Metabolomic and genetic associations with insulin resistance in pregnancy.
Diabetologia
; 63(9): 1783-1795, 2020 09.
Article
en En
| MEDLINE
| ID: mdl-32556615
ABSTRACT
AIMS/HYPOTHESIS:
Our study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance.METHODS:
Fasting and 1 h serum samples were collected from women in the Hyperglycemia and Adverse Pregnancy Outcome study who underwent an OGTT at â¼28 weeks' gestation. We obtained targeted and non-targeted metabolomics and genome-wide association data from 1600 and 4528 mothers, respectively, in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai); 1412 of the women had both metabolomics and genome-wide association data. Insulin sensitivity was calculated using a modified insulin sensitivity index that included fasting and 1 h glucose and C-peptide levels after a 75 g glucose load.RESULTS:
Per-metabolite and network analyses across the four ancestries identified numerous metabolites associated with maternal insulin sensitivity before and 1 h after a glucose load, ranging from amino acids and carbohydrates to fatty acids and lipids. Genome-wide association analyses identified 12 genetic variants in the glucokinase regulatory protein gene locus that were significantly associated with maternal insulin sensitivity, including a common functional missense mutation, rs1260326 (ß = -0.2004, p = 4.67 × 10-12 in a meta-analysis across the four ancestries). This SNP was also significantly associated with multiple fasting and 1 h metabolites during pregnancy, including fasting and 1 h triacylglycerols and 2-hydroxybutyrate and 1 h lactate, 2-ketoleucine/ketoisoleucine and palmitoleic acid. Mediation analysis suggested that 1 h palmitoleic acid contributes, in part, to the association of rs1260326 with maternal insulin sensitivity, explaining 13.7% (95% CI 4.0%, 23.3%) of the total effect. CONCLUSIONS/INTERPRETATION:
The present study demonstrates commonalities between metabolites and genetic variants associated with insulin sensitivity in the gravid and non-gravid states and provides insights into mechanisms underlying pregnancy-induced insulin resistance. Graphical abstract.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Resistencia a la Insulina
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Embarazo
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Metabolómica
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Adult
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Female
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Humans
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Pregnancy
Idioma:
En
Revista:
Diabetologia
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos