Abstract
Gestational diabetes mellitus (GDM), a metabolic disease that develops with the increase in insulin resistance during late pregnancy, is currently one of the most common complications affecting pregnancy. The polygenic nature of GDM, together with the interplay between different genetic variants with nutritional and environmental factors has hindered the full understanding of the etiology of this disease. However, an important genetic overlap has been found with type 2 diabetes mellitus (T2DM) and, as in the case of T2DM, most of the identified loci are associated with β-cell function. Early detection of GDM and adequate interventions to control the maternal glycemia are necessary to avoid the adverse outcomes for both the mother and the offspring. The in utero exposure to the diabetic milieu predispose these children for future diseases, among them T2DM, originating a vicious circle implicated in the increased prevalence of both GDM and T2DM. The involvement of inflammatory processes in the development of GDM highlights the importance of pancreatic β-cell factors able to favor the adaptation processes required during gestation, concomitantly with the protection of the islets from an inflammatory milieu. In this regard, two members of the Pax family of transcription factors, PAX4 and PAX8, together with the chromatin remodeler factor HMG20A, have gained great relevance due to their involvement in β-cell mass adaptation together with their anti-inflammatory properties. Mutations in these factors have been associated with GDM, highlighting these as novel candidates for genetic screening analysis in the identification of women at risk of developing GDM.
Highlights
Pregnancy is a period of metabolic plasticity with transient mild insulin resistance as a physiological adaptation to ensure the preferential use of the circulating glucose by the fetus, to prioritize, in this way, fetal growth [1]
Due to the exclusive PAX8 expression during pregnancy and its potential implication in inflammation-related processed, we argued that detrimental single nucleotide polymorphisms (SNPs) within the PAX8 gene may be associated with gestational diabetes mellitus (GDM)
SNPs, mutations and/or epigenetic alterations in β-cell genes will impair adequate adaptation resulting in hyperglycemia and GDM development with the subsequent detrimental effects to both the mother and the offspring
Summary
Pregnancy is a period of metabolic plasticity with transient mild insulin resistance as a physiological adaptation to ensure the preferential use of the circulating glucose by the fetus, to prioritize, in this way, fetal growth [1]. The important increase in the prevalence of Type 2 diabetes (T2DM) in the last decades, together with its earlier onset [7,8] has raised the number of women of childbearing age with undiagnosed T2DM or prediabetes that can develop to frank diabetes in response to the increased insulin demand that takes place during pregnancy. In these cases, diabetes can develop as early as in the first trimester of pregnancy and is not considered GDM but undiagnosed preexisting pregestational diabetes [5]. T4 supplementation has been shown to increase circulating insulin levels as well as glucose clearance in mice and to delay hyperglycemia in a mouse model of autoimmune diabetes, correlating with an increase in β-cell proliferation [19]
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