TY - JOUR
T1 - Metabolomic and genetic associations with insulin resistance in pregnancy
AU - for the HAPO Study Cooperative Research Group
AU - Liu, Yu
AU - Kuang, Alan
AU - Talbot, Octavious
AU - Bain, James R.
AU - Muehlbauer, Michael J.
AU - Hayes, M. Geoffrey
AU - Ilkayeva, Olga R.
AU - Lowe, Lynn P.
AU - Metzger, Boyd E.
AU - Newgard, Christopher B.
AU - Scholtens, Denise M.
AU - Lowe, William L.
N1 - Funding Information:
This study was funded by National Institutes of Health grants DK095963, DK117491, HD34242, HD34243, HG-004415 and R03CA211318. Authors’ relationships and activities
Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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. [Figure not available: see fulltext.].
AB - 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. [Figure not available: see fulltext.].
KW - GCKR
KW - Genome-wide association studies
KW - Insulin sensitivity
KW - Metabolomics
KW - Pregnancy
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U2 - 10.1007/s00125-020-05198-1
DO - 10.1007/s00125-020-05198-1
M3 - Article
C2 - 32556615
AN - SCOPUS:85086595312
SN - 0012-186X
VL - 63
SP - 1783
EP - 1795
JO - Diabetologia
JF - Diabetologia
IS - 9
ER -