Hyperinsulinemia precedes insulin resistance in offspring rats exposed to angiotensin II type 1 autoantibody in utero
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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.
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.
KeywordsInsulin resistance Autoantibody Angiotensin II type 1 receptor Offspring Liver
The authors thank Ligang Deng for technical assistance in liver proteomics.
This work was funded by grants from the Major Research Plan of the National Natural Science Foundation of China (NSFC; Grant no. 91539205) to Huirong Liu, NSFC (Grant no. 31771267 and 81300694) to Suli Zhang and NSFC (Grant no.81471478) to Xiaoli Yang.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 7.Z. Jin, W. Zhang, H. Yang, X. Wang, Y. Zheng, Q. Zhang, J. Zhi, Maternal treatment with agonistic autoantibodies against type-1 angiotensin II receptor in late pregnancy increases apoptosis of myocardial cells and myocardial susceptibility to ischemia-reperfusion injury in offspring rats. PLoS ONE 8, e80709 2013).CrossRefPubMedPubMedCentralGoogle Scholar
- 8.F. Herse, S. Verlohren, K. Wenzel, J. Pape, D.N. Muller, S. Modrow, G. Wallukat, F.C. Luft, C.W. Redman, R. Dechend, Prevalence of agonistic autoantibodies against the angiotensin II type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational age-matched case study. Hypertension 53, 393–398 (2009)CrossRefPubMedGoogle Scholar
- 10.F. Herse, S. Verlohren, K. Wenzel, J. Pape, D.N. Muller, S. Modrow, G. Wallukat, F.C. Luft, C.W. Redman, R. Dechend, Prevalence of agonistic autoantibodies against the angiotensin II type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational age-matched case study. Hypertension 53, 393–398 (2009)CrossRefPubMedGoogle Scholar
- 12.C.C. Zhou, R.A. Irani, Y. Zhang, S.C. Blackwell, T. Mi, J. Wen, H. Shelat, Y.J. Geng, S.M. Ramin, R.E. Kellems, Y. Xia, Angiotensin receptor agonistic autoantibody-mediated tumor necrosis factor-alpha induction contributes to increased soluble endoglin production in preeclampsia. Circulation 121, 436–444 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
- 15.S. Zhang, X. Zhang, L. Yang, Z. Yan, L. Yan, J. Tian, X. Li, L. Song, L. Wang, X. Yang, R. Zheng, W. Lau, X. Ma, H. Liu, Increased susceptibility to metabolic syndrome in adult offspring of angiotensin type 1 receptor autoantibody-positive rats. Antioxid. Redox Signal. 17, 733–743 (2012)CrossRefPubMedGoogle Scholar
- 17.L.V. Renna, F. Bosè, S. Iachettini, B. Fossati, L. Saraceno, V. Milani, R. Colombo, G. Meola, R. Cardani, Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle. PLoS ONE 12, e0184987 2017).CrossRefPubMedPubMedCentralGoogle Scholar
- 19.V.S. Effoe, L.E. Wagenknecht, J.B. Echouffo-Tcheugui, H. Chen, J.J. Joseph, R.R. Kalyani, R.A. Bell, W.H. Wu, R. Casanova, A.G. Bertoni, Sex differences in the association between insulin resistance and incident coronary heart disease and stroke among blacks without diabetes mellitus: the Jackson Heart Study. J. Am. Heart Assoc. 6, e004229 2017).CrossRefPubMedPubMedCentralGoogle Scholar
- 25.E. Mourmoura, K. Couturier, I. Hininger-Favier, C. Malpuech-Brugère, K. Azarnoush, M. Richardson, L. Demaison, Functional changes of the coronary microvasculature with aging regarding glucose tolerance, energy metabolism, and oxidative stress. Age 36, 9670 (2014)CrossRefPubMedPubMedCentralGoogle Scholar