Adoptive transfer of gestational diabetic CD4+T cells cause increased glucose, blood pressure, and placental mitochondrial dysfunction in a novel rat model of diabetes during pregnancy
Authors: Deer Evangeline , Williams Jan Michael , Herrock Owen , Campbell Nathan , Johnson Tyler , Wilson Mariah , Amaral Lorena , LaMarca Babbette 
Published: May 2023

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 preeclampsia and preterm labor in women with gestational diabetes mellitus (GDM), thereby indicating the importance of controlling maternal glucose and blood pressure during pregnancy. GDM is a complication of pregnancy that is characterized by insulin resistance, glucose intolerance, and beta-islet cell dysfunction causing characteristics of diabetes. Additionally, increased levels of inflammatory mediators, abnormal placental vascular function, and cytokines are associated with the pathogenesis of GDM, however, the importance of placental factors or inflammatory cells and cytokines in causing HTN or other pathophysiological factors associated with GDM is unknown. We hypothesize that placental CD4+ T cells from pregnant DM patients (GDM) causes a DM phenotype in normal pregnant (NP) athymic nude rats. CD4+ T cells were magnetically isolated from placentas from GDM patients and injected into NP athymic nude rats on Gestation Day (GD) 12. On GD19, blood pressure (MAP), blood and tissues were collected and glucose was measured from both GDM CD4+ T cell recipients and NP nude control rats. Placental mitochondrial respiration and mtROS were measured as indicators of tissue function from isolated placental mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. In another set of animals, a glucose tolerance test (GTT) was performed. A student’s t-test was used for statistical analysis. On GD19, MAP increased to 117±5.3 mmHg (n=3) in GDM T cell recipients compared to control pregnant athymic nude rats 102±0.0 mmHg (n=5). Blood glucose levels were elevated with GDM CD4+ T cells (275 ± 80 mg/dl, n=3, p<0.05) compared to NP athymic nude controls (91 ± 16 mg/dl, n=5). Placental state 3 (10±1 vs 433±113 pmol/sec/mg, p<0.05), indicative of ATP production, was reduced with GDM CD4+ T cells (n=3) compared to NP athymic nude controls (n=5). Placental mtROS (H2O2) was increased with GDM CD4+ T cells (264 ± 14 % gated, n=3, p<0.05) compared to NP athymic nude rats (100 ± 26 % gated, n=5). When performing the GTT, glucose tolerance was markedly impaired in GDM CD4+ T cells recipients compared to NP athymic nude controls. Collectively, these data indicate that GDM CD4+ T cells cause the GDM phenotype during pregnancy by increasing glucose and blood pressure in association with placental mitochondrial dysfunction/ROS during pregnancy, thereby introducing a new model to investigate mechanisms and new therapeutics for diabetes during pregnancy. This work was supported by National Institutes of Health (NIH) Grants R01 HD 067541 06 (B.L.) and P20 GM 121334 (L.M.A. and B.L.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.