{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:08:05Z","timestamp":1789380485605,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo de Chile","doi-asserted-by":"publisher","award":["1150416"],"award-info":[{"award-number":["1150416"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo de Chile","doi-asserted-by":"publisher","award":["1261881"],"award-info":[{"award-number":["1261881"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1150416"],"award-info":[{"award-number":["1150416"]}],"id":[{"id":"https:\/\/ror.org\/05btm5233","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1261881"],"award-info":[{"award-number":["1261881"]}],"id":[{"id":"https:\/\/ror.org\/05btm5233","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Objective: To estimate the frequency and potential impact of genetic variants involved in metformin pharmacokinetics, including gastrointestinal absorption, renal elimination, and hepatic transport in the Chilean population. Subjects and methods: The frequency of metformin-related gene variants was estimated using data from a genome-wide, exome-focused genotyping array in 918 participants of the Chilean Growth and Obesity Cohort Study (GOCS). Allele frequencies in Chileans were compared with those published worldwide, and the degree of Amerindian\/European ancestry was assessed. A predictive bioinformatic analysis was performed on relevant genetic variants using PolyPhen-2. Results and Discussion: The genetic polymorphism (p.Leu125Phe; p.L125F; rs77474263; C&gt;T) in the SLC47A1 gene (MATE1 transporter) showed a much higher frequency of the 125Phe (T-allele) in the Chilean population (15.3%) than in non-American populations, being virtually absent in Africa, Europe, or Asia. The 125Phe variant was associated with a higher percentage of Amerindian ancestry in the Chilean population. This result is consistent with a previous report indicating that this variant is enriched in Native American populations, given its high frequency among Mestizo and Indigenous populations in Mexico. The functional variant p.125Phe has been previously suggested to promote plasma metformin accumulation, mitochondrial dysfunction, and increased plasma lactate concentrations by altering renal metformin elimination. Conclusions: The missense variant p.Leu125Phe (rs77474263) in SLC47A1 is frequent in Chile and Mexico, and apparently absent in non-American populations. In homozygosis, the p.125Phe variant has been previously associated with impaired renal drug elimination, metformin systemic accumulation, and hyperlactatemia.<\/jats:p>","DOI":"10.3390\/genes17091114","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:10:23Z","timestamp":1789373423000},"page":"1114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Variants Involved in Metformin Pharmacokinetics in the Chilean Population"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8270-1112","authenticated-orcid":false,"given":"Jos\u00e9 P.","family":"Miranda","sequence":"first","affiliation":[{"name":"Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"},{"name":"Direcci\u00f3n de Desarrollo M\u00e9dico y Acad\u00e9mico, Bupa Chile, Santiago 7550000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gigliola","family":"Alberti","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Ana","family":"Pereira","sequence":"additional","affiliation":[{"name":"Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago 7830490, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0400-2164","authenticated-orcid":false,"given":"Juan","family":"Crist\u00f3bal Gana","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2895-0369","authenticated-orcid":false,"given":"Jos\u00e9 L.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Institute for Sustainability and Food Chain Innovation (IS-FOOD), Public University of Navarre, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"},{"name":"Doctoral Program in Epidemiology, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","unstructured":"American Diabetes Association Professional Practice Committee (2026). 9. Pharmacologic approaches to glycemic treatment: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S181\u2013S210."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1007\/s00125-022-05787-2","article-title":"Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)","volume":"65","author":"Davies","year":"2022","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/s11892-012-0334-z","article-title":"Current treatment options for type 2 diabetes mellitus in youth: Today\u2019s realities and lessons from the TODAY study","volume":"13","author":"George","year":"2013","journal-title":"Curr. Diabetes Rep."