Abstract
BackgroundOffspring of women with diabetes in pregnancy are at increased risk of type 2 diabetes mellitus (T2DM), potentially mediated by epigenetic mechanisms. The adipokines leptin, adiponectin, and resistin (genes: LEP, ADIPOQ, RETN) play key roles in the pathophysiology of T2DM. We hypothesized that offspring exposed to maternal diabetes exhibit alterations in epigenetic regulation of subcutaneous adipose tissue (SAT) adipokine transcription.We studied adipokine plasma levels, SAT gene expression, and DNA methylation of LEP, ADIPOQ, and RETN in adult offspring of women with gestational diabetes (O-GDM, N = 82) or type 1 diabetes (O-T1DM, N = 67) in pregnancy, compared to offspring of women from the background population (O-BP, N = 57).ResultsCompared to O-BP, we found elevated plasma leptin and resistin levels in O-T1DM, decreased gene expression of all adipokines in O-GDM, decreased RETN expression in O-T1DM, and increased LEP and ADIPOQ methylation in O-GDM. In multivariate regression analysis, O-GDM remained associated with increased ADIPOQ methylation and decreased ADIPOQ and RETN gene expression and O-T1DM remained associated with decreased RETN expression after adjustment for potential confounders and mediators.ConclusionsIn conclusion, offspring of women with diabetes in pregnancy exhibit increased ADIPOQ DNA methylation and decreased ADIPOQ and RETN gene expression in SAT. However, altered methylation and expression levels were not reflected in plasma protein levels, and the functional implications of these findings remain uncertain.
Highlights
Offspring of women with diabetes in pregnancy are at increased risk of type 2 diabetes mellitus (T2DM), potentially mediated by epigenetic mechanisms
Characteristics of the study population Two hundred fifty offspring were lost to follow-up/excluded for various reasons: declined future participation at the first round of follow-up in 2003 (n = 19, 7.6%), several unsuccessful attempts at contact by mail/phone (n = 94, 37.6%), declined participation (n = 88, 35.2%), emigrated (n = 13, 5.2%), pregnancy (n = 15, 6.0%), illnesses warranting exclusion, including known type 1 diabetes mellitus (T1DM) or MODY (n = 12, 4.8%), traveling, working, or studying abroad (n = 2, 0.8%), and a small group lost to follow-up for other reasons (n = 7, 2.8%)—leaving a total of 206 participants (45.2%)
No difference in the majority of baseline and anthropometric data was found between the exposure groups (O-gestational diabetes mellitus (GDM) and Offspring of women with type 1 diabetes (O-T1DM)) and Offspring of women from the background population (O-BP), as previously published [28]
Summary
Offspring of women with diabetes in pregnancy are at increased risk of type 2 diabetes mellitus (T2DM), potentially mediated by epigenetic mechanisms. We studied adipokine plasma levels, SAT gene expression, and DNA methylation of LEP, ADIPOQ, and RETN in adult offspring of women with gestational diabetes (O-GDM, N = 82) or type 1 diabetes (O-T1DM, N = 67) in pregnancy, compared to offspring of women from the background population (O-BP, N = 57). Studies of the association between maternal glycemia or BMI and offspring adipokine methylation have rendered contradictory results, showing decreased LEP and ADIPOQ methylation on the fetal side of the placenta with increasing maternal blood glucose concentrations [17, 18] or increased placental LEP DNA methylation with exposure to gestational diabetes mellitus (GDM) and maternal obesity [23]. Results on RETN methylation are lacking, as are studies of adipokine methylation in adulthood
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