Project description:Genome wide DNA methylation profiling of cord blood cells obtained from normal glucose tolerance (NGT) pregnancies. The Illumina EPIC methylation beadchip array was used to obtain DNA methylation profiles across approximately 850,000 CpG dinucleotide methylation loci in DNA isolated from cord blood. Samples include 61 NGT subjects.
Project description:Recent continuous glucose monitoring (CGM) studies have revealed that in pregnancies complicated by maternal diabetes, fluctuations in maternal glucose are linked to complications of fetal growth. The underlying mechanisms are unclear but likely involve the placenta. We cultured ex vivo human placental explants from term uncomplicated pregnancies with medium changes every 6-18 hours in variable (5/5.5 mM; normoglycaemia), or constant 5 mM (mild hypoglycaemia) or 7 mM glucose (mild hyperglycaemia) for 48 hours to recapitulate in vivo maternal glucose profiles and performed RNA sequencing. Additional placental explants were also exposed to 5.5 mM glucose.
Project description:Fetal progenitor endothelial cells (endothelial colony forming cells; ECFC) are recruited for repair, vascular growth and angiogenesis and their high abundance perinatally suggests a function in postnatal vasculogenesis and angiogenesis. In this study we profiled ECFCs from pregnancies of control, overweight and diabetic mothers to study if adverse pregnancies are associated with epigenetic variation in ECFCs.
Project description:High altitude conditions improve glucose tolerance and reduce diabetes risk, but the physiological mechanism is not well-understood. Using mouse models, we found that hypoxia alone robustly improved glucose tolerance and that the effect persisted for weeks after returning to normal oxygen levels. PET/CT imaging suggested a significant, unknown glucose sink beyond major internal organs. We hypothesized that hypoxia-induced red blood cells (RBCs) serve as this sink. Manipulating RBC numbers through phlebotomy or transfusion directly altered blood glucose, establishing RBCs as necessary and sufficient for this effect. In chronic hypoxia, RBCs showed a sustained ~3-fold increase in glucose uptake and ~2-fold increase in GLUT1 protein abundance, specifically in newly synthesized RBCs, which ultimately contributes to increased glycolytic flux towards 2,3-DPG. Mechanistically, acute hypoxia promotes displacement of GAPDH from inhibitory Band 3 binding through competitive interactions with deoxyhemoglobin, thereby boosting glycolytic flux and driving 2,3-DPG production. We also found that hypoxia or our small molecule hypoxia-mimetic, HypoxyStat, rescued hyperglycemia in mouse models of type 1 and type 2 diabetes. Our findings identify RBCs as key regulators of systemic glucose metabolism, highlighting a novel therapeutic approach for hyperglycemic disorders.
Project description:Genome wide DNA methylation profiling of cord blood cells obtained from gestational diabetes mellitus (GDM) pregnancies. The Illumina EPIC methylation beadchip array was used to obtain DNA methylation profiles across approximately 850,000 CpG dinucleotide methylation loci in DNA isolated from cord blood. Samples include 165 GDM subjects.
Project description:Liver transcriptome profile in subjects with impaired glucose metabolism and steatosis >3 revealed differences compared with subjects with steatosis <1 and normal glucose tolerance. Several well-characterized markers of non-alcoholic fatty liver disease (NAFLD) were identified as differentially expressed between the two groups.