title: Transgenerational glucose intolerance with Igf2/H19 epigenetic alterations in mouse islet induced by intrauterine hyperglycemia.
abstract: 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.
authors.affiliation: Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Guo-Lian
authors.initials: GL
authors.lastname: Ding
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Shu
authors.forename: Shen
authors.initials: S
authors.lastname: Tian
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Luo
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fan
authors.initials: F
authors.lastname: Jin
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Sheng
authors.forename: He-Feng
authors.initials: HF
authors.lastname: Huang
mesh_terms: D000818:Animals; D001786:Blood Glucose; D016640:Diabetes, Gestational; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance; D006943:Hyperglycemia / Q000209:etiology* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D009929:Organ Size; D010179:Pancreas / Q000033:anatomy & histology; D011247:Pregnancy; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C094335:H19 long non-coding RNA; C513121:IGF2 protein, mouse; D007328:Insulin; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II