{"doi":"10.1101/2023.05.23.23290391","title":"Relationship between branched chain amino acids and type 2 diabetes: a bidirectional Mendelian Randomization study","abstract":"ABSTRACT Background Human genetic studies suggest that the branched chain amino acids (BCAA) valine, leucine and isoleucine have a causal association with type 2 diabetes. However, inferences are based on analyses of a limited number of genetic loci associated with BCAAs. Whether these conclusions are supported when using instrumental variables for BCAAs that capture a broad set of genetic mechanisms is not known. Methods We constructed and validated instrumental variables for each BCAA using large well-powered datasets and tested their association with type 2 diabetes using the two-sample inverse variance weighted (IWV) Mendelian randomization (MR) approach. Sensitivity analyses were performed to ensure the accuracy of the findings. Instrumental variables for type 2 diabetes, fasting insulin and body mass index (BMI) were also tested for associations with BCAA levels. Results There were no significant associations with diabetes for valine (beta=0.17 change in log-odds per standard deviation change in valine, [95% CI, −0.28 - 0.62], p=0.45), leucine (beta=0.19 [−0.30 - 0.68] p=0.45) or isoleucine (beta=0.02 [−0.54 - 0.59], p=0.94). In contrast, type 2 diabetes was associated with each BCAA (valine: beta=0.08 per standard deviation change in levels per log-odds change in type 2 diabetes, [0.05 - 0.10], p=1.8×10 −9 ), (leucine: beta= 0.06 [0.04 - 0.09], p=4.5×10 −8 ) and isoleucine (beta= 0.06 [0.04 - 0.08], p=2.8×10 −8 ). The type 2 diabetes associations were replicated in an independent population, but not in a second population where type 2 diabetes cases were removed, highlighting the consistency and specificity of the association. Similar positive associations were seen for fasting insulin and BMI with the BCAAs. In multivariable MR analyses, type 2 diabetes and fasting insulin had consistent independent associations with each BCAA. Conclusions These data suggest that the BCAAs are not mediators of type 2 diabetes risk but are biomarkers of diabetes and higher insulin.","journal":"medRxiv","year":2023,"id":407742,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":405425,"name":"Mingjian Shi","orcid":"0000-0003-1569-9822","position":1,"is_corresponding":false},{"id":1186810,"name":"David Agamasu","orcid":null,"position":2,"is_corresponding":false},{"id":771299,"name":"Nataraja Sarma Vaitinadin","orcid":"0000-0003-0145-0348","position":3,"is_corresponding":false},{"id":326582,"name":"Venkatesh L. Murthy","orcid":"0000-0002-7901-1321","position":4,"is_corresponding":false},{"id":251876,"name":"Ravi V. Shah","orcid":"0000-0002-4471-7156","position":5,"is_corresponding":false},{"id":484412,"name":"Minoo Bagheri","orcid":"0000-0002-6093-613X","position":6,"is_corresponding":false},{"id":98916,"name":"Jane F. Ferguson","orcid":"0000-0001-6896-1025","position":7,"is_corresponding":false},{"id":405424,"name":"Jonathan D. Mosley","orcid":"0000-0001-6421-2887","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:21:10.867368Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}