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Review
. 2024 Jan 15:14:1245899.
doi: 10.3389/fendo.2023.1245899. eCollection 2023.

Multigenerational diabetes mellitus

Jennifer M Thornton  1   2 , Nishel M Shah  1   2 , Karen A Lillycrop  3 , Wei Cui  2 , Mark R Johnson  1   2 , Natasha Singh  1   2
Affiliations
Review

Multigenerational diabetes mellitus

Jennifer M Thornton et al. Front Endocrinol (Lausanne). .

Abstract

Gestational diabetes (GDM) changes the maternal metabolic and uterine environment, thus increasing the risk of short- and long-term adverse outcomes for both mother and child. Children of mothers who have GDM during their pregnancy are more likely to develop Type 2 Diabetes (T2D), early-onset cardiovascular disease and GDM when they themselves become pregnant, perpetuating a multigenerational increased risk of metabolic disease. The negative effect of GDM is exacerbated by maternal obesity, which induces a greater derangement of fetal adipogenesis and growth. Multiple factors, including genetic, epigenetic and metabolic, which interact with lifestyle factors and the environment, are likely to contribute to the development of GDM. Genetic factors are particularly important, with 30% of women with GDM having at least one parent with T2D. Fetal epigenetic modifications occur in response to maternal GDM, and may mediate both multi- and transgenerational risk. Changes to the maternal metabolome in GDM are primarily related to fatty acid oxidation, inflammation and insulin resistance. These might be effective early biomarkers allowing the identification of women at risk of GDM prior to the development of hyperglycaemia. The impact of the intra-uterine environment on the developing fetus, "developmental programming", has a multisystem effect, but its influence on adipogenesis is particularly important as it will determine baseline insulin sensitivity, and the response to future metabolic challenges. Identifying the critical window of metabolic development and developing effective interventions are key to our ability to improve population metabolic health.

Keywords: adipogenesis; epigenetics; gestational diabetes; metabolomics; multigenerational diabetes; transgenerational diabetes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The Multigenerational Cycle of Diabetes. Pregnancies affected by GDM increase risks for mothers and their offspring, including the offspring’s future risk of developing GDM, thus perpetuating this cycle. Created with BioRender.com.
Figure 2
Figure 2
Insulin signaling pathway demonstrating PI3K/Akt pathway and MAPK(Ras/Raf) pathways and their downstream effects on mTOR. Created with BioRender.com.
See this image and copyright information in PMC

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