Transgenerational Glucose Intolerance With Igf2/H19 Epigenetic Alterations in Mouse Islet Induced by Intrauterine Hyperglycemia
- Guo-Lian Ding1,
- Fang-Fang Wang1,
- Jing Shu1,
- Shen Tian1,
- Ying Jiang1,
- Dan Zhang1,
- Ning Wang1,
- Qiong Luo1,
- Yu Zhang1,
- Fan Jin1,
- Peter C.K. Leung2,
- Jian-Zhong Sheng3 and
- He-Feng Huang1,4⇓
- 1Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- 2Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- 3Department of Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China
- 4Key Laboratory of Reproductive Genetics, Ministry of Education, Hangzhou, China
- Corresponding author: He-Feng Huang, , or Jian-Zhong Sheng, .
G.-L.D. and F-F.W. contributed equally to this study.
Gestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved and the possibilities of transgenerational transmission are still unclear. We intercrossed male and female adult control and first-generation offspring of GDM (F1-GDM) mice to obtain the second-generation (F2) offspring in four groups: C♂-C♀, C♂-GDM♀, GDM♂-C♀, and GDM♂-GDM♀. We found that birth weight significantly increased in F2 offspring through the paternal line with impaired glucose tolerance (IGT). Regardless of birth from F1-GDM with or without IGT, high risk of IGT appeared as early as 3 weeks in F2 offspring and progressed through both parental lineages, especial the paternal line. IGT in male offspring was more obvious than that in females, with parental characteristics and sex-specific transmission. In both F1 and F2 offspring of GDM, the expression of imprinted genes Igf2 and H19 was downregulated in pancreatic islets, caused by abnormal methylation status of the differentially methylated region, which may be one of the mechanisms for impaired islet ultrastructure and function. Furthermore, altered Igf2 and H19 gene expression was found in sperm of adult F1-GDM, regardless of the presence of IGT, indicating that changes of epigenetics in germ cells contributed to transgenerational transmission.
- Received September 23, 2011.
- Accepted January 21, 2012.
- © 2012 by the American Diabetes Association.
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