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.

Environmental chemical stressors as epigenome modifiers: a new horizon in assessment of toxicological effects

“…It is probable that such epigenetic markers will be used for early molecular diagnosis in those with a predisposition to developing adult diseases due to environmental exposure. For instance, the abnormal methylation of Igf2 and H19 gene expression in sperm of adults may indicate a susceptibility to diabetes in subsequent generations [96]. Furthermore, as the epigenome is modifiable or reversible, this allows for the implementation of strategies to allow disease prevention and targeted treatment.…”

Insulin secretion in health and disease: nutrients dictate the pace

“…This study unveiled that intrauterine hyperglycaemia alters the methylation of the gene and reduces the expression of Igf2/H19 in the islets of Langerhans. Igf2 and H19 expressions were also altered in the sperm of adult progeny from hyperglycaemic mothers, indicating that epigenetic changes in germ cells contribute to transgenerational transmission of metabolic disorders (125) .…”

“…Among the coding-genes and the 493 lncRNA detected in islet cells, multiple SNP were associated with known T2D-associated genes differing according to the normoglycaemic or hyperglycaemic status of the patients (124) . The imprinted lncRNA H19 that is generated from the Igf2 locus has been involved in the transgenerational transmission of epigenetic changes in germ cells in a mouse model of gestational diabetes mellitus (125) . This study unveiled that intrauterine hyperglycaemia alters the methylation of the gene and reduces the expression of Igf2/H19 in the islets of Langerhans.…”

Transgenerational epigenetic inheritance of diabetes risk as a consequence of early nutritional imbalances

“…As we have previously described, gestational diabetes is strongly associated with a higher risk of obesity and diabetes in the offspring (see section Epigenetic inheritance of diabetes risk from nutritional cues). In mice, gestational diabetes has been reported to impair insulin secretion in the offspring (F1), leading to glucose intolerance (92) . Impaired β-cell function was attributed, in part, to reduced expression of the imprinted genes encoding insulin growth factor-2 and H19.…”