Boden G
Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, PA, USA.
Front Biosci. 1998 Feb 15;3:d169-75. doi: 10.2741/a272.
Evidence, gained from human studies, is reviewed showing that elevation of plasma FFA levels produce peripheral and probably also hepatic insulin resistance in obese healthy and diabetic subjects. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations of plasma FFA inhibit acutely as well as chronically insulin stimulated glucose uptake in a dose dependent fashion. Responsible for this inhibition is a FFA induced defect in insulin stimulated glucose transport and/or phosphorylation which develops after 3-4 hours of raising plasma FFA and a second defect, consisting of inhibition of glycogen synthase, the rate limiting enzyme of glycogen synthesis, which develops after 4-6 hours. FFA induced inhibition of fatty acid oxidation (Randle effect) does not affect insulin stimulated glucose uptake or glycogen synthesis and thus does not cause insulin resistance. Elevated plasma FFA levels also modestly increase insulin suppressed endogenous glucose production (EGP) although this effect has not been found by all investigators. The reasons why it has been difficult to demonstrate unequivocal effects of FFA on EGP include 1) the fact that FFA promote insulin secretion which counteracts its effect on EGP (FFA increase, while insulin decreases EGP); 2) the recognition that FFA induced increase in gluconeogenesis may be compensated by intrahepatic downregulation of EGP (i.e., by a decrease in glycogenolysis). The FFA induced insulin resistance is physiologically important during starvation by preserving carbohydrate for oxidation in the central nervous system and during pregnancy, where the well recognized accelerated starvation pattern provides carbohydrate for the growing fetus. In obesity, however, there is no need to spare carbohydrate and the FFA induced insulin resistance may result in type 2 diabetes and other cardiovascular risk factors.
来自人体研究的证据显示，在肥胖的健康受试者和糖尿病患者中，血浆游离脂肪酸（FFA）水平升高会导致外周胰岛素抵抗，可能还会导致肝脏胰岛素抵抗。首先，大多数肥胖受试者的血浆FFA水平升高。其次，血浆FFA的生理性升高会以剂量依赖的方式急性和慢性抑制胰岛素刺激的葡萄糖摄取。造成这种抑制的原因是，血浆FFA升高3-4小时后会出现FFA诱导的胰岛素刺激的葡萄糖转运和/或磷酸化缺陷，以及4-6小时后出现的第二个缺陷，即糖原合成限速酶糖原合酶受到抑制。FFA诱导的脂肪酸氧化抑制（兰德尔效应）不会影响胰岛素刺激的葡萄糖摄取或糖原合成，因此不会导致胰岛素抵抗。血浆FFA水平升高也会适度增加胰岛素抑制的内源性葡萄糖生成（EGP），不过并非所有研究人员都发现了这种效应。难以明确证明FFA对EGP有明确作用的原因包括：1）FFA会促进胰岛素分泌，这抵消了其对EGP的作用（FFA增加，而胰岛素降低EGP）；2）认识到FFA诱导的糖异生增加可能会被肝内EGP下调（即糖原分解减少）所补偿。在饥饿期间，FFA诱导的胰岛素抵抗通过为中枢神经系统保留碳水化合物以供氧化，以及在怀孕期间，通过为生长中的胎儿提供碳水化合物的公认加速饥饿模式，在生理上具有重要意义。然而，在肥胖症中，无需节省碳水化合物，FFA诱导的胰岛素抵抗可能会导致2型糖尿病和其他心血管危险因素。
