Metabolomic and genetic associations with insulin resistance in pregnancy

• Published in: Diabetologia 2020-09, Vol.63 (9), p.1783-1795
• Main Authors: Liu, Yu, Kuang, Alan, Talbot, Octavious, Bain, James R., Muehlbauer, Michael J., Hayes, M. Geoffrey, Ilkayeva, Olga R., Lowe, Lynn P., Metzger, Boyd E., Newgard, Christopher B., Scholtens, Denise M., Lowe, William L.
• Format: Article
• Language: English
• Subjects: Carbohydrates; Diabetes; Fatty acids; Genetic analysis; Genetic diversity; Genomes; Gestation; Glucokinase; Glucose; Human Physiology; Hyperglycemia; Insulin; Insulin resistance; Internal Medicine; Lactic acid; Lipids; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolites; Metabolomics; Missense mutation; Palmitoleic acid; Pregnancy; Single-nucleotide polymorphism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-020-05198-1

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 ∼28 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 (β = −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