Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study
Authors' conclusion
Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions.
Study context
- Population
- IMI-DIRECT consortium plasma samples; 911 metabolites (132 targeted, 779 untargeted) passed quality control3,000 plasma samples
- Comparison
- Glycaemic status: normal glucose regulation vs impaired glucose regulation/prediabetes vs T2D
- Outcome
- Metabolites significantly different between glycaemic groups (targeted; untargeted in parentheses)
Methodological detailstargeted and untargeted metabolomics, multivariable linear and logistic regression, Bonferroni corrected, causal mediation test, two-sample Mendelian randomisation (2SMR)
- Targeted and untargeted metabolomics
- Multivariable linear and logistic regression
- Bonferroni corrected
- Causal mediation test
- Two-sample Mendelian randomisation (2SMR)
Main finding
As reported in the abstract
Normal glucose regulation vs impaired glucose regulation/prediabetes
4
15
Normal glucose regulation vs T2D
34
99
Impaired glucose regulation vs T2D
50
108
Further findings
Mediation of T2D and association with HbA1c progression rate · baseline to 18 and 48 months
- Lysophosphatidylcholine a C17:0, sum of hexoses, BCAA-metabolism amino acids (leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine, formiminoglutamate), lactate and unknown X-24295 associated with HbA1c progression rate and significant mediators of T2D
2SMR causal effects (UK Biobank GWAS summary statistics)
- T2D causal effect on levels of hexose, glutamate and caproate [fatty acid (FA) 6:0]
- PC aa C36:2, PC aa C36:5, PC ae C36:3, PC ae C34:3, stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially causal for development of T2D
Original publication
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