UC Riverside

Diabetes is a devastating public health problem affecting millions around the globe. One of the populations most vulnerable to the complications related to this disorder are pregnant women. Diabetes causes miscarriage in 1 of 5 pregnancies and major birth defects in another 10%, statistics that are truly frightening considering that this disorder has reached near pandemic levels in many countries around the world. Though high blood glucose levels have been isolated as the major cause of pregnancy problems among diabetics, the mechanisms by which hyperglycemia threaten the life and health of human embryos still remain to be elucidated. Using embryonic stem cells as a model for pre-implantation embryos, we have begun to examine the effects of hyperglycemia on early stages of pregnancy. By culturing the cells in different glucose concentrations and tracking changes in pluripotency state, cell cycle regulation, and oxidative stress management, we hope to gain further insights into what may be happening during these critical stages of development when the plan for life is being laid out. Specifically, we have examined changes in the expression and localization of CTNNB1 and other proteins it is known to interact with, as CTNNB1 is one of the major regulators of human embryonic development. Specifically, we have determined that hyperglycemia increases levels of nuclear CTNNB1 as well as nuclear levels of the pluripotency inhibitor TCF7L1 and the oxidative stress regulator FoxO3a. Upstream of these transcription factors, we have found that JNK, activated in response to oxidative stress, may be responsible for their increased accumulation in the nucleus. In response to misregulation of these transcription factors that are critical for proper development, embryonic stem cells increase proliferation while initiating the process of differentiation, a possible mechanism for ensuring that these abnormal cells do not contribute to future generation of body tissues. This abnormal differentiation may contribute to gastrulation defects that harm the embryo in such a way that it cannot survive or sustains a major structural defect, thus contributing to diabetic pregnancy complications. Through uncovering mechanisms related to proper maintenance of the stem state and differentiation, we hope to provide knowledge that will inform future treatments to protect diabetic mothers and their unborn children.