Placental CD4⁺ T cells from women with gestational diabetes recapitulate disease features in a pregnant rat model, improved by metformin or mitotempo

Objective Gestational diabetes mellitus (GDM) refers to glucose intolerance, insulin sensitivity, and beta islet cell dysfunction during pregnancy. GDM pathogenesis is associated with hypertension, impaired placental and renal function, oxidative stress, and increased circulating CD4+ T cells. There are limited animal models to explore GDM pathology and treatment. This study sought to determine a role for GDM placental CD4+ T cells to parallel manifestations of the GDM phenotype in pregnant athymic nude rats.Methods GDM placental CD4+ T cells (GDM T cells) were isolated upon delivery and injected into pregnant nude rats on gestational day (GD) 12. Mean arterial pressure and markers of renal injury, proteinuria, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin, were assessed on GD19. Glucose, insulin tolerance, and glucose tolerance tests were also performed. Renal and pancreatic tissues were stained using Periodic acid Schiff and hematoxylin and eosin, respectively. A one-way ANOVA was used for statistical analysis.Results Adoptive transfer of GDMT cells increased blood pressure (120.8 ± 2.2 mmHg, p < 0.05) compared to controls (105.4 ± 2.8 mmHg) and normotensive Tcell recipients (96.3 ± 3.9 mmHg). Metformin or MitoTEMPO attenuated this response. GDM T cell recipients had elevated blood glucose (p < 0.05) and impaired glucose tolerance and insulin sensitivity, which improved with metformin or MitoTEMPO treatment. Renal injury was more severe in GDM T cell recipients, but attenuated with metformin or MitoTEMPO. Pancreatic morphology showed reduced beta islet numbers in GDM T cell recipients.Conclusion GDM CD4+ T cells contribute to hypertension, glucose intolerance, and renal dysfunction, improved byMitoTEMPO. These findings supports optional therapeutics that support mitochondrial function during pregnancy.