{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:50:32Z","timestamp":1791597032604,"version":"4.3.4"},"reference-count":49,"publisher":"Elsevier BV","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["iScience"],"published-print":{"date-parts":[[2026,9]]},"DOI":"10.1016\/j.isci.2026.117243","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T17:48:35Z","timestamp":1787248115000},"page":"117243","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"title":["A functional missense variant in MRI1 links methionine salvage to reduced type 2 diabetes risk"],"prefix":"10.1016","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5057-7313","authenticated-orcid":false,"given":"Khushdeep","family":"Bandesh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Traurig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendrick","family":"Freeland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Piaggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie J.","family":"Baier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.isci.2026.117243_bib1","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","article-title":"Genetic drivers of heterogeneity in type 2 diabetes pathophysiology","volume":"627","author":"Suzuki","year":"2024","journal-title":"Nature"},{"key":"10.1016\/j.isci.2026.117243_bib2","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s00125-025-06605-1","article-title":"Modelling the effects of human SUR1 R1420H variation on insulin secretory function using isogenic iPSC-derived pancreatic islets","volume":"69","author":"Nair","year":"2026","journal-title":"Diabetologia"},{"key":"10.1016\/j.isci.2026.117243_bib3","doi-asserted-by":"crossref","first-page":"6119","DOI":"10.1038\/s41467-023-41860-z","article-title":"PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development","volume":"14","author":"Lau","year":"2023","journal-title":"Nat. Commun."},{"key":"10.1016\/j.isci.2026.117243_bib4","doi-asserted-by":"crossref","first-page":"527","DOI":"10.2337\/db15-0602","article-title":"Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans","volume":"65","author":"Pal","year":"2016","journal-title":"Diabetes"},{"key":"10.1016\/j.isci.2026.117243_bib5","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/nature13425","article-title":"A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes","volume":"512","author":"Moltke","year":"2014","journal-title":"Nature"},{"key":"10.1016\/j.isci.2026.117243_bib6","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/s41431-017-0062-6","article-title":"Functional and association analysis of an Amerindian-derived population-specific p.(Thr280Met) variant in RBPJL, a component of the PTF1 complex","volume":"26","author":"Nair","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"10.1016\/j.isci.2026.117243_bib7","doi-asserted-by":"crossref","first-page":"334","DOI":"10.2337\/db17-1142","article-title":"A Partial Loss-of-Function Variant in AKT2 Is Associated With Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study","volume":"67","author":"Latva-Rasku","year":"2018","journal-title":"Diabetes"},{"key":"10.1016\/j.isci.2026.117243_bib8","doi-asserted-by":"crossref","DOI":"10.1002\/dmrr.3504","article-title":"A missense variant Arg611Cys in LIPE which encodes hormone sensitive lipase decreases lipolysis and increases risk of type 2 diabetes in American Indians","volume":"38","author":"Muller","year":"2022","journal-title":"Diabetes. Metab. Res. Rev."},{"key":"10.1016\/j.isci.2026.117243_bib9","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1038\/s41588-019-0513-9","article-title":"Loss of ZnT8 function protects against diabetes by enhanced insulin secretion","volume":"51","author":"Dwivedi","year":"2019","journal-title":"Nat. Genet."},{"key":"10.1016\/j.isci.2026.117243_bib10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ajhg.2020.06.009","article-title":"Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US","volume":"107","author":"Kim","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.isci.2026.117243_bib11","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1900\/RDS.2015.12.299","article-title":"Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?","volume":"12","author":"Nair","year":"2015","journal-title":"Rev. Diabet. Stud."},{"key":"10.1016\/j.isci.2026.117243_bib12","doi-asserted-by":"crossref","first-page":"D925","DOI":"10.1093\/nar\/gkae977","article-title":"The evolution of dbSNP: 25 years of impact in genomic research","volume":"53","author":"Phan","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib13","doi-asserted-by":"crossref","first-page":"D609","DOI":"10.1093\/nar\/gkae1010","article-title":"UniProt: the Universal Protein Knowledgebase in 2025","volume":"53","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib14","doi-asserted-by":"crossref","DOI":"10.26508\/lsa.202201376","article-title":"Islet Gene View-a tool to facilitate islet research","volume":"5","author":"Asplund","year":"2022","journal-title":"Life Sci. Alliance"},{"key":"10.1016\/j.isci.2026.117243_bib15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cmet.2024.09.001","article-title":"HumanIslets.com: Improving accessibility, integration, and usability of human research islet data","volume":"37","author":"Ewald","year":"2025","journal-title":"Cell Metab."