Metabolomics and Type 2 Diabetes Risk: An Updated Systematic Review and Meta-analysis of Prospective Cohort Studies

Background Due to the rapidly increasing availability of metabolomics data in prospective studies, an update of the meta evidence on metabolomics and type 2 diabetes risk is warranted. Purpose To conduct an updated systematic review and meta-analysis of plasma, serum, or urine metabolite markers and incident type 2 diabetes. Data Sources PubMed and Embase. Study Selection Prospective observational studies investigating the relationship between plasma, serum, or urine metabolites using high throughput techniques and incident type 2 diabetes. Data Extraction Baseline metabolites per-standard deviation risk estimates and 95% confidence intervals for incident type 2 diabetes were extracted from all eligible studies. Data Synthesis Sixty-one reports with 71,196 participants and 11,771 type 2 diabetes cases/events were included in the updated review. Overall, 412 metabolites were meta-analyzed, of which 123 were statistically significantly associated (FDR-P<0.05) with type 2 diabetes risk. Higher plasma and serum levels of certain amino acids (branched-chain, aromatic, alanine, glutamate, lysine, and methionine), carbohydrates and energy-related metabolites (mannose, trehalose, pyruvate), acylcarnitines (C4DC, C4OH, C5, C5OH, C8:1), the majority of meta-analyzed glycerolipids (di- and triacylglycerols), (lyso)phosphatidylethanolamines, and ceramides were associated with higher risk of type 2 diabetes (hazard ratio [HR] 1.07-2.58). Higher levels of glycine, glutamine, betaine, indolepropionate, and (lyso)phosphatidylcholines were associated with lower type 2 diabetes risk (HR 0.69-0.90). Limitations Substantial heterogeneity (I2>50%, t2>0.1) was observed for some of the metabolites. Conclusions Several plasma and serum metabolites, including amino acids, lipids, and carbohydrates are associated with type 2 diabetes risk.