Abstract
Aims/hypothesis
Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes.
Methods
This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks’ gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1 h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM).
Results
Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1 h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10−18, OR 1.55) and GCKR (rs1260326, p=5.17×10−13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10−13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10−9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1 h metabolites that were associated with insulin-resistant GDM.
Conclusions/interpretation
This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.
Graphical Abstract
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Abbreviations
- AC:
-
Acylcarnitine
- DC:
-
Dicarboxylate
- FDR:
-
False discovery rate
- GDM:
-
Gestational diabetes mellitus
- GWAS:
-
Genome-wide association studies
- HAPO:
-
Hyperglycemia and Adverse Pregnancy Outcome
- PC:
-
Principal component
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This work was presented, in part, at ENDO 2023 in Chicago, USA.
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Data are available from the corresponding author upon request.
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This study was funded by NIH grants DK095963, DK117491, HD34242, HD34243, HG-004415 and R03CA211318. The study funder was not involved in the design of the study, the collection, analysis and interpretation of data or writing the report, and did not impose any restrictions regarding publication of the report.
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KL contributed to interpretation of the data and manuscript writing. AK contributed to analysis, interpretation of the data and manuscript writing. DMS and AK led the data analysis. JRB, MJM, MGH, ORI and CBN contributed to acquisition and interpretation of the data. M-FH and CEP contributed to interpretation of the data and manuscript writing. DMS and WLL were involved in all aspects of the study, including study design and data collection, analysis and interpretation. All authors made critical intellectual contributions to drafting and/or revising the manuscript, and all approved the final version. WLL is the guarantor of this work, and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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Lee, K., Kuang, A., Bain, J.R. et al. Metabolomic and genetic architecture of gestational diabetes subtypes. Diabetologia 67, 895–907 (2024). https://doi.org/10.1007/s00125-024-06110-x
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DOI: https://doi.org/10.1007/s00125-024-06110-x