},{"key":"10.1016\/j.isci.2026.117243_bib16","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.2337\/dc25-0151","article-title":"Human Physiologic Responses to Insulin in Indigenous Americans Identify a Metabolic Susceptibility Profile Linked to Diabetes","volume":"48","author":"Murthy","year":"2025","journal-title":"Diabetes Care"},{"key":"10.1016\/j.isci.2026.117243_bib17","doi-asserted-by":"crossref","first-page":"D1331","DOI":"10.1093\/nar\/gkaf1250","article-title":"The UCSC Genome Browser database: 2026 update","volume":"54","author":"Casper","year":"2026","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib18","doi-asserted-by":"crossref","first-page":"D384","DOI":"10.1093\/nar\/gkac1096","article-title":"The conserved domain database in 2023","volume":"51","author":"Wang","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib19","doi-asserted-by":"crossref","first-page":"W229","DOI":"10.1093\/nar\/gkx439","article-title":"SDM: a server for predicting effects of mutations on protein stability","volume":"45","author":"Pandurangan","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib20","doi-asserted-by":"crossref","first-page":"W239","DOI":"10.1093\/nar\/gkl190","article-title":"CUPSAT: prediction of protein stability upon point mutations","volume":"34","author":"Parthiban","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib21","doi-asserted-by":"crossref","first-page":"W194","DOI":"10.1093\/nar\/gkae415","article-title":"CASTpFold: Computed Atlas of Surface Topography of the universe of protein Folds","volume":"52","author":"Ye","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib22","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"10.1016\/j.isci.2026.117243_bib23","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1074\/mcp.M900178-MCP200","article-title":"A mediator of Rho-dependent invasion moonlights as a methionine salvage enzyme","volume":"8","author":"Kabuyama","year":"2009","journal-title":"Mol. Cell. Proteomics"},{"key":"10.1016\/j.isci.2026.117243_bib24","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.2337\/db17-0187","article-title":"A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes","volume":"66","author":"Mercader","year":"2017","journal-title":"Diabetes"},{"key":"10.1016\/j.isci.2026.117243_bib25","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41568-019-0187-8","article-title":"Methionine metabolism in health and cancer: a nexus of diet and precision medicine","volume":"19","author":"Sanderson","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.isci.2026.117243_bib26","doi-asserted-by":"crossref","first-page":"4111","DOI":"10.1111\/j.1742-4658.2008.06552.x","article-title":"A complete inventory of all enzymes in the eukaryotic methionine salvage pathway","volume":"275","author":"Pirkov","year":"2008","journal-title":"FEBS J."},{"key":"10.1016\/j.isci.2026.117243_bib27","doi-asserted-by":"crossref","first-page":"7092","DOI":"10.1096\/fj.201900150R","article-title":"Methionine restriction prevents onset of type 2 diabetes in NZO mice","volume":"33","author":"Casta\u00f1o-Martinez","year":"2019","journal-title":"FASEB J."},{"key":"10.1016\/j.isci.2026.117243_bib28","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0136822","article-title":"Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease","volume":"10","author":"Pacana","year":"2015","journal-title":"PLoS One"},{"key":"10.1016\/j.isci.2026.117243_bib29","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0140-6736(98)11058-9","article-title":"Homocysteine and vascular disease","volume":"354","author":"Hankey","year":"1999","journal-title":"Lancet"},{"key":"10.1016\/j.isci.2026.117243_bib30","doi-asserted-by":"crossref","DOI":"10.1016\/j.redox.2022.102595","article-title":"Effects of methionine intake on cognitive function in mild cognitive impairment patients and APP\/PS1 Alzheimer\u2019s Disease model mice: Role of the cystathionine-\u03b2-synthase\/H2S pathway","volume":"59","author":"Xi","year":"2023","journal-title":"Redox Biol."},{"key":"10.1016\/j.isci.2026.117243_bib31","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1016\/j.celrep.2018.07.089","article-title":"Methionine Restriction Extends Lifespan in Progeroid Mice and Alters Lipid and Bile Acid Metabolism","volume":"24","author":"B\u00e1rcena","year":"2018","journal-title":"Cell Rep."},{"key":"10.1016\/j.isci.2026.117243_bib32","doi-asserted-by":"crossref","first-page":"7010","DOI":"10.1038\/s41598-019-43431-z","article-title":"Serum amino acid profiles and risk of type 2 diabetes among Japanese adults in the Hitachi Health Study","volume":"9","author":"Chen","year":"2019","journal-title":"Sci. Rep."},{"key":"10.1016\/j.isci.2026.117243_bib33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3389\/fendo.2013.00037","article-title":"Beta cell dysfunction and insulin resistance","volume":"4","author":"Cerf","year":"2013","journal-title":"Front. Endocrinol."},{"key":"10.1016\/j.isci.2026.117243_bib34","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.2337\/db18-0856","article-title":"\u03b2-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity","volume":"68","author":"Mezza","year":"2019","journal-title":"Diabetes"},{"key":"10.1016\/j.isci.2026.117243_bib35","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.cmet.2025.01.012","article-title":"adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue","volume":"37","author":"Zhong","year":"2025","journal-title":"Cell Metab."