Hyperinsulinemia precedes insulin resistance in offspring rats exposed to angiotensin II type 1 autoantibody in utero
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ORIGINAL ARTICLE
Hyperinsulinemia precedes insulin resistance in offspring rats exposed to angiotensin II type 1 autoantibody in utero Suli Zhang1 Mingming Wei1 Mingming Yue1 Pengli Wang1 Xiaochen Yin1 Li Wang2 Xiaoli Yang3 Huirong Liu 1,4 ●
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Received: 19 March 2018 / Accepted: 26 July 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract Objective Insulin resistance is highly associated with an adverse intrauterine environment. We previously reported that fetal rats exposed to angiotensin II type 1 receptor (AT1R) 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. Methods 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. Results 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. Conclusion 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. Keywords Insulin resistance Autoantibody Angiotensin II type 1 receptor Offspring Liver ●
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Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12020-018-1700-7) contains supplementary material, which is available to authorized users. * Huirong Liu [email protected] 1
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
2
Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China
3
Department of Reproductive Center, Taiyuan Central Hospital, Taiyuan, Shanxi, China
4
Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease, Capital Medical University, Beijing, China
Insulin resistance is a pathological state in which insulin action in peripheral target tissues (liver,
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