Placental GDM T cells cause hypertension and impaired glucose utilization

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance, insulin resistance, and beta islet cell dysfunction during pregnancy. Additionally, GDM pathogenesis is associated with hypertension, increased insulin and maternal glucose, impaired placental and renal function, oxidative stress and increased circulating CD4+ T cells. Importantly, there are limited animal models available to study GDM or alternative treatment options. We hypothesized placental CD4+ T cells from pregnant GDM patients play a role in GDM programming in the patient and aimed to test alternative treatment options for GDM. Immediately after delivery, blood and placental GDM (GDM-CD4+ T cells) and normotensive (NP+NP) placental CD4+ T cells were magnetically separated and injected into normal pregnant athymic nude rats on Gestation Day (GD) 12. On GD 13, a separate cohort rats were treated with Metformin (GDM+Met; 300 mg/kg/day) or MitoTempo (GDM+Mito;1 mg/kg/d). Mean arterial pressure (MAP), circulating glucose, and glucose tolerance tests (GTT) were performed on GD 19. HUVECS were incubated with human sera overnight from GDM, GDM women treated with Metformin (GDM+Met) or Normotensive women. After being serum starved the following day, HUVECS were incubated with MitoSox Red, collected, and analyzed using flow cytometry to measure mitochondrial (mt) ROS production. A one-way ANOVA was used for statistical analysis. MAP was increased in rat recipients of GDM-CD4+ T cells (121±2, n=8, p<0.05) compared to GDM+MET (95±2, n=6), GDM+Mito (95±4, n=7), normotensive CD4+ T cells recipients (96±4, n=7), NP+NP MET (99±4, n=8), and NP nude controls (105±3 mmHg, n=8) rats. Blood glucose was elevated in GDM-CD4+ T cell recipients (227±39 mg/dl, n=8, p<0.05) compared to GDM+MET (111±11 mg/dl, n=7), GDM+Mito (97±2 mg/dl, n=7), NP+NP CD4+ T cells (89±3 mg/dl, n=7), NP+NP MET (96±2 mg/dl, n=8), and NP nude controls (82±9 mg/dl, n=8) rats. GTT results indicated impaired glucose tolerance in GDM CD4+ T rats, but was improved with Met and Mito treatment. Mitochondrial ROS production was significantly increased in HUVECS treated with GDM patient sera (p<0.05) compared to GDM+Met or Normotensive patient sera. Collectively, our data indicate that adoptive transfer of GDM-CD4+ T cells may contribute to GDM programming in patients by causing increased blood pressure, impaired glucose utilization, and increased oxidative stress production, and can be improved with metformin or the use of antioxidant treatment. Therefore, our findings indicate that GDM CD4+ T cells cause a maternal diabetic phenotype suggesting a new model to investigate mechanisms and therapies to use in GDM pregnancies. NIH grants RO1HD067541-06 (BL), P20GM121334 (BL,LMA), AHA 19CDA34670055 (LMA), and T32 Trainee Grant T32-HL105324 (ED). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.