},{"key":"10.1016\/j.isci.2026.117243_bib36","doi-asserted-by":"crossref","DOI":"10.1126\/science.adx2678","article-title":"A human pan-disease blood atlas of the circulating proteome","volume":"390","author":"\u00c1lvez","year":"2025","journal-title":"Science"},{"key":"10.1016\/j.isci.2026.117243_bib37","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1000002","article-title":"How protein stability and new functions trade off","volume":"4","author":"Tokuriki","year":"2008","journal-title":"PLoS Comput. Biol."},{"key":"10.1016\/j.isci.2026.117243_bib38","doi-asserted-by":"crossref","first-page":"8662","DOI":"10.1038\/s41467-025-63802-7","article-title":"Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release","volume":"16","author":"Zarifi","year":"2025","journal-title":"Nat. Commun."},{"key":"10.1016\/j.isci.2026.117243_bib39","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41467-024-55316-5","article-title":"MAT2A inhibitor AG-270\/S095033 in patients with advanced malignancies: a phase I trial","volume":"16","author":"Gounder","year":"2025","journal-title":"Nat. Commun."},{"key":"10.1016\/j.isci.2026.117243_bib40","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1271\/bbb.70209","article-title":"Enzymatic characterization of 5-methylthioribose 1-phosphate isomerase from Bacillus subtilis","volume":"71","author":"Saito","year":"2007","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"10.1016\/j.isci.2026.117243_bib41","doi-asserted-by":"crossref","first-page":"9598","DOI":"10.1016\/S0021-9258(19)81558-2","article-title":"Intermediates in the conversion of 5\u2019-S-methylthioadenosine to methionine in Klebsiella pneumoniae","volume":"263","author":"Furfine","year":"1988","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.isci.2026.117243_bib42","doi-asserted-by":"crossref","first-page":"7463","DOI":"10.1039\/C9AN01364D","article-title":"Solvent-independent determination of heteroatom protonation states from NMR spectra by differential deuterium isotope shifts","volume":"144","author":"Tassoti","year":"2019","journal-title":"Analyst"},{"key":"10.1016\/j.isci.2026.117243_bib43","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1021\/bi7000483","article-title":"Mechanistic diversity in the RuBisCO superfamily: the \u201cenolase\u201d in the methionine salvage pathway in Geobacillus kaustophilus","volume":"46","author":"Imker","year":"2007","journal-title":"Biochemistry"},{"key":"10.1016\/j.isci.2026.117243_bib44","doi-asserted-by":"crossref","first-page":"44236","DOI":"10.1021\/jacs.5c13980","article-title":"Methionine Salvage Enzyme Uses a Unique Mechanism to Overcome a Challenging Aldose-Ketose Isomerization","volume":"147","author":"Ubayawardhana","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.isci.2026.117243_bib45","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0022-2836(82)90515-0","article-title":"A simple method for displaying the hydropathic character of a protein","volume":"157","author":"Kyte","year":"1982","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.isci.2026.117243_bib46","first-page":"531","article-title":"Protein identification and analysis tools in the ExPASy server","volume":"112","author":"Wilkins","year":"1999","journal-title":"Methods Mol. Biol."},{"key":"10.1016\/j.isci.2026.117243_bib47","doi-asserted-by":"crossref","first-page":"W294","DOI":"10.1093\/nar\/gks493","article-title":"GalaxyWEB server for protein structure prediction and refinement","volume":"40","author":"Ko","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.isci.2026.117243_bib48","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/1471-2105-13-198","article-title":"GalaxyTBM: template-based modeling by building a reliable core and refining unreliable local regions","volume":"13","author":"Ko","year":"2012","journal-title":"BMC Bioinf."},{"key":"10.1016\/j.isci.2026.117243_bib49","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/s41401-019-0228-6","article-title":"CB-Dock: a web server for cavity detection-guided protein-ligand blind docking","volume":"41","author":"Liu","year":"2020","journal-title":"Acta Pharmacol. Sin."}],"container-title":["iScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2589004226026210?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2589004226026210?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:15:08Z","timestamp":1791594908000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2589004226026210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":49,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["S2589004226026210"],"URL":"https:\/\/doi.org\/10.1016\/j.isci.2026.117243","relation":{},"ISSN":["2589-0042"],"issn-type":[{"value":"2589-0042","type":"print"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"A functional missense variant in MRI1 links methionine salvage to reduced type 2 diabetes risk","name":"articletitle","label":"Article Title"},{"value":"iScience","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.isci.2026.117243","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"117243"}}