Metabolome-wide Mendelian Randomization and observational study reveal causal links between circulating metabolites and youth-onset Type 2 Diabetes

Despite the increasing prevalence of Type 2 Diabetes in youth, its causal associations with circulating biomarkers remain elusive. We first aimed to identify circulating metabolites causally linked to youth-onset Type 2 Diabetes using Mendelian randomization (MR). By analyzing 675 metabolites from large metabolomic European GWASs and data on youth Type 2 Diabetes from the multi-ancestry ProDiGY consortium, we identified 34 candidate metabolites. Among these, phosphatidylcholine ae C42:3 and propionylcarnitine provided the strongest evidence of association with youth-onset Type 2 Diabetes, based also on positive genetic colocalization and sensitivity analyses accounting for adiposity. Among the 34 candidate metabolites, 23 were retained following colocalization and a replication MR using independent metabolomic GWAS and testing effects on adult Type 2 Diabetes. Furthermore, we validated associations of six of these metabolites with glucose metabolism-related traits in an observational study in the Avon Longitudinal Study of Parents and Children (ALSPAC). Notably, phosphatidylcholine ae C42:3 levels at age 7 years were linked to dysglycemia and insulin resistance in adolescence. These findings underscore the dynamic role of metabolites in glucose metabolism in childhood, offering insights for future screening and treatment strategies.