Czech M P, Malbon C C, Kerman K, Gitomer W, Pilch P F
J Clin Invest. 1980 Sep;66(3):574-82. doi: 10.1172/JCI109889.
Isolated adipocytes and soleus muscles prepared from mature rats, rendered hypothyroid by a low iodine diet and propylthiouracil, markedly resisted the ability of insulin to increase glucose utilization. In adipocytes, the sum of basal d-(1-(14)C)-glucose conversion to CO(2), glyceride-glycerol, and fatty acid was unaltered by hypothyroidism, although conversion to fatty acid was decreased. The response of each of these metabolic pathways to insulin at all concentrations tested was greatly diminished in hypothyroid rat adipocytes. 3-O-Methylglucose transport rates in the presence of insulin were not significantly different in adipocytes from hypothyroid as compared with euthyroid rats, although basal transport rates were significantly higher in the hypothyroid state. Lipolysis and cyclic AMP accumulation in adipocytes from hypothyroid rats in response to theophylline were markedly diminished compared with euthyroid controls, but insulin was about as effective in inhibiting lipolysis in these cells as in those derived from euthyroid animals. The binding of (125)I-insulin to adipocytes at several hormone concentrations was also shown to be unaffected by hypothyroidism. In soleus muscle, basal glucose conversion to H(2)O and glycogen was unaltered in the hypothyroid state, whereas insulin action on these pathways was markedly inhibited. The decrease in muscle insulin responsiveness was less marked than that observed in adipocytes. Uptake of either 2-deoxyglucose or l-arabinose in the presence or absence of insulin was similar in soleus muscles derived from euthryoid vs. hypothyroid rats. Similarly, insulin action on the conversion of soleus muscle glycogen synthase D to the I form in the absence of glucose was unaltered by hypothyroidism. We conclude that (a) hypothyroidism in mature rats leads to a marked decrease in the responsiveness of glucose metabolism in adipocytes and skeletal muscle to insulin; (b) no detectable impairment of the membrane insulin effector systems that mediate the regulation of adipocyte hexose transport and glycogen synthase is caused by hypothyroidism in this animal model; and (c) the cellular defect that leads to apparent insulin resistance of adipocyte and soleus muscle glucose utilization resides at the level of one or more intracellular enzymes involved in glucose catabolism.
从成熟大鼠制备的分离脂肪细胞和比目鱼肌，通过低碘饮食和丙硫氧嘧啶使其甲状腺功能减退，对胰岛素增加葡萄糖利用的能力有明显抵抗。在脂肪细胞中，基础d-（1-（14）C）-葡萄糖转化为CO₂、甘油甘油和脂肪酸的总和在甲状腺功能减退时未改变，尽管转化为脂肪酸的量减少。在所有测试浓度下，这些代谢途径中每一条对胰岛素的反应在甲状腺功能减退的大鼠脂肪细胞中都大大减弱。与甲状腺功能正常的大鼠相比，甲状腺功能减退的大鼠脂肪细胞在有胰岛素存在时3-O-甲基葡萄糖转运速率无显著差异，尽管基础转运速率在甲状腺功能减退状态下显著更高。与甲状腺功能正常的对照相比，甲状腺功能减退的大鼠脂肪细胞对茶碱的脂解和环磷酸腺苷积累明显减少，但胰岛素在抑制这些细胞脂解方面与在甲状腺功能正常动物来源的细胞中一样有效。在几种激素浓度下，（125）I-胰岛素与脂肪细胞的结合也显示不受甲状腺功能减退的影响。在比目鱼肌中，基础葡萄糖转化为H₂O和糖原在甲状腺功能减退状态下未改变，而胰岛素对这些途径的作用明显受到抑制。肌肉胰岛素反应性的降低不如在脂肪细胞中观察到的明显。在有或无胰岛素存在的情况下，甲状腺功能正常与甲状腺功能减退的大鼠比目鱼肌对2-脱氧葡萄糖或l-阿拉伯糖的摄取相似。同样，在无葡萄糖时，胰岛素对比目鱼肌糖原合酶D转化为I型的作用不受甲状腺功能减退的影响。我们得出结论：（a）成熟大鼠的甲状腺功能减退导致脂肪细胞和骨骼肌中葡萄糖代谢对胰岛素的反应性显著降低；（b）在该动物模型中，甲状腺功能减退不会导致介导脂肪细胞己糖转运和糖原合酶调节的膜胰岛素效应系统出现可检测到的损害；（c）导致脂肪细胞和比目鱼肌葡萄糖利用出现明显胰岛素抵抗的细胞缺陷存在于参与葡萄糖分解代谢的一种或多种细胞内酶水平。
