Boden G, Chen X
Division of Endocrinology/Metabolism, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
J Clin Invest. 1995 Sep;96(3):1261-8. doi: 10.1172/JCI118160.
It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus.
本研究旨在确定游离脂肪酸（FFA）是否会抑制非胰岛素依赖型糖尿病患者胰岛素刺激的全身葡萄糖摄取和利用。我们进行了五种等血糖（约11mM）钳夹试验：（a）仅用胰岛素；（b）胰岛素加脂肪/肝素；（c）胰岛素加甘油；（d）用生理盐水；（e）生理盐水加脂肪/肝素，以及两种正常血糖（约5mM）钳夹试验：（a）仅用胰岛素；（b）胰岛素加脂肪/肝素。在这些研究过程中，我们测定了葡萄糖摄取率、糖酵解（均用3[3H]葡萄糖）、糖原合成（测定为葡萄糖摄取量减去糖酵解量）、碳水化合物氧化（通过间接量热法）和非氧化糖酵解（测定为糖酵解量减去碳水化合物氧化量）。脂肪/肝素输注不影响基础葡萄糖摄取，但在等血糖和正常血糖患者中，当血浆FFA浓度分别约为950和约550μM时，脂肪/肝素输注会抑制总刺激（胰岛素刺激加基础）葡萄糖摄取40 - 50%。在等血糖患者中，总刺激葡萄糖摄取被抑制40 - 50%是由于胰岛素刺激的葡萄糖摄取部分几乎完全被抑制。葡萄糖摄取、糖原合成和糖酵解的比例性抑制表明存在一个主要的FFA介导的缺陷，涉及葡萄糖转运和/或磷酸化。总之，脂肪对胰岛素刺激的葡萄糖摄取和细胞内葡萄糖利用产生了比例性抑制。我们得出结论，生理水平升高的FFA可能是导致非胰岛素依赖型糖尿病患者外周胰岛素抵抗的很大一部分原因。
