Metabolome-Defined Obesity and the Risk of Future Type 2 Diabetes and Mortality

Abstract

OBJECTIVE Obesity is a key risk factor for type 2 diabetes; however, up to 20% of patients are normal weight. Our aim was to identify metabolite patterns reproducibly predictive of BMI and subsequently to test whether lean individuals who carry an obese metabolome are at hidden high risk of obesity-related diseases, such as type 2 diabetes. RESEARCH DESIGN AND METHODS Levels of 108 metabolites were measured in plasma samples of 7,663 individuals from two Swedish and one Italian population-based cohort. Ridge regression was used to predict BMI using the metabolites. Individuals with a predicted BMI either >5 kg/m2 higher (overestimated) or lower (underestimated) than their actual BMI were characterized as outliers and further investigated for obesity-related risk factors and future risk of type 2 diabetes and mortality. RESULTS The metabolome could predict BMI in all cohorts (r2 = 0.48, 0.26, and 0.19). The overestimated group had a BMI similar to individuals correctly predicted as normal weight, had a similar waist circumference, were not more likely to change weight over time, but had a two times higher risk of future type 2 diabetes and an 80% increased risk of all-cause mortality. These associations remained after adjustments for obesity-related risk factors and lifestyle parameters. CONCLUSIONS We found that lean individuals with an obesity-related metabolome have an increased risk for type 2 diabetes and all-cause mortality compared with lean individuals with a healthy metabolome. Metabolomics may be used to identify hidden high-risk individuals to initiate lifestyle and pharmacological interventions.