Circadian regulation of metabolism is increasingly recognised as an important component of metabolic health. A study published in Diabetes, Obesity and Metabolism investigated whether circulating rhythmic metabolites are associated with the development of type 2 diabetes and evaluated potential causal relationships using Mendelian randomisation.

The analysis included 9992 community-dwelling adults aged 45-85 years (49.1% male) from the Canadian Longitudinal Study on Aging. Baseline serum metabolomics data were collected between 2012 and 2015. Untargeted metabolomics profiling was performed using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Incident type 2 diabetes at three-year follow-up was defined based on diabetes medication use and glycated haemoglobin (HbA1c) levels. Associations between rhythmic metabolites and diabetes risk were assessed using multivariable binomial regression. Pathway and network analyses were conducted, and two-sample Mendelian randomisation was applied to metabolites significantly associated with diabetes risk.

Twenty rhythmic metabolites were associated with type 2 diabetes risk. Some of these metabolites overlapped with genetic predisposition to chronotype. Pathway analyses identified involvement of branched-chain amino acid metabolism, including leucine, isoleucine and valine biosynthesis and degradation, as well as glycine, serine and threonine metabolism.

Mendelian randomisation indicated that higher levels of mannose, valine, isoleucine, threonine and sphingomyelin were associated with higher diabetes risk. In contrast, creatine, glycine and several phospholipid metabolites showed protective associations. These findings highlight metabolic pathways that may contribute to type 2 diabetes development.