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Background: Fetal exposure to maternal diabetes increases the risk of type 2 diabetes (T2DM), possibly mediated by epigenetic mechanisms. Low blood TXNIP DNA methylation has been associated with elevated glucose levels and risk of T2DM, and increased skeletal muscle TXNIP gene expression was reported in subjects with impaired glucose metabolism or T2DM. Subcutaneous adipose tissue (SAT) and skeletal muscle play a key role in the control of whole body glucose metabolism and insulin action. The extent to which TXNIP DNA methylation levels are decreased and/or gene expression levels increased in SAT or skeletal muscle of a developmentally programmed at-risk population is unknown., Objective and Methods: The objective of this study was to investigate TXNIP DNA methylation and gene expression in SAT and skeletal muscle, and DNA methylation in blood, from adult offspring of women with gestational diabetes (O-GDM, n = 82) or type 1 diabetes (O-T1DM, n = 67) in pregnancy compared with offspring of women from the background population (O-BP, n = 57)., Results: SAT TXNIP DNA methylation was increased (p = 0.032) and gene expression decreased (p = 0.001) in O-GDM, but these differences were attenuated after adjustment for confounders. Neither blood/muscle TXNIP DNA methylation nor muscle gene expression differed between groups., Conclusion: We found no evidence of decreased TXNIP DNA methylation or increased gene expression in metabolic target tissues of offspring exposed to maternal diabetes. Further studies are needed to confirm and understand the paradoxical SAT TXNIP DNA methylation and gene expression changes in O-GDM subjects.

Background: Offspring 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)., Results: Compared 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., Conclusions: In 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.

Aims/hypothesis: Low birthweight (LBW) is associated with dysfunctions of adipose tissue and metabolic disease in adult life. We hypothesised that altered epigenetic and transcriptional regulation of adipose-derived stem cells (ADSCs) could play a role in programming adipose tissue dysfunction in LBW individuals., Methods: ADSCs were isolated from the subcutaneous adipose tissue of 13 normal birthweight (NBW) and 13 LBW adult men. The adipocytes were cultured in vitro, and genome-wide differences in RNA expression and DNA methylation profiles were analysed in ADSCs and differentiated adipocytes., Results: We demonstrated that ADSCs from LBW individuals exhibit multiple expression changes as well as genome-wide alterations in methylation pattern. Reduced expression of the transcription factor cyclin T2 encoded by CCNT2 may play a key role in orchestrating several of the gene expression changes in ADSCs from LBW individuals. Indeed, silencing of CCNT2 in human adipocytes decreased leptin secretion as well as the mRNA expression of several genes involved in adipogenesis, including MGLL, LIPE, PPARG, LEP and ADIPOQ. Only subtle genome-wide mRNA expression and DNA methylation changes were seen in mature cultured adipocytes from LBW individuals., Conclusions/interpretation: Epigenetic and transcriptional changes in LBW individuals are most pronounced in immature ADSCs that in turn may programme physiological characteristics of the mature adipocytes that influence the risk of metabolic diseases. Reduced expression of CCNT2 may play a key role in the developmental programming of adipose tissue.

Prenatal exposure to maternal hyperglycemia is associated with an increased risk of later adverse metabolic health. Changes in the regulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) in skeletal muscle and subcutaneous adipose tissue (SAT) is suggested to play a role in the developmental programming of dysmetabolism based on studies of human subjects exposed to an abnormal intrauterine environment (e.g., individuals with a low birth weight). We studied 206 adult offspring of women with gestational diabetes mellitus (O-GDM) or type 1 diabetes (O-T1D) and of women from the background population (O-BP) using a clinical examination, oral glucose tolerance test, and gene expression and DNA methylation of PPARGC1A in skeletal muscle and SAT. Plasma glucose was significantly higher for both O-GDM and O-T1D compared with O-BP (P < 0.05). PPARGC1A gene expression in muscle was lower in O-GDM compared with O-BP (P = 0.0003), whereas no differences were found between O-T1D and O-BP in either tissue. PPARGC1A DNA methylation percentages in muscle and SAT were similar among all groups. Decreased PPARGC1A gene expression in muscle has previously been associated with abnormal insulin function and may thus contribute to the increased risk of metabolic disease in O-GDM. The unaltered PPARGC1A gene expression in muscle of O-T1D suggests that factors other than intrauterine hyperglycemia may contribute to the decreased PPARGC1A expression in O-GDM., (© 2016 by the American Diabetes Association.)