High-Calorie Diet Exacerbates the Crosstalk Between Gestational Diabetes and Youth-Onset Diabetes in Female Offspring Through Disrupted Estrogen Signaling.

Background/Objectives: Recent global trends highlight a concerning rise in youth-onset type 2 diabetes (YOT2D), with a marked female preponderance. We aim to explore the crosstalk between gestational diabetes mellitus (GDM) and YOT2D in female offspring. Methods: In vivo, GDM mice were induced by Western diet (WD), and their female offspring were fed normal diet or WD within 3 to 8 weeks. We continuously detected the glucose metabolism disorders, serum estradiol level (ELISA), and the process of ovarian maturation. Meanwhile, the dynamic changes in ERα and insulin signal in liver were monitored (qPCR, Western blot). In vitro, LO2 cells were treated with estradiol or ER antagonist BHPI to further explore the mechanism. Results: More than 85% of pregnant mice induced by WD were GDM models. The serum estradiol level in GDM offspring mice was decreased during sexual maturation, accompanied by marked oral glucose intolerance, insulin resistance, and even diabetes. The advance of sexual maturation and the decrease in serum estradiol in GDM offspring were mainly due to the downregulation of CYP19A1 in the ovaries, the reduced area of secondary follicles, and the increased number of atresia follicles, which could be greatly worsened by WD. Furthermore, GDM suppressed the protein levels of ERα, p-IRS-1, and p-Akt in liver tissue, that is, estrogen signals and insulin signaling were simultaneously weakened. WD further exacerbated the above changes. In vitro, estradiol upregulated the protein levels of ERα, p-IRS-1, and p-Akt in LO2 cells, while BHPI inhibited these changes. Conclusions: Maternal GDM promotes a high incidence of YOT2D in female offspring by affecting ovarian maturation, and a high-calorie diet exacerbates this process.