Reduced Insulin Receptor Expression and Altered DNA Methylation in Fat Tissues and Blood of Women With GDM and Offspring

Abstract

Context Altered expression of the insulin receptor (IR) in adipose tissue (AT) could contribute to gestational diabetes mellitus (GDM) etiopathogenesis. Transcriptional regulation via epigenetic mechanisms (e.g., DNA methylation) may play a critical role. However, the human IR promoter DNA methylation patterns and involvement in gene expression are unknown. Objective We evaluated IR mRNA and protein expression accompanied by targeted DNA methylation analyses in AT and blood cells of women with GDM and their offspring. Design Prospective observational study. Setting Academic clinic and research unit. Participants GDM-affected (n = 25) and matched control (n = 30) mother-child dyads. Main Outcome Measures Maternal IR gene and protein expression in paired subcutaneous (SAT) and visceral adipose tissue samples (VAT). DNA methylation levels in IR promoter and intronic regions in maternal AT and blood cells of mother-offspring pairs. Results In SAT and VAT, IR mRNA/protein expressions were significantly reduced in women with GDMs (P < 0.05). The decrease in VAT was more pronounced and independent of maternal body mass index. VAT IR protein levels were inversely associated with key maternal and neonatal anthropometric and metabolic parameters (P < 0.05). DNA methylation patterns were similar across tissues, with significant yet small size alterations between groups in mothers and offspring (P < 0.05). Conclusion Decreased IR levels in AT may be a relevant pathogenic factor in GDM, affecting materno-fetal metabolism. Further investigation of causal factors for IR dysregulation is necessary, especially in VAT. Potential functional and/or clinical roles of altered DNA methylation also should be evaluated.

Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology

“…However, recent data support the suggestion of an explicit part of VAT and visceral adiposity in GDM [18,[36][37][38][39]. Particularly, the expression of insulin receptor and adiponectin were found to be altered in GDM patients, accompanied by altered promoter methylation [16,17]. Importantly, this has been shown to occur even independent of the BMI, which is so far the only adipogenic indicator/marker clinically considered in GDM screening/treatment but, on the other hand, hardly serves as a marker for visceral type of obesity.…”

“…The research presented here is part of the prospective observational 'Early CHARITÉ (EaCH)' cohort study [16,17,19,44]. Genes involved in the inflammatory process were further investigated on the cases in which the optimal material and factors (such as transcription, metabolic and hormonal) could be measured in a complete set so as to avoid a missing data bias.…”

“…No oral antidiabetic drugs were administered in the GDM group, eight were treated by diet and eleven were treated with diet and additional insulin therapy to achieve glycemic control. Further clinical parameters such as plasma insulin, C-peptide, glucose and HOMA-IR were determined for these cases as described elsewhere [16,17,44,47]. The research design and methodology were conducted in accordance with the Declaration of Helsinki, revised in 2004, and approved by the local Ethics Committee (Ethikausschuss 2 am Campus Virchow-Klinikum, Charité Universitätsklinikum Berlin, EA2/026/04).…”

“…As obesity is associated with inflammatory changes [15], we wanted to build on our previous investigations/findings on the 'EaCH' cohort [16][17][18] and now focused on the inflammatory markers, tumor necrosis factor-alpha (TNF-α) and suppressor of cytokine signaling 3 (SOCS3) which have been identified as key candidates of obesity-related insulin resistance [19][20][21]. Through intensified inflammation comes the promotion of cell death/apoptosis critical in restoring tissue homeostasis.…”

“…Epigenetic alterations, especially of promoter methylation patterns, have been proposed as potential causes of insulin resistance, GDM, and obesity in a variety of aspects [2,13,16,17]. Therefore, in order to contribute to a better understanding of GDM pathophysiology, we sought to investigate the potential alterations of both TNF-α and/or SOCS3 mRNA expression and methylation in adipose tissues of women with GDM compared to pregnancies with normal glucose tolerance (NGT).…”