, Volume 62, Issue 3, pp 588–601 | Cite as

Hyperinsulinemia precedes insulin resistance in offspring rats exposed to angiotensin II type 1 autoantibody in utero

  • Suli Zhang
  • Mingming Wei
  • Mingming Yue
  • Pengli Wang
  • Xiaochen Yin
  • Li Wang
  • Xiaoli Yang
  • Huirong LiuEmail author
Original Article



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.


Insulin 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.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

12020_2018_1700_MOESM1_ESM.xlsx (123 kb)
Supplementary Table


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Physiology & Pathophysiology, School of Basic Medical SciencesCapital Medical UniversityBeijingChina
  2. 2.Department of PathologyShanxi Medical UniversityTaiyuanChina
  3. 3.Department of Reproductive CenterTaiyuan Central HospitalTaiyuanChina
  4. 4.Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular DiseaseCapital Medical UniversityBeijingChina

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