SynthesisPLoS medicine2016
Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.
Synthesis in PLoS medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 262 papers, 8 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
262 citing papers in PubMed, 8 syntheses or guidelines pooled it, 420 citations in OpenAlex.
- Pooled it
- Use of Mendelian Randomization to Unveil Metabolic Markers inJournal of Korean medical science · 2026Pooled it
- Causal role of genetically predicted impairment of branched-chain amino acid catabolism on insulin secretion and insulin resistance in type 2 diabetes.Diabetes, obesity & metabolism · 2026Pooled it
- Pooled it
- Causal Relationship Between Branched-Chain Amino Acids and Hypertension: A Mendelian Randomization Study.Journal of the American Heart Association · 2024Pooled it
- Protein intake and type 2 diabetes mellitus: an umbrella review of systematic reviews for the evidence-based guideline for protein intake of the German Nutrition Society.European journal of nutrition · 2024Pooled it
- An atlas of genome-wide gene expression and metabolite associations and possible mediation effects towards body mass index.Journal of molecular medicine (Berlin, Germany) · 2023Pooled it
- Metabolomics and Type 2 Diabetes Risk: An Updated Systematic Review and Meta-analysis of Prospective Cohort Studies.Diabetes care · 2022Pooled it
- Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes.Pediatric nephrology (Berlin, Germany) · 2023Trial
- Association of Modifiable Lifestyle Factors with Plasma Branched-Chain Amino Acid Metabolites in Women.The Journal of nutrition · 2022Trial
- Trial
- Association of Plasma Branched-Chain Amino Acid With Biomarkers of Inflammation and Lipid Metabolism in Women.Circulation. Genomic and precision medicine · 2021Trial
- Metabolic reprogramming drives pancreatic β cell neogenesis from α cells.Nature chemical biology · 2026Article
- Amino acid homeostasis in the kidney: Physiological roles and pathological dysregulation.Physiological reports · 2026Review
- Metabolome-wide association study identifies metabolites associated with human exposure to perfluoroalkyl substances.Journal of exposure science & environmental epidemiology · 2026Article
- Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.Nature communications · 2026Article
- Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review).International journal of molecular medicine · 2026Review
- Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.Nature medicine · 2026Article
- Article
- Functional genetic signatures of the gut microbiome in cardiometabolic diseases: mechanisms and translational opportunities.Frontiers in microbiomes · 2026Review
202 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
28 authors at 6 institutions in 3 countries.
Funding
Abstract
backgroundHigher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. METHODS AND
findingsGenome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes.
conclusionsEvidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.