(733.4) CD4+T Cells cause increased glucose, mitochondrial dysfunction, and hypertension in a Novel Pregnant Rodent Model of Gestational Diabetes Mellitus

Poster Board Number: E271

Evangeline Deer (University of Mississippi Medical Center), Jan Michael Williams (University of Mississippi Medical Center), Lorena Amaral (University of Mississippi Medical Center), Sarah Fitzgerald (University of Mississippi Medical Center), Owen Herrock (University of Mississippi Medical Center), Ty Turner (University of Mississippi Medical Center), Nathan Campbell (University of Mississippi Medical Center), Babbette LaMarca (University of Mississippi Medical Center)

Hypertensive (HTN) disorders of pregnancy complicate approximately 10% of all pregnancies worldwide and contribute to maternal and fetal morbidity and mortality. HTN increases risks for greater pathophysiology in gestational diabetes mellitus (GDM) pregnant women, thereby supporting a need for controlling maternal glucose and blood pressure. GDM is a major medical complication characterized by hyperglycemia and/or β-cell dysfunction and associated with increased inflammatory cytokines, oxidative stress, and activated CD4+ T cells. Streptozotocin (STZ) is utilized in nonpregnant rats to induce β-cell destruction causing features of diabetes. However, STZ is not ideal for pregnancy and leads to unsuccessful pregnancy outcomes, and, therefore other ways to establish animal models of GDM must be pursued. Previously, we have shown CD4+T cells from a rat model of preeclampsia causes HTN and mitochondrial (mt) dysfunction/ROS compared to normal pregnant (NP) rats. Therefore, we hypothesize CD4+ T cells cause pancreatic β-islet cell destruction/dysfunction via mt dysfunction/ROS leading to HTN during pregnancy. To examine our hypothesis, we adoptively transferred CD4+ T cells from STZ Dahl diabetic rats to cause features of GDM in pregnant Sprague Dawley (SD) rats. Circulating CD4+ T cells were isolated from STZ induced diabetic Dahl virgin female rats and injected into pregnant SD rats on gestational day (GD) 12. On GD18 carotid catheters were inserted. On GD19, blood pressure (MAP) and tissues were collected and glucose levels were measured after 2h fasting in STZ CD4+ T cell recipients (GDM) and NP controls. Mt respiration and mtROS was measured in isolated mitochondria using an Oxygraph 2K and by production of H2O2 using a fluorescent microplate reader, respectively. A student’s t-test was used for statistical analysis. On GD19, MAP increased to 106±4 mmHg (n=5, plt;0.05) in GMD pregnant rats compared to control NP rats 90±2 mmHg (n=4). Blood glucose levels were elevated in GDM rats (138 ± 6 mg/dl, n=5, plt;0.05) compared to NP controls (86 ± 7 mg/dl, n=4). Placental state 3 (27±3 vs 50.3±3 pmol/sec/mg, plt;0.05) respiration rates, indicative of ATP production, was reduced in GDM rats (n=5) cells compared to NP controls (n=4). Placental mtROS was significantly increased in GDM rats (266 ± 34 % gated, n=5, plt;0.05) compared to NP rats (100 ± 48 % gated, n=4). Collectively, the data indicate adoptive transfer of STZ CD4+ T cells causes increased circulating glucose, placental mt dysfunction and mtROS and HTN during pregnancy. These data demonstrate the importance of CD4+T cells in mechanisms causing the pathophysiology of GDM, and also introduces a potential novel animal model of GDM.

Keywords: Gestational diabetes, Hypertension, Oxidative stress

This study was supported by NIH grants RO1HD067541-06 (BL) and P20GM121334 (BL, LMA), American heart association (AHA) early career award 19CDA34670055 (LMA), and the T32 Trainee Grant T32-HL105324 (ED).