Intergenerational transmission of glucose intolerance associated with gestational diabetes mellitus

Abstract

OBJECTIVE: To investigate the mechanism of intergenerational transmission of glucose intolerance by in utero high glucose associated with gestational diabetes mellitus (GDM). DESIGN: We established a mouse model of GDM and observed the phenotype of GDM offspring (F1-GDM). Furthermore, we intercrossed male and female F1 adult control (C) and GDM mice and investigated phenotype in F2 offspring. MATERIALS AND METHODS: Mouse model of GDM was induced by a single intraperitoneal injection of streptozotocin on the day of pregnancy. F2 offspring were obtained from 4 groups including (1) C♂-C♀ (2) C♂-GDM♀ (3) GDM♂-C♀ and (4) GDM♂-GDM♀. Intraperitoneal glucose tolerance tests were performed on 3-week-old and 8-week-old mice. Gene expression was detected by real-time quantitative PCR. T test was used to compare with control group. A P<0.05 was considered statistically different. RESULTS: (1) Compared with control group, birth weight decreased in F1-GDM (1.49g, p<0.05) and increased in F2 offspring through the paternal line (C♂-GDM♀=1.65g; GDM♂-C♀=1.72g, p<0.05; GDM♂-GDM♀=1.79g, p<0.05); (2) in F1-GDM, impaired glucose tolerance (IGT) appeared at adult (glucose tolerance test area under curve (AUC)= 167.17, p<0.05), however, IGT in F2 offspring was observed as early as 3-week-old through both parental lineages (AUC of C♂-GDM♀= 226.35, p<0.05; GDM♂-C♀= 255.96, p<0.05; GDM♂-GDM♀= 518.55, p<0.05). IGT in both F1 and F2 generations is linked to impaired function of pancreas, partly because of abnormal Igf2 expression. CONCLUSIONS: During pregnancy, in utero significant high glucose environment of GDM lead to reduced birth weight in first-generation offspring. However, birth weight increased in second first-generation offspring. GDM induced IGT in both first- and second-generation offspring. Sex-specific transmission of phenotypes may be related to epigenetic regulation.