'Estrogen Decoupling': How High-Calorie Diets Increase Juvenile Diabetes Risk in Daughters of Mothers with Gestational Diabetes

New data from Nutrients show that in mice, gestational diabetes (GDM) paves the way for impaired glucose metabolism in daughters during puberty – and high-calorie diets in adolescence make the problem worse. Key to this is that the offspring have lower estradiol levels and a breakdown in the delicate link between estrogen and insulin signals in the liver. The work highlights the vulnerability of women to juvenile-onset type 2 diabetes and a biological mechanism that partly explains this predisposition.

Background of the study

Juvenile-onset type 2 diabetes (YOT2D) is increasing worldwide and often manifests during puberty, with metabolic disturbances being particularly common in girls. This is an alarming trend: early onset is associated with a more rapid decline in β-cell function and high comorbidity by early adulthood. In the context of the global diabetes epidemic, the issue of early vulnerability factors in adolescents is becoming central to prevention and clinical strategies.

One such factor is maternal gestational diabetes (GDM): it not only complicates pregnancy, but also “programs” metabolic risk in the offspring via placental and hormonal mechanisms. In populations, GDM is diagnosed in a significant proportion of pregnancies, and women who have had it have a significantly increased risk of developing type 2 diabetes later in life, highlighting the intergenerational nature of the problem. Mouse models show that GDM alters organ development and endocrine axes in the offspring, but the specific “targets” and windows of greatest vulnerability have not been fully defined.

Of particular interest is the role of estrogens: they normally increase insulin sensitivity and maintain glucose homeostasis, and puberty in girls is a period of fine-tuning of this axis. Disruptions in estrogen signaling (e.g., via the ERα receptor) can potentially lead to disruption of hepatic insulin signaling and insulin resistance, making hormonal levels a key mediator between early exposures and adolescent metabolic outcomes.

Against this backdrop, two questions remain open: whether a “westernized” high-calorie diet during puberty exacerbates the effects of maternal GDM in daughters, and whether the putative effect is related to disruption of estrogen regulation of hepatic insulin signaling. The work in Nutrients addresses this gap by combining a mouse model of GDM with dietary manipulation during adolescence and assessment of ERα-IRS-1-Akt nodes to clarify the mechanisms of female vulnerability to YOT2D.

Key findings

• 85% of pregnant mice on a "westernized" diet (WD) develop a model of GDM; their daughters are more likely to develop glucose intolerance, insulin resistance, and even diabetes at puberty.
• In the ovaries of the offspring, the expression of CYP19A1 (aromatase) decreases, the area of secondary follicles decreases, and the number of atretic follicles increases - this leads to a decrease in serum estradiol.
• In the liver, the ERα → IRS-1 → Akt pathway is weakened; WD itself in the offspring enhances all these shifts.
• In cell culture, estradiol "raises" ERα/IRS-1/Akt, and the ER blocker (BHPI) suppresses the effect - direct confirmation of the role of estrogen signaling.

Researchers emphasize that juvenile type 2 diabetes (YOT2D) is growing worldwide and is more common in girls, while estrogens normally increase insulin sensitivity. A failure in estradiol levels and the functioning of the ERα receptor in the liver may become the bridge between GDM in the mother and metabolic disorders in the daughter.

How it was tested (design)

• C57BL/6 females were fed WD (≈41% energy from fat, 42.5% from carbohydrates) before mating and until parturition; control was a standard diet. On the 16.5th day of pregnancy, OGTT was performed to verify GDM.
• Weaned daughters were fed either a normal diet or WD from 3 to 8 weeks of age (the period of sexual maturation in mice).
• The following were performed: OGTT/insulin tests, estradiol ELISA, ovarian histology (follicles, atresia), qPCR/Western blot of ERα and insulin pathway nodes in the liver; in vitro - treatment of LO2 cells with estradiol and BHPI.

The mechanistic picture is as follows: maternal GDM disrupts ovarian maturation in daughters, reducing estradiol production; against the background of ERα signal deficiency, IRS-1 stability and Akt activity decrease, which worsens the liver's response to insulin. A high-calorie diet in adolescence "squeezes" the system, converting latent vulnerability into obvious glucose intolerance disorders.

Why is this important to people?

• Juvenile type 2 diabetes is more severe than “adult” diabetes: β-cell function is lost more quickly and combination treatment regimens are more often required.
• Daughters of women with GDM are a risk group, and nutritional quality during puberty may have a disproportionately large metabolic effect in them.
• The target for prevention is not only weight and sugar control in pregnant women, but also supporting a healthy diet in adolescent girls from families with a history of GDM.

The authors emphasize, however, that this is an animal study, and translating the findings directly to clinical recommendations requires caution and confirmation in cohort observations and intervention trials in humans. Limitations include the animal species/strain, the specific composition of the diet, and the focus on liver and ovaries (without detailed analysis of other tissues).

What's Next (Research Ideas)

• Prospective observations of daughters of women with GDM, taking into account nutrition during puberty and hormonal profile.
• Search for interventions that support ERα signaling (diet, exercise, pharmacological modulators) and reduce the risk of insulin resistance.
• Marking the "window of vulnerability" - when exactly in adolescence diet has its maximum effect on the estrogen-insulin axis.

Source: Jia X. et al. High-Calorie Diet Exacerbates the Crosstalk Between Gestational Diabetes and Youth-Onset Diabetes in Female Offspring Through Disrupted Estrogen Signaling. Nutrients. Accepted 16 June 2025, published 26 June 2025. https://doi.org/10.3390/nu17132128