Boden G
Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Exp Clin Endocrinol Diabetes. 2003 May;111(3):121-4. doi: 10.1055/s-2003-39781.
Most obese individuals have elevated plasma levels of free fatty acids (FFA) which are known to cause peripheral (muscle) insulin resistance. They do this by inhibiting insulin-stimulated glucose uptake and glycogen synthesis. The mechanism involves intramyocellular accumulation of diacylglycerol and activation of protein kinase C. FFAs also cause hepatic insulin resistance. They do this by inhibiting insulin-mediated suppression of glycogenolysis. On the other hand, FFAs support between 30 and 50 % of basal insulin secretion and potentiate glucose-stimulated insulin secretion. The insulin stimulatory action of FFAs is responsible for the fact that the vast majority ( approximately 80 %) of obese insulin resistant people do not develop type 2 diabetes. They are able to compensate for their FFA mediated insulin resistance with increased FFA mediated insulin secretion. Individuals who are unable to do this (probably for genetic reasons) eventually develop type 2 diabetes. FFAs have recently been shown to activate the IkappaB/NFkappaB pathway which is involved in many inflammatory processes. Thus, elevated plasma levels of FFAs are not only a major cause of insulin resistance in skeletal muscle and liver but may, in addition, play a role in the pathogenesis of coronary artery disease.
大多数肥胖个体的血浆游离脂肪酸（FFA）水平升高，已知游离脂肪酸会导致外周（肌肉）胰岛素抵抗。它们通过抑制胰岛素刺激的葡萄糖摄取和糖原合成来实现这一点。其机制涉及二酰甘油在肌细胞内的积累和蛋白激酶C的激活。游离脂肪酸还会导致肝脏胰岛素抵抗。它们通过抑制胰岛素介导的糖原分解抑制作用来实现这一点。另一方面，游离脂肪酸支持30%至50%的基础胰岛素分泌，并增强葡萄糖刺激的胰岛素分泌。游离脂肪酸的胰岛素刺激作用解释了绝大多数（约80%）肥胖胰岛素抵抗人群不会患2型糖尿病这一事实。他们能够通过增加游离脂肪酸介导的胰岛素分泌来补偿游离脂肪酸介导的胰岛素抵抗。无法做到这一点的个体（可能是由于遗传原因）最终会发展为2型糖尿病。最近研究表明，游离脂肪酸可激活参与许多炎症过程的IkappaB/NFkappaB途径。因此，血浆游离脂肪酸水平升高不仅是骨骼肌和肝脏胰岛素抵抗的主要原因，此外还可能在冠状动脉疾病的发病机制中起作用。
