Shadoan Melanie K, Kavanagh Kylie, Zhang Li, Anthony Mary S, Wagner Janice D
Department of Endocrinology, Lexicon Pharmaceuticals, The Woodlands, TX 77381, USA.
Metabolism. 2007 Jun;56(6):830-7. doi: 10.1016/j.metabol.2007.01.014.
The purpose of this study was to determine if the insulin resistance we have previously reported in surgically postmenopausal primates treated with combined hormone therapy (HT) is due in part to effects on adipose tissue. Eighty-seven ovariectomized monkeys were fed a moderately atherogenic diet (0.28 mg cholesterol per kilocalorie [0.07 mg/kJ]) and randomized to receive no hormones (control, n = 29), estrogen therapy (ET, conjugated equine estrogens, 0.625 mg/d human equivalent; n = 29), or HT (ET + medroxyprogesterone acetate, 2.5 mg/d human equivalent; n = 29) in the diet for 2 years. Fasting glycemic measures were made at baseline and at the end of treatment. Circulating adiponectin measures, insulin tolerance tests, glucose tolerance tests, and isolated adipocyte glucose uptake assays were performed at the end of the trial. Hormone therapy-treated animals were insulin resistant, as determined by greater fasting insulin concentrations (P = .008), greater homeostasis model assessment of insulin resistance (HOMA-R) value (P = .005) and slower glucose disposal after insulin administration (K(ITT); P = .02) when compared with controls. Subcutaneous adipocytes from HT-treated monkeys had a greater ED(50) for insulin (P = .04) and lower maximal glucose uptake per cell (P < .001) compared with controls, suggesting impaired adipocyte insulin sensitivity. Adipocytes were smaller (P = .001) and adiponectin concentrations were greatest in the ET group (P = .02), with no difference between controls and HT-treated monkeys. In conclusion, estrogen therapy resulted in smaller adipocyte size and greater adiponectin concentrations than control or HT. Hormone therapy resulted in impaired insulin sensitivity and adipocyte glucose uptake compared with controls, whereas there was no difference between ET and controls. Because no adverse effects were found with ET alone, it is likely that the progestin, medroxyprogesterone acetate, resulted in the negative effects of the combined HT regimen on whole-body insulin sensitivity, which were mediated, in part, by reductions in adipose tissue responses to insulin.
本研究的目的是确定我们先前报道的接受联合激素疗法（HT）治疗的手术绝经后灵长类动物中的胰岛素抵抗是否部分归因于对脂肪组织的影响。87只去卵巢猴子被喂食中度致动脉粥样化饮食（每千卡0.28毫克胆固醇[0.07毫克/千焦]），并随机分为在饮食中不接受激素（对照组，n = 29）、雌激素疗法（ET，结合马雌激素，0.625毫克/天人类等效剂量；n = 29）或HT（ET + 醋酸甲羟孕酮，2.5毫克/天人类等效剂量；n = 29），为期2年。在基线和治疗结束时进行空腹血糖测量。在试验结束时进行循环脂联素测量、胰岛素耐量试验、葡萄糖耐量试验和分离的脂肪细胞葡萄糖摄取测定。与对照组相比，激素疗法治疗的动物存在胰岛素抵抗，这通过更高的空腹胰岛素浓度（P = 0.008）、更高的胰岛素抵抗稳态模型评估（HOMA-R）值（P = 0.005）以及胰岛素给药后葡萄糖清除较慢（K(ITT)；P = 0.02）来确定。与对照组相比，HT治疗猴子的皮下脂肪细胞对胰岛素的半数有效剂量（ED(50)）更高（P = 0.04），每个细胞的最大葡萄糖摄取更低（P < 0.001），表明脂肪细胞胰岛素敏感性受损。脂肪细胞更小（P = 0.001），脂联素浓度在ET组中最高（P = 0.02），对照组和HT治疗猴子之间无差异。总之，与对照组或HT相比，雌激素疗法导致脂肪细胞尺寸更小且脂联素浓度更高。与对照组相比，激素疗法导致胰岛素敏感性和脂肪细胞葡萄糖摄取受损，而ET与对照组之间无差异。由于单独使用ET未发现不良反应，很可能是醋酸甲羟孕酮这种孕激素导致联合HT方案对全身胰岛素敏感性产生负面影响，这部分是由脂肪组织对胰岛素反应的降低介导的。
