Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China.
Endocrine. 2018 Dec;62(3):588-601. doi: 10.1007/s12020-018-1700-7. Epub 2018 Aug 12.
Insulin resistance is highly associated with an adverse intrauterine environment. We previously reported that fetal rats exposed to angiotensin II type 1 receptor (ATR) autoantibody (AT1-AA) displayed increased susceptibility to metabolic diseases during middle age. However, the timing of the onset of insulin resistance remains unknown. In this study, we examined the offspring of AT1-AA-positive rats, tracking the development of insulin resistance.
Pregnant rats were intravenously injected with AT1-AA. Afterwards, we collected serum samples and liver tissues of the offspring at various stages, including gestation day 18, 3 weeks (weaning period), 18 weeks (young adulthood), and 48 weeks (middle age) after birth.
Compared with saline control group, hepatic vacuolar degeneration was visible in AT1-AA offspring rats as early as 3 weeks; hyperinsulinemia and impaired glucose tolerance occurred at 18 weeks of age, however, insulin resistance was not observed until 48 weeks. At 18 weeks we detected suppressed protein levels of insulin receptor (IR) but increased levels of IR substrate 1 (IRS1) in the liver of AT1-AA group rats. Interestingly, both IR and IRS1/2 were significantly decreased at 48 weeks. Liver proteomic analysis indicated that the differences in protein expression between the AT1-AA and control rats became more pronounced with age, particularly in terms of mitochondrial energy metabolism.
Rats exposed to AT1-AA in utero developed hyperinsulinemia from young adulthood which subsequently progressed to insulin resistance, and was linked with abnormal hepatic structure and impaired IR signaling. Additionally, dysregulation of energy metabolism may play a fundamental role in predisposing offspring to insulin resistance.
胰岛素抵抗与不良宫内环境高度相关。我们之前报道过，暴露于血管紧张素 II 型 1 型受体（ATR）自身抗体（AT1-AA）的胎鼠在中年时更容易患代谢疾病。然而，胰岛素抵抗的发病时间尚不清楚。在这项研究中，我们检查了 AT1-AA 阳性大鼠的后代，以跟踪胰岛素抵抗的发展。
给怀孕的大鼠静脉注射 AT1-AA。之后，我们在不同阶段收集后代的血清样本和肝组织，包括妊娠第 18 天、3 周（断奶期）、18 周（成年早期）和 48 周（中年）。
与生理盐水对照组相比，AT1-AA 后代大鼠早在 3 周时就出现肝空泡变性；18 周时出现高胰岛素血症和葡萄糖耐量受损，但直到 48 周时才出现胰岛素抵抗。在 18 周时，我们检测到 AT1-AA 组大鼠肝脏中胰岛素受体（IR）的蛋白水平降低，但胰岛素受体底物 1（IRS1）的水平升高。有趣的是，48 周时 IR 和 IRS1/2 均显著降低。肝脏蛋白质组学分析表明，随着年龄的增长，AT1-AA 和对照组大鼠之间的蛋白质表达差异变得更加明显，尤其是在线粒体能量代谢方面。
在子宫内暴露于 AT1-AA 的大鼠从成年早期开始出现高胰岛素血症，随后发展为胰岛素抵抗，这与肝脏结构异常和 IR 信号转导受损有关。此外，能量代谢失调可能在使后代易患胰岛素抵抗方面起着根本作用。
