Abstract 42: Diabetes Metabolomics Score and Risk of Progression from Gestational Diabetes to Type 2 Diabetes

Background: A number of individual metabolites have been identified for their relationship with type 2 diabetes (T2D) risk. We sought to evaluate a pattern of T2D metabolites to estimate the collective impact of these markers on elevating the risk of progression to T2D among high risk women with a history of gestational diabetes mellitus (GDM). Methods: We conducted a prospective nested case-control study among women with a history of GDM in the Nurses’ Health Study II longitudinal cohort. Three panels of plasma metabolites were assayed via liquid chromatography tandem mass spectroscopy among 175 T2D cases and 175 controls, matched for age and fasting status at blood draw in 1997-1999. Incident type 2 diabetes cases occurred a median of 7 years after blood collection (range 1-15 years). Based on the published literature, we identified 38 metabolites associated with T2D and available among our measured panels, including branched-chain and other amino acids, lipids, and others. Metabolite levels were log-transformed and standardized. We derived a T2D MET SCORE, summing across the points corresponding to individuals’ assigned quintile level for each of the 38 metabolites. We estimated the odds ratios (OR) and 95% confidence intervals (CI) for the association of the T2D MET SCORE with incident T2D risk using multivariable conditional logistic regression models, adjusted for age, fasting status, body mass index (BMI), physical activity, and other established T2D risk factors. Results: Cases and controls were on average 43 years at blood draw with a mean of BMI 28.6 kg/m 2 . In the model adjusted for age and fasting status, the T2D MET SCORE was significantly associated with a step-wise increase in T2D risk across quartiles (Q1: [reference]; Q2: OR=2.5 CI=1.2, 5.6; Q3: OR=7.0 CI=3.2, 15.2; Q4: OR=10.9 CI=4.7, 24.9). Adjusting for BMI and other risk factors attenuated the relationship, although the score remained significantly associated with T2D risk (Q4 vs. Q1: OR=7.2 CI=2.5, 20.3). The T2D MET SCORE was associated with T2D risk among both obese and non-obese women (p for interaction=0.4). A BCAA sub-score (3 metabolites) and a lipid sub-score (16 metabolites) were also positively associated with T2D risk (BCAA Q4 vs. Q1: OR=3.5 CI=1.4, 8.8; lipids Q4 vs. Q1: OR=3.6 CI=1.4, 9.1). Conclusions: A pattern of high-risk circulating metabolites is significantly associated with progression from GDM to type 2 diabetes later in life.