{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T04:27:29Z","timestamp":1768969649913,"version":"3.49.0"},"reference-count":55,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,19]],"date-time":"2020-12-19T00:00:00Z","timestamp":1608336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Federal Ministry of Science, Germany","award":["01 EA 9401"],"award-info":[{"award-number":["01 EA 9401"]}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["SOC 95201408 05F02"],"award-info":[{"award-number":["SOC 95201408 05F02"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"German Cancer Aid","doi-asserted-by":"publisher","award":["70-2488-Ha I"],"award-info":[{"award-number":["70-2488-Ha I"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Community","award":["SOC 98200769 05F02"],"award-info":[{"award-number":["SOC 98200769 05F02"]}]},{"name":"German Ministry of Education and Research (BMBF) and the State of Brandenburg","award":["DZD grant 82DZD00302"],"award-info":[{"award-number":["DZD grant 82DZD00302"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization studies. Selection of genetic instruments for amino acid traits relied on genome-wide association studies in a representative sub-cohort (up to 2265 participants) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from genome-wide association studies on single amino acids. For the selected instruments, outcome associations were drawn from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis, 74,124 cases and 824,006 controls) consortium. Mendelian randomization results indicate an inverse association for a per standard deviation increase in ln-transformed tyrosine\/methionine ratio with type 2 diabetes (OR = 0.87 (0.81\u20130.93)). Multivariable Mendelian randomization revealed inverse association for higher log10-transformed tyrosine levels with type 2 diabetes (OR = 0.19 (0.04\u20130.88)), independent of other amino acids. Tyrosine might be a causal trait for type 2 diabetes independent of other diabetes-associated amino acids.<\/jats:p>","DOI":"10.3390\/nu12123890","type":"journal-article","created":{"date-parts":[[2020,12,20]],"date-time":"2020-12-20T22:33:53Z","timestamp":1608503633000},"page":"3890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-0861","authenticated-orcid":false,"given":"Susanne","family":"J\u00e4ger","sequence":"first","affiliation":[{"name":"Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany"},{"name":"German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Cuadrat","sequence":"additional","affiliation":[{"name":"Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany"},{"name":"German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Wittenbecher","sequence":"additional","affiliation":[{"name":"Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany"},{"name":"German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany"},{"name":"Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Floegel","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Prevention Research and Epidemiology-BIPS, 28359 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Human Genomics Research Group, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland"},{"name":"Institute of Human Genetics, Division of Genomics, Life &amp; Brain Research Centre, University Hospital of Bonn, 53105 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1274-4715","authenticated-orcid":false,"given":"Cornelia","family":"Prehn","sequence":"additional","affiliation":[{"name":"Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9259-0199","authenticated-orcid":false,"given":"Jerzy","family":"Adamski","sequence":"additional","affiliation":[{"name":"German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany"},{"name":"Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany"},{"name":"Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universit\u00e4t M\u00fcnchen, 85354 Freising-Weihenstephan, Germany"},{"name":"Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1568-767X","authenticated-orcid":false,"given":"Tobias","family":"Pischon","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology Research Group, Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany"},{"name":"Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin and Berlin Institute of Health (BIH), 10117 Berlin, Germany"},{"name":"MDC\/BIH Biobank, Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC) and Berlin Institute of Health (BIH), 13125 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0830-5277","authenticated-orcid":false,"given":"Matthias B.","family":"Schulze","sequence":"additional","affiliation":[{"name":"Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany"},{"name":"German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany"},{"name":"Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e249","DOI":"10.1038\/nutd.2016.55","article-title":"Plasma-free amino acid profiles are predictors of cancer and diabetes development","volume":"7","author":"Bi","year":"2017","journal-title":"Nutr. Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"Mendelian randomization: Can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"Smith","year":"2003","journal-title":"Int. J. Epidemiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1007\/s00125-018-4599-x","article-title":"Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose","volume":"61","author":"Merino","year":"2018","journal-title":"Diabetologia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.2337\/db12-0876","article-title":"Genetic Variants Associated with Glycine Metabolism and Their Role in Insulin Sensitivity and Type 2 Diabetes","volume":"62","author":"Xie","year":"2013","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/s41467-019-08936-1","article-title":"Assessing the causal association of glycine with risk of cardio-metabolic diseases","volume":"10","author":"Wittemans","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lotta, L.A., Scott, R.A., Sharp, S.J., Burgess, S., Luan, J., Tillin, T., Schmidt, A.F., Imamura, F., Stewart, I.D., and Perry, J.R.B. (2016). Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis. PLoS Med., 13.","DOI":"10.1371\/journal.pmed.1002179"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s00125-017-4222-6","article-title":"Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels","volume":"60","author":"Mahendran","year":"2017","journal-title":"Diabetologia"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Krumsiek, J., St\u00fcckler, F., Suhre, K., Gieger, C., Spector, T.D., Soranzo, N., Kastenm\u00fcller, G., and Theis, F.J. (2016). Network-Based Metabolite Ratios for an Improved Functional Characterization of Genome-Wide Association Study Results. bioRxiv, Available online: https:\/\/www.biorxiv.org\/content\/10.1101\/048512v1.full.","DOI":"10.1101\/048512"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/aje\/kwu283","article-title":"Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects","volume":"181","author":"Burgess","year":"2015","journal-title":"Am. J. Epidemiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"639","DOI":"10.2337\/db12-0495","article-title":"Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach","volume":"62","author":"Floegel","year":"2012","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/ng.2982","article-title":"An atlas of genetic influences on human blood metabolites","volume":"46","author":"Shin","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000012786","article-title":"EPIC-Germany--A source for studies into diet and risk of chronic diseases. European Investigation into Cancer and Nutrition","volume":"43","author":"Boeing","year":"1999","journal-title":"Ann. Nutr. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.2337\/db08-0538","article-title":"Plasma Fetuin-A Levels and the Risk of Type 2 Diabetes","volume":"57","author":"Stefan","year":"2008","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1038\/s41588-018-0241-6","article-title":"Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps","volume":"50","author":"Mahajan","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/ng.2385","article-title":"Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways","volume":"44","author":"Scott","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Langenberg, C., Sharp, S.J., Franks, P.W., Scott, R.A., Deloukas, P., Forouhi, N.G., Froguel, P., Groop, L.C., Hansen, T., and Palla, L. (2014). Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study. PLoS Med., 11.","DOI":"10.1371\/journal.pmed.1001647"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"J\u00e4ger, S., Cuadrat, R.R.C., Hoffmann, P., Wittenbecher, C., and Schulze, M.B. (2020). Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study. Nutrients, 12.","DOI":"10.3390\/nu12082261"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/ng.3571","article-title":"Fast and accurate long-range phasing in a UK Biobank cohort","volume":"48","author":"Loh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/ng.3656","article-title":"Next-generation genotype imputation service and methods","volume":"48","author":"Das","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"(2016). The Haplotype Reference Consortium A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet., 48, 1279\u20131283.","DOI":"10.1038\/ng.3643"},{"key":"ref_21","first-page":"133","article-title":"Procedure for tissue sample preparation and metabolite extraction for high-throughput targeted metabolomics","volume":"8","author":"Prehn","year":"2011","journal-title":"Metabolomics"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Floegel, A., Drogan, D., Wang-Sattler, R., Prehn, C., Illig, T., Adamski, J., Joost, H.-G., Boeing, H., and Pischon, T. (2011). Reliability of Serum Metabolite Concentrations over a 4-Month Period Using a Targeted Metabolomic Approach. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021103"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/ng2088","article-title":"A new multipoint method for genome-wide association studies by imputation of genotypes","volume":"39","author":"Marchini","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hemani, G., Zheng, J., Elsworth, B., Wade, K.H., Haberland, V., Baird, D., Laurin, C., Burgess, S., Bowden, J., and Langdon, R.J. (2018). The MR-Base platform supports systematic causal inference across the human phenome. eLife, 7.","DOI":"10.7554\/eLife.34408"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1093\/ije\/dyx034","article-title":"MendelianRandomization: An R package for performing Mendelian randomization analyses using summarized data","volume":"46","author":"Yavorska","year":"2017","journal-title":"Int. J. Epidemiology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1093\/ije\/dyy101","article-title":"Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression","volume":"47","author":"Bowden","year":"2018","journal-title":"Int. J. Epidemiology"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sanderson, E., Spiller, W., and