Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Diabetes: a sticky situation at conception (#134)

Hannah M Brown 1 , Sarah A Robertson 2 , Jeremy G Thompson 1
  1. The Robinson Research Institute, Centre for Nanoscale BioPhotonics, University of Adelaide, Adelaide, SA, Australia
  2. The Robinson Institute, University of Adelaide, Adelaide, SA, Australia

Diabetes is becoming a leading cause of morbidity and mortality across the developed world, where it is estimated that one third of the adult population will be diabetic by 2050.  The Developmental Origins of Health and Disease (DOHaD) hypothesis, initially developed by David Barker and colleagues in the 1990s, suggests that the maternal environment in which a foetus develops is instrumental in establishing its lifelong health and disease trajectory. Thus, the health of every individual reflects not only their genetic makeup, but also the environment in which conception and early development occurs.  Modelling diabetes in vivo and in vitro, we have shown that there are dramatic changes to the ovary, oviductal and uterine epithelium, during early pregnancy, including hyperglycosylation (25-30% increases in the oviducal and uterine luminal epithelium), activation of the heat shock pathway (HSP90AA1, GRP94, HSPA5), a mechanism for stress deflection and excessive inflammation (Il1a, Il6, Tnfa, Ifng).  Additionally, we have shown that the embryo is susceptible to hyper-glycosylation (30-50% increases in pronuclear and 2-cell embryos, alterations in spatial patterning), of both cytoplasmic and nuclear proteins, and that stress (HSF1, Hsp90aa1, Hsp90ab1, Atf4) and DNA damage (ɣH2AX) pathways are also activated in the embryo.  Within the COC, we saw aberrant glycosylation patterns, dysregulation of key epigenetic modifying and imprinted genes (Dnmt1: 3-fold increase, Dnmt3a: 10-fold decrease in presence of insulin, Dnmt3l: 4-fold increase and Peg3: 20-fold increase; P≤0.05), as well as abnormal localisation of glycosylating enzyme,  O-linked β-N-acetylglucosamine transferase (OGT) to the MII spindle (2-3 fold increase in cumulus cells, 30% increase in oocyte cytoplasm, 20% increase in MII spindle).  Defining a clear understanding of the impact of peri-conception hyperglycaemia influencing the embryo is essential to devise interventions and recommendations that support these women to conceive a healthy child with no further disease legacy, and therefore promoting an intergenerational “healthy start to life”, whether through natural conception or assisted reproductive technologies.