Raffael Ott1, Kerstin Melchior1, Jens H Stupin2, Thomas Ziska1, Karen Schellong1, Wolfgang Henrich2, Rebecca C Rancourt1, Andreas Plagemann1. 1. Division of 'Experimental Obstetrics,' Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, Berlin, Germany. 2. Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, Berlin, Germany.
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.
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 humanIR 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.
Authors: Robert Hauffe; Vanessa Stein; Chantal Chudoba; Tanina Flore; Michaela Rath; Katrin Ritter; Mareike Schell; Kristina Wardelmann; Stefanie Deubel; Johannes Florian Kopp; Maria Schwarz; Kai Kappert; Matthias Blüher; Tanja Schwerdtle; Anna P Kipp; André Kleinridders Journal: JCI Insight Date: 2020-06-04
Authors: Carmen Pheiffer; Tarryn Willmer; Stephanie Dias; Yoonus Abrahams; Johan Louw; Julia H Goedecke Journal: Front Genet Date: 2020-09-29 Impact factor: 4.599