Causal role of genetically predicted impairment of branched‐chain amino acid catabolism on insulin secretion and insulin resistance in type 2 diabetes
Authors' conclusion
Our genetic analysis indicates BCAA catabolism and insulin secretion/action interact with each other; their aberrance might form a vicious cycle promoting T2D progression.
Study context
- Population
- European population, publicly available genome-wide association studies (GWAS) datasets
- Comparison
- Genetically determined branched-chain amino acids (BCAAs) and their catabolites vs 10 traits related to insulin and glucose metabolism, in both directions
- Outcome
- Causal associations between BCAAs/catabolites and insulin/glucose traits
Methodological detailsGWAS meta-analysis, multi-trait analysis of GWAS (MTAG), sensitivity analyses
- GWAS meta-analysis
- Multi-trait analysis of GWAS (MTAG)
- Sensitivity analyses
Pooled result
As reported in the abstract
- Novel genetic loci identified by MTAG for circulating leucine, valine and isoleucine, respectively
- 57.14%, 59.09%, 63.41%
- Genetically elevated valine → increased insulin fold change during OGTT, β [95% CI]
- 0.135 [0.045, 0.225], p FDR = 0.022
- Genetically elevated valine → fasting glucose (suggestive), β [95% CI]
- 0.031 [0.004, 0.058], p IVW = 0.025
- Reverse: genetically determined HOMA-B → leucine (inverse), β [95% CI]
- −0.140 [−0.244, −0.036], p FDR = 0.034
- Reverse: genetically determined HOMA-B → valine (inverse), β [95% CI]
- −0.147 [−0.255, −0.040], p FDR = 0.030
- Reverse: genetically determined HOMA-B → isoleucine (inverse), β [95% CI]
- −0.149 [−0.248, −0.049], p FDR = 0.020
- β-hydroxyisovalerate (leucine catabolite) → 2-h glucose after OGTT (inverse), β [95% CI]
- −0.149 [−0.227, −0.071], p FDR = 0.045
- Reverse: genetically predicted peak insulin response → 2-hydroxy-3-methylvalerate (isoleucine catabolite) (suggestive), β [95% CI]
- 0.074 [0.018, 0.130], p IVW = 9.20 × 10-3
Original publication
Causal role of genetically predicted impairment of branched‐chain amino acid catabolism on insulin secretion and insulin resistance in type 2 diabetes. Diabetes Obes Metab. Published 18 February 2026. doi:10.
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