},{"key":"ref_4","first-page":"eS1","article-title":"Uso de medicamentos en Chile: Resultados de la Encuesta Nacional de Salud ENS 2017","volume":"19","author":"Passi","year":"2019","journal-title":"Medwave"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/dom.12854","article-title":"Understanding and overcoming metformin gastrointestinal intolerance","volume":"19","author":"Bonnet","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cmet.2016.05.011","article-title":"Metformin as a tool to target aging","volume":"23","author":"Barzilai","year":"2016","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/CS20110386","article-title":"Cellular and molecular mechanisms of metformin: An overview","volume":"122","author":"Viollet","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-019-1911-y","article-title":"GDF15 mediates the effects of metformin on body weight and energy balance","volume":"578","author":"Coll","year":"2020","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/s42255-019-0146-4","article-title":"Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss","volume":"1","author":"Day","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"538","DOI":"10.5604\/01.3001.0010.0284","article-title":"Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis","volume":"16","author":"Said","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/j.mcna.2007.06.001","article-title":"Non-alcoholic fatty liver disease as a complication of insulin resistance","volume":"91","author":"Abdelmalek","year":"2007","journal-title":"Med. Clin. N. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1007\/s00125-017-4343-y","article-title":"60 years of metformin use: A glance at the past and a look to the future","volume":"60","author":"Marshall","year":"2017","journal-title":"Diabetologia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.2174\/092986712800672094","article-title":"Mechanisms involved in the protective effects of metformin against non-alcoholic fatty liver disease","volume":"19","author":"Uribe","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/s41574-019-0242-2","article-title":"Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus","volume":"15","author":"Foretz","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"156589","DOI":"10.1016\/j.metabol.2026.156589","article-title":"Metformin: Antidiabetic actions from cells to tissues","volume":"179","author":"Bailey","year":"2026","journal-title":"Metabolism"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP activated protein kinase in mechanism of metformin action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature13270","article-title":"Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase","volume":"510","author":"Madiraju","year":"2014","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"198","DOI":"10.2337\/dc15-0488","article-title":"The primary glucose-lowering effect of metformin resides in the gut, not the circulation: Results from short-term pharmacokinetic and 12-week dose-ranging studies","volume":"39","author":"Buse","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2337\/dci15-0013","article-title":"Mechanism of metformin: A tale of two sites","volume":"39","author":"Song","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"afac156","DOI":"10.1093\/ageing\/afac156","article-title":"New horizons in life extension, healthspan extension and exceptional longevity","volume":"51","author":"Barzilai","year":"2022","journal-title":"Age Ageing"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"54","DOI":"10.2337\/dc16-1324","article-title":"Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid\u2013producing microbiota in the gut","volume":"40","author":"Mueller","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"554","DOI":"10.2337\/dc17-1386","article-title":"TCF7L2 genetic variation augments incretin resistance and influences response to a sulfonylurea and metformin: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)","volume":"41","author":"Srinivasan","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"715","DOI":"10.2217\/pgs-2018-0010","article-title":"A gene variant near ATM affects the response to metformin and metformin plasma levels: A post hoc analysis of an RCT","volume":"19","author":"Out","year":"2018","journal-title":"Pharmacogenomics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S2213-8587(14)70050-6","article-title":"Heritability of variation in glycaemic response to metformin: A genome-wide complex trait analysis","volume":"2","author":"Zhou","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.2337\/db17-1164","article-title":"Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes","volume":"67","author":"Rotroff","year":"2018","journal-title":"Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.2337\/db22-0702","article-title":"Identification of genetic variation influencing metformin response in a multiancestry genome-wide association study in the Diabetes Prevention Program (DPP)","volume":"72","author":"Li","year":"2023","journal-title":"Diabetes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"208","DOI":"10.2337\/dc22-2494","article-title":"Genome-wide association study identifies pharmacogenomic variants associated with metformin glycemic response in African American patients with type 2 diabetes","volume":"47","author":"Wu","year":"2024","journal-title":"Diabetes Care"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/ng.3632","article-title":"Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin","volume":"48","author":"Zhou","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical pharmacokinetics of metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1007\/s00125-017-4227-1","article-title":"Pharmacogenetics in type 2 diabetes: Precision medicine or discovery tool?","volume":"60","author":"Florez","year":"2017","journal-title":"Diabetologia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"179017","DOI":"10.1016\/j.ejphar.2026.179017","article-title":"Metformin-associated lactic acidosis: Bridging pharmacokinetic determinants, metabolic pathways, and clinical outcomes","volume":"1029","author":"Anwar","year":"2026","journal-title":"Eur. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Miranda, J.P., Pereira, A., Corval\u00e1n, C., Miquel, J.F., Alberti, G., Gana, J.C., and Santos, J.L. (2024). Genetic determinants of serum bilirubin using inferred Native American gene variants in Chilean adolescents. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1382103"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1007\/s00439-021-02290-3","article-title":"Novel loci and Mapuche genetic ancestry are associated with pubertal growth traits in Chilean boys","volume":"140","author":"Norambuena","year":"2021","journal-title":"Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112009","DOI":"10.1016\/j.biopha.2021.112009","article-title":"The L125F MATE1 variant enriched in populations of Amerindian origin is associated with increased plasma levels of metformin and lactate","volume":"142","author":"Mirzaeicheshmeh","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/tpj.2008.19","article-title":"Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function","volume":"9","author":"Chen","year":"2009","journal-title":"Pharmacogenom. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1111\/j.1476-5381.2012.01853.x","article-title":"Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis","volume":"166","author":"Toyama","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.2337\/db14-1388","article-title":"Association of Organic Cation Transporter 1 with intolerance to metformin in type 2 diabetes: A GoDARTS study","volume":"64","author":"Dujic","year":"2015","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.2337\/dc16-0706","article-title":"Effect of serotonin transporter 5-HTTLPR polymorphism on gastrointestinal intolerance to metformin: A GoDARTS study","volume":"39","author":"Dujic","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1097\/FPC.0b013e3283561666","article-title":"Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients","volume":"22","author":"Tarasova","year":"2012","journal-title":"Pharmacogenet. Genom."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1111\/j.1476-5381.2011.01394.x","article-title":"Importance of the multidrug and toxin extrusion MATE\/SLC47A family to pharmacokinetics, pharmacodynamics\/toxicodynamics and pharmacogenomics","volume":"164","author":"Yonezawa","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","first-page":"509","article-title":"Cimetidine-induced lactic acidosis in a patient on metformin therapy","volume":"33","author":"Berger","year":"1990","journal-title":"Diabetologia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"305","DOI":"10.4067\/S0034-98872013000300004","article-title":"Mitochondrial DNA heteroplasmy of the m.3243A>G mutation in maternally inherited diabetes and deafness","volume":"141","author":"Cataldo","year":"2013","journal-title":"Rev. Med. Chile"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108111","DOI":"10.1016\/j.jdiacomp.2021.108111","article-title":"Neurological manifestations in  m.3243A>G-related disease triggered by metformin","volume":"36","author":"Tong","year":"2022","journal-title":"J. Diabetes Complicat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1097\/FPC.0b013e328335639f","article-title":"Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients","volume":"20","author":"Toyama","year":"2010","journal-title":"Pharmacogenet. Genom."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Mlcuchova, N., Lipovy, B., Zendulka, O., Janosek, J., and Borilova Linhartova, P. (2026). Transporter gene variants influencing metformin pharmacokinetics and pharmacodynamics common in European populations: A pharmacogenetic narrative review. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1794405"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"dgag262","DOI":"10.1210\/clinem\/dgag262","article-title":"Genetic and clinical factors associated with metformin plasma concentrations following an acute metformin challenge","volume":"111","author":"Kuo","year":"2026","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0140-6736(22)01841-4","article-title":"A 12-gene pharmacogenetic panel to prevent adverse drug reactions: An open-label, multicentre, controlled, cluster-randomised crossover implementation study","volume":"401","author":"Swen","year":"2023","journal-title":"Lancet"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:49:58Z","timestamp":1789379398000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091114"],"URL":"https:\/\/doi.org\/10.3390\/genes17091114","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]}}}