OR18-06 Metabolomic And Genetic Architecture Of Gestational Diabetes Subtypes

Abstract Disclosure: K. Lee: None. A. Kuang: None. J. Bain: None. M.G. Hayes: None. M. Muehlbauer: None. O. Ilkayeva: None. C.B. Newgard: None. M. Hivert: None. D. Scholtens: None. W.L. Lowe: None. Gestational diabetes mellitus (GDM) is the most common complication of pregnancy. Recent studies defined physiological subtypes of GDM based on insulin sensitivity and secretion, i.e., GDM with a defect in insulin sensitivity and GDM with a defect in insulin secretion, which has been linked to different risks for adverse pregnancy outcomes. We hypothesized that the maternal metabolome and genetic architecture differed between GDM subtypes. This hypothesis was addressed using genetic and metabolomic analyses performed with fasting and 1-hr serum samples from a large multinational, multi-ancestry cohort of women enrolled in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study who underwent an oral glucose-tolerance test at ∼28 weeks’ gestation. GDM was defined retrospectively using IADPSG/WHO criteria and classified as GDM with insulin sensitivity defect (predominant sensitivity defect) or GDM with insulin secretion defect (predominant secretion defect). Targeted and non-targeted metabolomics analyses were performed on samples from 3463 mothers using tandem mass spectrometry and gas chromatography/mass spectrometry. Genome-wide genotyping was performed on 8067 mothers (1323 with GDM) from the multi-ancestry HAPO cohort. Per metabolite analyses were used to characterize GDM subtype metabolite profiles compared to no GDM.In a fully adjusted model that included adjustment for maternal BMI, 38 metabolites were associated with GDM with an insulin secretion defect (N=289) and 26 with GDM with an insulin sensitivity defect (N=742) (normoglycemic as reference group), only 3 of which (glycerol, palmitate, and 2-hydroxybutyrate) were common to the two subtypes. GDM with an insulin secretion defect was characterized by differences in 26 medium-and long-chain acylcarnitines in the fasting state, while GDM with an insulin sensitivity defect was associated with multiple amino acids, including the branched-chain amino acids and their metabolites in the fasting state. Differences in the maternal metabolome between the subtypes 1-hr after a glucose load were also observed, although the differences were not as evident compared to the fasting state. Genome-wide association analyses among all mothers with GDM demonstrated genome-wide significant association of SNPs within MTNR1B (most significant SNP rs1387153, p=1.05 x 10-10, OR = 1.038) and GCKR (most significant SNP rs397872078, p=9.85 x 10-10, OR = 1.037) with GDM (overall). GCKR variants demonstrated genome-wide association with GDM with an insulin-sensitivity defect (rs397872078, p=1.16 x 10-10, OR = 1.038), while no significant associations were observed for genetic variants with GDM with an insulin secretion defect. The present findings demonstrated differences in the maternal metabolome and underlying genetic architecture of GDM with an insulin secretion defect compared to GDM with an insulin sensitivity defect. Presentation: Saturday, June 17, 2023