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

Abstract

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, and urine metabolite markers and incident type 2 diabetes.

Data sources: We searched PubMed and Embase until 6 March 2021.

Study selection: We selected prospective observational studies where investigators used high-throughput techniques to investigate the relationship between plasma, serum, or urine metabolites and incident type 2 diabetes.

Data extraction: Baseline metabolites per-SD risk estimates and 95% CIs for incident type 2 diabetes were extracted from all eligible studies.

Data synthesis: A total of 61 reports with 71,196 participants and 11,771 type 2 diabetes cases/events were included in the updated review. Meta-analysis was performed for 412 metabolites, of which 123 were statistically significantly associated (false discovery rate-corrected 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, and pyruvate), acylcarnitines (C4-DC, C4-OH, C5, C5-OH, and C8:1), the majority of glycerolipids (di- and triacylglycerols), (lyso)phosphatidylethanolamines, and ceramides included in meta-analysis were associated with higher risk of type 2 diabetes (hazard ratio 1.07-2.58). Higher levels of glycine, glutamine, betaine, indolepropionate, and (lyso)phosphatidylcholines were associated with lower type 2 diabetes risk (hazard ratio 0.69-0.90).

Limitations: Substantial heterogeneity (I2 > 50%, τ2 > 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.

Figure 1

Flowchart presenting information on the search and selection of studies included in the updated systematic review on metabolomics and incident type 2 diabetes.

Figure 2

Chord diagram illustrating groups of metabolites identified in the current review. The thickness of ribbons and sectors is proportional to the number of metabolites. Red, gray, and blue colors correspond, respectively, with metabolites positively, not, and inversely associated with type 2 diabetes risk. AA, amino acids; AcylC, acylcarnitines; Bile, bile acids; CHO, carbohydrates; FA, fatty acids; (L)PC, (lyso)phosphatidylcholine; (L)PE, (lyso)phosphatidylethanolamine; L(PI), (lyso)phosphatidylinositol; Org, organic compounds; T2D, type 2 diabetes.

Figure 3

Summary relative risk (SRR) with corresponding 95% CIs for the association between 1 SD increase in levels of amino acids and other organic compounds and risk of incident type 2 diabetes. N, number of studies; TCA, tricarboxylic acid.

Figure 4

Summary relative risk (SRR) with corresponding 95% CIs for the association between 1-SD increase in levels of lipid metabolites and risk of incident type 2 diabetes. N, number of studies; CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; HexCer, hexosylceramide.

Figure 4

Summary relative risk (SRR) with corresponding 95% CIs for the association between 1-SD increase in levels of lipid metabolites and risk of incident type 2 diabetes. N, number of studies; CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; HexCer, hexosylceramide.