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Review
. 2024 Sep 20;14(9):508.
doi: 10.3390/metabo14090508.

Understanding the Genetic Landscape of Gestational Diabetes: Insights into the Causes and Consequences of Elevated Glucose Levels in Pregnancy

Caroline Brito Nunes  1 , Maria Carolina Borges  2   3 , Rachel M Freathy  4 , Deborah A Lawlor  2   3 , Elisabeth Qvigstad  5   6 , David M Evans  1   2   7 , Gunn-Helen Moen  1   5   7   8
Affiliations
Review

Understanding the Genetic Landscape of Gestational Diabetes: Insights into the Causes and Consequences of Elevated Glucose Levels in Pregnancy

Caroline Brito Nunes et al. Metabolites. .

Abstract

Background/Objectives: During pregnancy, physiological changes in maternal circulating glucose levels and its metabolism are essential to meet maternal and fetal energy demands. Major changes in glucose metabolism occur throughout pregnancy and consist of higher insulin resistance and a compensatory increase in insulin secretion to maintain glucose homeostasis. For some women, this change is insufficient to maintain normoglycemia, leading to gestational diabetes mellitus (GDM), a condition characterized by maternal glucose intolerance and hyperglycaemia first diagnosed during the second or third trimester of pregnancy. GDM is diagnosed in approximately 14.0% of pregnancies globally, and it is often associated with short- and long-term adverse health outcomes in both mothers and offspring. Although recent studies have highlighted the role of genetic determinants in the development of GDM, research in this area is still lacking, hindering the development of prevention and treatment strategies. Methods: In this paper, we review recent advances in the understanding of genetic determinants of GDM and glycaemic traits during pregnancy. Results/Conclusions: Our review highlights the need for further collaborative efforts as well as larger and more diverse genotyped pregnancy cohorts to deepen our understanding of the genetic aetiology of GDM, address research gaps, and further improve diagnostic and treatment strategies.

Keywords: diagnosis; genetics; gestational diabetes; glucose metabolism; pregnancy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Illustration depicting key changes in glucose metabolism that occur during a healthy pregnancy based on the literature reviewed and summarised above. Throughout pregnancy, the body undergoes a dynamic adjustment to maternal insulin resistance through β-cell compensation. This shift in insulin resistance is influenced by placental growth hormone, which acts locally to induce insulin resistance in maternal peripheral tissues. To counterbalance this, gestational β-cell compensation begins in the second trimester, marked by increased insulin secretion, and reaches its peak level in the third trimester, ensuring adequate glucose regulation despite increased insulin resistance. GDM, however, might occur if glucose utilization and the compensatory increase in insulin secretion are not sufficient to reduce and maintain blood glucose levels within the regulated range. GDM: gestational diabetes mellitus.
Figure 2
Figure 2
Estimated prevalence of gestational diabetes across global regions; prevalences taken from Wang et al., 2022 [45] and visualised using MapChart. A fixed-effects meta-analysis of 57 studies covering 45 countries was performed, with the diagnostic criteria and universal OGTT strategy proposed by IADPSG, as well as the age group of 25–30 years, serving as benchmarks for standardizing the prevalence of GDM across various practices and age groups. The global standardized prevalence was reported to be 14.2%, with the pooled prevalence in pregnant women around 25–30 years of age being 27.6%, 20.8%, 14.7%, 14.2%, 10.4%, 7.8%, and 7.1% in the Middle East and North Africa (MENA), South-East Asia (SEA), Western Pacific (WP), Africa (AFR), South and Central America (SACA), Europe (EUR), and North America and Caribbean (NAC). Although the study controlled for diagnostic criteria, screening approach, and age group, population characteristics were not taken into account. Pooled prevalence should be interpreted with caution as it was calculated based on varying and arbitrary cut points. OGTT: Oral glucose tolerance test; IADPSG: International Association of the Diabetes and Pregnancy Study Group; GDM: gestational diabetes mellitus.
Figure 3
Figure 3
Venn diagram of genetic loci associated with gestational diabetes, 1-h glucose, fasting glucose, and 2-h glucose. This Venn diagram depicts the genetic loci that harbour variants associated with GDM, fasting glucose levels, 1-h glucose levels post OGTT, and 2-h glucose levels post OGTT, as identified by multiple genome-wide association studies of pregnant women. Each circle represents the genetic variants linked to one of the four traits. The distinct, non-overlapping areas of each circle indicate genetic variants uniquely associated with each trait, while the overlapping regions illustrate genetic variants shared between two or more traits. The central overlapping area represents variants common to all four traits. All genetic variants included in this diagram reached genome-wide significance (p < 5 × 10−8) in the studies of Kwak et al. [95], Hayes et al. [202], Pervjakova et al. [70], Elliot et al. [96], and Zhen et al. [92]. Loci with GDM-predominant effects are highlighted in green, whereas loci with type-2 diabetes mellitus predominant effects are highlighted in orange as reported by Elliot et al. [96]. Loci not highlighted remain unclassified. Loci also detected by Chen et al. [110], in the general, non-pregnant population can be distinguished based on the asterisks (*), with blue asterisks indicating associations with fasting glucose values, yellow asterisks indicating associations with 2-h post-OGTT glucose values, and red asterisks indicating associations with both fasting and 2-h post-OGTT glucose values. Colocalization analyses, however, are needed to properly compare variants inside and outside of pregnancy [269]. GDM: gestational diabetes mellitus; OGTT: oral glucose tolerance test.
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