Cerny David, Sartori Claudio, Rimoldi Stefano F, Meister Théo, Soria Rodrigo, Bouillet Elisa, Scherrer Urs, Rexhaj Emrush
Departments of Cardiology.
Clinical Research, University Hospital Bern, 3010 Bern, Switzerland.
Endocrinology. 2017 May 1;158(5):1152-1159. doi: 10.1210/en.2016-1475.
Assisted reproductive technology (ART) alters glucose homeostasis in mice and humans, but the underlying mechanisms are incompletely understood. ART induces endothelial dysfunction and arterial hypertension by epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene. In eNOS-deficient mice, insulin resistance is related to impaired insulin stimulation of muscle blood flow and substrate delivery and defective intrinsic skeletal muscle glucose uptake. We therefore assessed glucose tolerance, insulin sensitivity (euglycemic clamp), insulin stimulation of muscle blood flow in vivo, and muscle glucose uptake in vitro in male ART and control mice fed a normal chow (NC) or challenged with a high-fat diet (HFD) during 8 weeks. Glucose tolerance and insulin sensitivity were similar in NC-fed animals. When challenged with a HFD, however, ART mice developed exaggerated obesity, fasting hyperinsulinemia and hyperglycemia, and a 20% lower insulin-stimulated glucose utilization than did control mice (steady-state glucose infusion rate (GIR), 51.3 ± 7.3 vs 64.0 ± 10.8 mg/kg/min, P = 0.012). ART-induced insulin resistance was associated with defective insulin stimulation of muscle blood flow, whereas intrinsic skeletal muscle glucose uptake was normal. In conclusion, ART-induced endothelial dysfunction, when challenged with a metabolic stress, facilitates glucose intolerance and insulin resistance. Similar mechanisms may contribute to ART-induced alterations of the metabolic phenotype in humans.
辅助生殖技术（ART）会改变小鼠和人类的葡萄糖稳态，但其潜在机制尚未完全明确。ART通过内皮型一氧化氮合酶（eNOS）基因的表观遗传改变诱导内皮功能障碍和动脉高血压。在eNOS基因缺陷的小鼠中，胰岛素抵抗与胰岛素刺激的肌肉血流和底物输送受损以及骨骼肌内在葡萄糖摄取缺陷有关。因此，我们评估了雄性ART小鼠和对照小鼠在喂食正常饲料（NC）或接受8周高脂饮食（HFD）挑战后的葡萄糖耐量、胰岛素敏感性（正常血糖钳夹）、体内胰岛素刺激的肌肉血流以及体外肌肉葡萄糖摄取情况。在喂食NC的动物中，葡萄糖耐量和胰岛素敏感性相似。然而，当接受HFD挑战时，ART小鼠出现了更严重的肥胖、空腹高胰岛素血症和高血糖，并且胰岛素刺激的葡萄糖利用率比对照小鼠低20%（稳态葡萄糖输注率（GIR），51.3±7.3对64.0±10.8mg/kg/min, P = 0.012）。ART诱导的胰岛素抵抗与胰岛素刺激的肌肉血流缺陷有关，而骨骼肌内在葡萄糖摄取正常。总之，当受到代谢应激挑战时，ART诱导的内皮功能障碍会促进葡萄糖不耐受和胰岛素抵抗。类似的机制可能导致人类ART引起的代谢表型改变。
