Patient-Specific Effects of Metformin on Hepatic Metabolism in Adolescent NAFLD Patients

Patient-Specific Effects of Metformin on Hepatic Metabolism in Adolescent NAFLD Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Patient-Specific Effects of Metformin on Hepatic Metabolism in Adolescent NAFLD Patients Hermann-Georg Holzhuetter, Christian Hudert, Nikolaus Berndt This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4717542/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 May, 2025 Read the published version in Journal of Molecular Medicine → Version 1 posted 5 You are reading this latest preprint version Abstract Objective: Metformin is a commonly prescribed antidiabetic drug that inhibits hepatic glucose production (HGP). The effect of metformin on other key metabolic functions of the liver and the extent of inter-individual variation are largely unknown. Methods: We used our mathematical model HEPATOKIN1 of liver metabolism, developed and validated in a previously published study, to assess the effect of metformin on liver metabolism in adolescent patients with non-alcoholic fatty liver disease. Results: On average, a single dose of metformin reduced diurnal hepatic glucose production (HGP) by 19%. Based on the z(1) score, 15% of patients were classified as low responders or high responders. During elevated metformin plasma levels for about four hours after metformin ingestion, energy metabolism, cystosolic and mitochondrial redox potential, urea synthesis and ketone body synthesis were reduced by 10-30%, but averaged over 24 hours, these metabolic side effects were not significant. The reduction in HGP correlated strongly with the reduction in lactate uptake, making the increase in plasma lactate after drug ingestion a likely indicator of metformin efficacy. Of the 50 clinical parameters tested, only plasma lactate and plasma insulin activity correlated positively with the reduction in HGP. Conclusion: On a daily average, metformin selectively affects hepatic glucose production, glycogen storage and lactate uptake, while numerous other metabolic functions are significantly altered for several hours after administration of the drug. Our method provides a patient-specific analysis of the potential effects of metformin therapy on central hepatic metabolism and may therefore help guide the physician's therapeutic decision. Metformin Liver Metabolism Computational Model Adolescent Patients NAFLD Full Text Cite Share Download PDF Status: Published Journal Publication published 27 May, 2025 Read the published version in Journal of Molecular Medicine → Version 1 posted Editorial decision: Major Revisions Needed 12 Sep, 2024 Reviewers agreed at journal 28 Jul, 2024 Reviewers invited by journal 24 Jul, 2024 Editor assigned by journal 11 Jul, 2024 First submitted to journal 11 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4717542","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":331129079,"identity":"4fab1c00-f655-4080-b80c-910b65c3c5e4","order_by":0,"name":"Hermann-Georg Holzhuetter","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABY0lEQVRIie2Rv2vCQBTHnwSey7VZX4hN/oULgaRCoWP/jYiQyc2lkwqCLnFP6dB/oW4dOgQO4pJ2VhQqlGayoNAhgoVGKzREl26F5jMc9+7dh+/9ACgo+IPwXB3AKbD9vNzBdKT8tkMFd4qTNliwU+gXCjlbBfKKXR683a8fZqBfdcPVB8w0lJ9CWiUbzb55jefrx/OWDNJw/qNUvZE1GUQxGFFYv61AbCI8u4rvcLMydW3Di4mUDjYzMXzs4vikJ9pDv2FKBKLWK3mWyhxe89UGEguIeMAsyigvMU4+ewKMu8VekZilbhze9pUIlU2qXAbMTrIpiNM0BXRiZmm5VTBV0us7RAzVXQowK/tikYvTs1ThzK1LwIWJjJlVzzUNn7mWWglI8QU2swcbhTh536b0hSgl10KT5cgYJxeaTmURK4ugJcv97nAJh/AAQGL5b/pGOroKegeglBzvFRQUFPxzvgC/63bg/dJOswAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-5054-6023","institution":"Charité Universitätsmedizin Berlin Campus Charite Mitte: Charite Universitatsmedizin Berlin","correspondingAuthor":true,"prefix":"","firstName":"Hermann-Georg","middleName":"","lastName":"Holzhuetter","suffix":""},{"id":331129081,"identity":"05491faf-e9d4-4e6f-b34e-37dfbb35aa5b","order_by":1,"name":"Christian Hudert","email":"","orcid":"","institution":"Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Hudert","suffix":""},{"id":331129082,"identity":"e6d3e735-6f43-48d0-a6e6-c963f0bfaa9a","order_by":2,"name":"Nikolaus Berndt","email":"","orcid":"","institution":"Charité Universitätsmedizin Berlin Campus Charite Mitte: Charite Universitatsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Nikolaus","middleName":"","lastName":"Berndt","suffix":""}],"badges":[],"createdAt":"2024-07-10 11:02:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4717542/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4717542/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00109-025-02551-y","type":"published","date":"2025-05-27T15:57:37+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83783081,"identity":"4e177cc7-96ab-45d7-a7cb-f6f4a606a975","added_by":"auto","created_at":"2025-06-02 16:10:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":615270,"visible":true,"origin":"","legend":"","description":"","filename":"MetforminandLiverMetabolism.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4717542/v1_covered_47c32984-d568-418f-b534-02e8e4623258.pdf"}],"financialInterests":"","formattedTitle":"Patient-Specific Effects of Metformin on Hepatic Metabolism in Adolescent NAFLD Patients","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-molecular-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jmme","sideBox":"Learn more about [Journal of Molecular Medicine](https://www.springer.com/journal/109)","snPcode":"109","submissionUrl":"https://submission.nature.com/new-submission/109/3","title":"Journal of Molecular Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Metformin, Liver Metabolism, Computational Model, Adolescent Patients, NAFLD","lastPublishedDoi":"10.21203/rs.3.rs-4717542/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4717542/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Objective: Metformin is a commonly prescribed antidiabetic drug that inhibits hepatic glucose production (HGP). The effect of metformin on other key metabolic functions of the liver and the extent of inter-individual variation are largely unknown.\nMethods: We used our mathematical model HEPATOKIN1 of liver metabolism, developed and validated in a previously published study, to assess the effect of metformin on liver metabolism in adolescent patients with non-alcoholic fatty liver disease.\nResults: On average, a single dose of metformin reduced diurnal hepatic glucose production (HGP) by 19%. Based on the z(1) score, 15% of patients were classified as low responders or high responders. During elevated metformin plasma levels for about four hours after metformin ingestion, energy metabolism, cystosolic and mitochondrial redox potential, urea synthesis and ketone body synthesis were reduced by 10-30%, but averaged over 24 hours, these metabolic side effects were not significant. 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