Boden G
Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University Hospital, Philadelphia, PA 19140, USA.
Proc Assoc Am Physicians. 1999 May-Jun;111(3):241-8. doi: 10.1046/j.1525-1381.1999.99220.x.
Evidence is presented that shows that free fatty acids (FFA) are one important link between obesity, insulin resistance, and type 2 diabetes. Plasma FFA levels are elevated in most obese subjects, and physiological elevations of plasma FFA inhibit insulin-stimulated glucose uptake into muscle. This peripheral insulin resistance is caused by an FFA-induced defect, which develops 3-4 hr after raising plasma FFA, in insulin-stimulated glucose transport or phosphorylation, or both. This resistance is also caused by a second defect, which develops after 4-6 hr, consisting of inhibition of glycogen synthase activity. Whether elevated plasma FFA levels inhibit insulin action on endogenous glucose production (EGP), that is, cause central insulin resistance, is more difficult to demonstrate. On the one hand, FFA increase gluconeogenesis, which enhances EGP; on the other hand, FFA increase insulin secretion, which decreases EGP. Basal plasma FFA support approximately one third of basal insulin secretion in diabetic and nondiabetic subjects and, hence, are responsible for some of the hyperinsulinemia in obese, normoglycemic patients. In addition, elevated plasma FFA levels potentiate glucose-stimulated insulin secretion acutely and during prolonged exposure (48 hr). It is hypothesized that obese subjects who are genetically predisposed to develop type 2 diabetes will become partially "lipid blind," that is, unable to compensate for their FFA-induced insulin resistance with FFA-induced insulin oversecretion. The resulting insulin resistance/secretion deficit will then have to be compensated for with glucose-induced insulin secretion, which, because of their partial "glucose blindness," will result in hyperglycemia and eventually in type 2 diabetes.
有证据表明，游离脂肪酸（FFA）是肥胖、胰岛素抵抗和2型糖尿病之间的一个重要联系。大多数肥胖受试者的血浆FFA水平升高，血浆FFA的生理性升高会抑制胰岛素刺激的葡萄糖进入肌肉的摄取。这种外周胰岛素抵抗是由FFA诱导的缺陷引起的，该缺陷在血浆FFA升高后3 - 4小时出现，涉及胰岛素刺激的葡萄糖转运或磷酸化，或两者皆有。这种抵抗还由另一个缺陷引起，该缺陷在4 - 6小时后出现，包括糖原合酶活性的抑制。血浆FFA水平升高是否会抑制胰岛素对内源性葡萄糖生成（EGP）的作用，即是否会导致中枢胰岛素抵抗，更难证明。一方面，FFA增加糖异生，从而增强EGP；另一方面，FFA增加胰岛素分泌，从而降低EGP。基础血浆FFA在糖尿病和非糖尿病受试者中支持约三分之一的基础胰岛素分泌，因此，是肥胖、血糖正常患者高胰岛素血症的部分原因。此外，血浆FFA水平升高在急性和长时间暴露（48小时）期间都会增强葡萄糖刺激的胰岛素分泌。据推测，具有2型糖尿病遗传易感性的肥胖受试者将部分变得“对脂质不敏感”，即无法通过FFA诱导的胰岛素分泌过多来补偿其FFA诱导的胰岛素抵抗。由此产生的胰岛素抵抗/分泌缺陷将不得不通过葡萄糖诱导的胰岛素分泌来补偿，而由于他们部分“对葡萄糖不敏感”，这将导致高血糖并最终导致2型糖尿病。