Bowden, J. (2020). Testing and Correcting for Weak and Pleiotropic Instruments inTwo-Sample Multivariable Mendelian Randomisation. bioRxiv.","DOI":"10.1101\/2020.04.02.021980"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1086\/383251","article-title":"A Simple Correction for Multiple Testing for Single-Nucleotide Polymorphisms in Linkage Disequilibrium with Each Other","volume":"74","author":"Nyholt","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D662","DOI":"10.1093\/nar\/gku1010","article-title":"Ensembl 2015","volume":"43","author":"Cunningham","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e60","DOI":"10.1093\/nar\/gky175","article-title":"Efficient pathway enrichment and network analysis of GWAS summary data using GSA-SNP2","volume":"46","author":"Yoon","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database Hallmark Gene Set Collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41588-020-0631-4","article-title":"Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics","volume":"52","author":"Morrison","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11122","DOI":"10.1038\/ncomms11122","article-title":"Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA","volume":"7","author":"Kettunen","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_38","first-page":"323","article-title":"Exome sequencing of Finnish isolates enhances rare-variant association power","volume":"572","author":"Locke","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.2337\/db14-0319","article-title":"Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity","volume":"63","author":"Scott","year":"2014","journal-title":"Diabetes"},{"key":"ref_40","first-page":"310","article-title":"Faculty Opinions recommendation of A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Mulder","year":"2017","journal-title":"Fac. Opin. Post Publ. Peer Rev. Biomed. Lit."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1007\/s00125-020-05253-x","article-title":"An atlas on risk factors for type 2 diabetes: A wide-angled Mendelian randomisation study","volume":"63","author":"Yuan","year":"2020","journal-title":"Diabetologia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/nm.2307","article-title":"Metabolite profiles and the risk of developing diabetes","volume":"17","author":"Wang","year":"2011","journal-title":"Nat. Med."},{"key":"ref_43","first-page":"54","article-title":"Human metabolic individuality in biomedical and pharmaceutical research","volume":"477","author":"Suhre","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1006\/geno.2001.6678","article-title":"The Human T-Type Amino Acid Transporter-1: Characterization, Gene Organization, and Chromosomal Location","volume":"79","author":"Kim","year":"2002","journal-title":"Genomics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.phrs.2015.12.029","article-title":"Dopaminergic drugs in type 2 diabetes and glucose homeostasis","volume":"109","author":"Vicchi","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"k2396","DOI":"10.1136\/bmj.k2396","article-title":"Food based dietary patterns and chronic disease prevention","volume":"361","author":"Schulze","year":"2018","journal-title":"BMJ"},{"key":"ref_47","unstructured":"(2020, June 12). Modulating Glucose Tolerance with Dietary Tyrosine. Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/record\/NCT03872557."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.molmet.2019.02.008","article-title":"A role for foregut tyrosine metabolism in glucose tolerance","volume":"23","author":"Korner","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.ajhg.2011.12.022","article-title":"Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci","volume":"90","author":"Saxena","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"868","DOI":"10.3389\/fnins.2019.00868","article-title":"The Relevance of Insulin Action in the Dopaminergic System","volume":"13","author":"Fiory","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1016\/j.celrep.2020.01.066","article-title":"The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances \u03b2-Cell Function","volume":"30","author":"Brial","year":"2020","journal-title":"Cell Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/ng.120","article-title":"Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes","volume":"40","author":"Zeggini","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"915","DOI":"10.2337\/db19-0795","article-title":"DLL1- and DLL4-Mediated Notch Signaling Is Essential for Adult Pancreatic Islet Homeostasis","volume":"69","author":"Rubey","year":"2020","journal-title":"Diabetes"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: Genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Smith","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/gepi.22284","article-title":"Power calculation for the general two-sample Mendelian randomization analysis","volume":"44","author":"Deng","year":"2020","journal-title":"Genet. Epidemiol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/12\/3890\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:47:19Z","timestamp":1760179639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/12\/3890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,19]]},"references-count":55,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["nu12123890"],"URL":"https:\/\/doi.org\/10.3390\/nu12123890","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,19]]}}}