Gestational diabetes mellitus (GDM) is a metabolic disorder that can influence fetal immune development, particularly in infants born to mothers with pre-existing kidney disease. Given the intricate relationship between metabolic dysfunction, inflammation, and renal health, this study explores how maternal insulin therapy modulates immune responses in utero. Specifically, we investigated the effect of insulin on regulatory T cell development, proinflammatory cytokine production, and immune gene expression in the cord blood of infants born to mothers with kidney disease and GDM.

Cord blood mononuclear cells (CBMCs) were isolated from 124 infants born to mothers with kidney disease and GDM and 48 infants born to obese mothers without GDM. Flow cytometry was used to quantify CD4+CD25+FOXP3+ regulatory T cells, both ex vivo and after in vitro insulin stimulation. Reverse transcription polymerase chain reaction (RT-PCR) was performed to analyze mRNA expression of immune-related genes, including FOXP3, NFATc2, STIM1, IL-10, IFN-γ, TNF-α, and TGF-β. Immune markers were correlated with levels of anti-GAD65 autoantibodies, a key indicator of autoimmune risk.

Infants of mothers with kidney disease and GDM exhibited a significantly higher percentage of FOXP3+ regulatory T cells within the CD4+CD25(high) population compared to those born to obese mothers without GDM. In vitro insulin stimulation further enhanced FOXP3+ cell proportions and upregulated FOXP3, NFATc2, STIM1, IL-10, and TGF-β expression, a response exclusive to infants of mothers with kidney disease and GDM. Additionally, infants carrying the PTPN22 allele demonstrated reduced activation of STIM1 and NFATc2 post-insulin stimulation. TNF-α and IL-10 levels were elevated, correlating with an increased frequency of CD4+CD25+ T cells and higher anti-GAD65 autoantibody levels.

Maternal insulin therapy enhances regulatory T cells and modulates inflammation in infants of mothers with kidney disease and GDM, potentially improving renal resilience and reducing autoimmune risk.