Sleep Patterns, Plasma Metabolome, and Risk of Incident Type 2 Diabetes Mellitus

Abstract Context A healthy sleep pattern has been related to a lower risk of type 2 diabetes mellitus (T2DM). Objective We aimed to identify the metabolomic signature for the healthy sleep pattern and assess its potential causality with T2DM. Methods This study included 78 659 participants with complete phenotypic data (sleep information and metabolomic measurements) from the UK Biobank study. Elastic net regularized regression was applied to calculate a metabolomic signature reflecting overall sleep patterns. We also performed genome-wide association analysis of the metabolomic signature and one-sample mendelian randomization (MR) with T2DM risk. Results During a median of 8.8 years of follow-up, we documented 1489 incident T2DM cases. Compared with individuals who had an unhealthy sleep pattern, those with a healthy sleep pattern had a 49% lower risk of T2DM (multivariable-adjusted hazard ratio [HR], 0.51; 95% CI, 0.40-0.63). We further constructed a metabolomic signature using elastic net regularized regressions that comprised 153 metabolites, and robustly correlated with sleep pattern (r = 0.19; P = 3×10−325). In multivariable Cox regressions, the metabolomic signature showed a statistically significant inverse association with T2DM risk (HR per SD increment in the signature, 0.56; 95% CI, 0.52-0.60). Additionally, MR analyses indicated a significant causal relation between the genetically predicted metabolomic signature and incident T2DM (P for trend < .001). Conclusion In this large prospective study, we identified a metabolomic signature for the healthy sleep pattern, and such a signature showed a potential causality with T2DM risk independent of traditional risk factors.