Perinatal Research Center, Department of Pediatrics, University of Colorado School of Medicine , Aurora, Colorado.
Department of Radiology, University of Colorado School of Medicine , Aurora, Colorado.
Am J Physiol Regul Integr Comp Physiol. 2019 May 1;316(5):R427-R440. doi: 10.1152/ajpregu.00359.2018. Epub 2019 Feb 13.
Intrauterine growth-restricted (IUGR) fetal sheep have increased hepatic glucose production (HGP) that is resistant to suppression during a hyperinsulinemic-isoglycemic clamp (insulin clamp). We hypothesized that the IUGR fetal liver would have activation of metabolic and signaling pathways that support HGP and inhibition of insulin-signaling pathways. To test this, we used transcriptomic profiling with liver samples from control (CON) and IUGR fetuses receiving saline or an insulin clamp. The IUGR liver had upregulation of genes associated with gluconeogenesis/glycolysis, transcription factor regulation, and cytokine responses and downregulation of genes associated with cholesterol synthesis, amino acid degradation, and detoxification pathways. During the insulin clamp, genes associated with cholesterol synthesis and innate immune response were upregulated in CON and IUGR. There were 20-fold more genes differentially expressed during the insulin clamp in IUGR versus CON. These genes were associated with proteasome activation and decreased amino acid and lipid catabolism. We found increased , , and expression and decreased expression as molecular targets for increased HGP in IUGR. As candidate genes for resistance to insulin's suppression of HGP, expression of , , and increased more during the insulin clamp in CON compared with IUGR. Metabolites were measured with H-nuclear magnetic resonance and support increased amino acid concentrations, decreased mitochondria activity and energy state, and increased cell stress in the IUGR liver. These results demonstrate a robust response, beyond suppression of HGP, during the insulin clamp and coordinate responses in glucose, amino acid, and lipid metabolism in the IUGR fetus.
宫内发育受限（IUGR）胎儿的肝脏葡萄糖生成（HGP）增加，在高胰岛素-等血糖钳夹（胰岛素钳夹）期间对抑制作用有抗性。我们假设 IUGR 胎儿肝脏将具有支持 HGP 的代谢和信号通路的激活以及胰岛素信号通路的抑制。为此，我们使用来自接受生理盐水或胰岛素钳夹的对照（CON）和 IUGR 胎儿的肝组织进行了转录组谱分析。IUGR 肝脏中与糖异生/糖酵解、转录因子调节和细胞因子反应相关的基因上调，与胆固醇合成、氨基酸降解和解毒途径相关的基因下调。在胰岛素钳夹期间，与胆固醇合成和固有免疫反应相关的基因在 CON 和 IUGR 中上调。在 IUGR 与 CON 相比，胰岛素钳夹期间差异表达的基因多 20 倍。这些基因与蛋白酶体激活以及氨基酸和脂质分解代谢减少有关。我们发现，在 IUGR 中，作为 HGP 增加的分子靶标， 、 和 表达增加，而 表达减少。作为对胰岛素抑制 HGP 作用的抗性的候选基因，与 CON 相比，在 CON 中， 、 和 表达在胰岛素钳夹期间增加更多。使用 H-核磁共振测量代谢物，并支持氨基酸浓度增加、线粒体活性和能量状态降低以及 IUGR 肝脏细胞应激增加。这些结果表明，在胰岛素钳夹期间存在除抑制 HGP 以外的强大反应，并在葡萄糖、氨基酸和脂质代谢中协调 IUGR 胎儿的反应。
