正相关（r = 0.62；P < 0.01）。与消瘦的非糖尿病受试者相比，肥胖者的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以克服这一缺陷。NIDDM患者对胰岛素抑制FFA代谢的作用敏感性正常；然而，胰岛素的最大抑制作用受损。肥胖合并NIDDM与单独出现肥胖或NIDDM相比，FFA的再酯化作用进一步增强。在肥胖和NIDDM中，胰岛素抑制肝糖生成的剂量 - 反应曲线均受损。肥胖主要表现为对胰岛素刺激葡萄糖代谢的氧化及非氧化途径的敏感性降低，而NIDDM中对胰岛素影响葡萄糖代谢的抵抗表现为最大反应降低。肥胖合并NIDDM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。提出的假说是，在单纯性肥胖中，FFA的可利用性增加和氧化，通过FFA/葡萄糖循环，导致葡萄糖利用受损。另一方面，在NIDDM中，葡萄糖利用的缺陷是原发性的，FFA氧化速率的增加可能是一种代偿现象。
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-H-3]glucose and [1-C-14]palmitate. Obesity was characterized by enlarged fat mass, which correlated positively with the plasma FFA concentration (r = 0.62; P < 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 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.