Introduction and Objective: Women with gestational diabetes (GDM) are at elevated risk of type 2 diabetes and cardiovascular disease, but the contributing mechanisms remain unknown. While GDM models exist, long-term consequences remain unexplored. We selected a model in which FoxM1 is deleted in beta cells (Foxm1Δβ mice), representing the substantial minority of GDM driven by β-cell failure, to address this gap. Methods: We assessed glycemic status by GTTs, ITTs, and fasting insulin, β-cell mass by morphology, and β-cell RNA expression was analyzed by RNAseq with immunolabeling confirmation. Heart damage markers were assessed by qPCR (e.g. Nppa, Tgfb, and Acta). Results: Young female Foxm1Δβ mice exhibit β-cell mass reductions of ~60% compared to controls and maintain low β-cell mass during pregnancy. They display normoglycemia except during pregnancy, when they show impaired glucose tolerance, fulfilling GDM criteria. Both parous and non-parous Foxm1Δβ mice develop type 2 diabetes by 12 months of age accompanied by low serum insulin. Strikingly, non-parous Foxm1Δβ mice develop diabetes by just 6 months of age. scRNAseq revealed increased β-cell ER and mitochondrial stress in both parous and non-parous Foxm1Δβ mice compared to their respective heterozygous controls. However, few differentially expressed genes (25) distinguished parous from non-parous Foxm1Δβ mice. The accelerated diabetes onset in non-parous Foxm1Δβ mice may be explained by a difference in β-cell mass: compared to controls, β-cell mass was ~10% in non-parous versus ~70% in parous Foxm1Δβ mice. Although parous and non-parous controls showed no glycemic differences, parous controls had elevated mitochondrial stress markers. Importantly, we observed elevated heart damage markers in parous Foxm1Δβ mice. Conclusion: We demonstrate that pregnancy may protect β cells despite GDM-associated hyperglycemia. In contrast, hyperglycemic insults during pregnancy may cause lasting cardiovascular damage. Together, our findings provide the first model for studying the major long-term consequences of GDM. Disclosure D. Kasinathan: Research Support; Current; Islex Therapeutics. J. Lee: None. Y. Wang: None. S.F. Kim: None. M. Golson: Research Support; Current; Islex Therapeutics. Funding American Diabetes Association (7-23-IBSWH-05)
Kasinathan et al. (Fri,) studied this question.