Early intervention and lifelong treatment with GLP1 receptor agonist liraglutide in a Wolfram Syndrome rat model with an emphasis on visual neurodegeneration, sensorineural hearing loss and diabetic phenotype

Early intervention and lifelong treatment with GLP1 receptor agonist liraglutide in a Wolfram Syndrome rat model with an emphasis on visual neurodegeneration, sensorineural hearing loss and diabetic phenotype | 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 Early intervention and lifelong treatment with GLP1 receptor agonist liraglutide in a Wolfram Syndrome rat model with an emphasis on visual neurodegeneration, sensorineural hearing loss and diabetic phenotype Toomas Jagomäe, Kadri Seppa, Riin Reimets, Marko Pastak, Mihkel Plaas, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-903256/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Nov, 2021 Read the published version in Cells → Version 1 posted You are reading this latest preprint version Abstract Background Wolfram syndrome (WS), also known as a DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, Optic nerve Atrophy and Deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 ( WFS1 ) gene. Previous studies revealed that glucagonlike peptide-1 receptor agonist (GLP1 RA) anti-diabetic drugs are effective in delaying and restoring glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats, reducing neuroinflammation, retinal ganglion cell death and optic nerve degeneration. WS is an early-onset, chronical condition and, therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression in WS patients. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide (0.4mg/kg/day) up to the age of 18 months and changes in diabetes markers, visual acuity, hearing sensitivity were monitored in vivo over the course of the 16-month treatment period. Results Early and chronic (16-month) intervention with the GLP-1 RA liraglutide delayed the development of glucose intolerance in WS rats. At the end of the experiment, 91% of saline- and 55% of liraglutide-treated WS rats needed daily insulin supplementation. Liraglutide administration was effective in maintaining visual acuity in WS rats by stalling the progression of cataract, degeneration of retinal ganglion cells and of optic nerve atrophy. Prolonged liraglutide therapy could not prevent sensorineural hearing loss at low frequencies. Conclusion The rat model of WS used in this study is an excellent predictive model for preclinical trials as it closely recapitulates the relative onset and severity of the main symptoms of WS observed in human patients. We found that a 16-month treatment with GLP1 receptor agonist liraglutide delays or prevents the onset of diabetes and protects against vision loss in a rat model of Wolfram syndrome. Therefore, early diagnosis and prophylactic treatment with the GLP-1R agonist liraglutide may also prove to be a promising treatment option for Wolfram syndrome patients by increasing the quality of life of WS patients. Plant Physiology and Morphology Translational Medicine Wolfram syndrome Wfs1 GLP1 receptor agonist liraglutide rat model neurodegeneration optic nerve atrophy hearing loss visual acuity diabetes Full Text Cite Share Download PDF Status: Published Journal Publication published 16 Nov, 2021 Read the published version in Cells → Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-903256","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":53406010,"identity":"9d052350-d6a4-4383-831b-b11f931d56ff","order_by":0,"name":"Toomas 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10:49:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-903256/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-903256/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.3390/cells10113193","type":"published","date":"2021-11-16T17:18:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":15602362,"identity":"7a2f72a4-03c0-48b0-addb-f4ade0fc1bee","added_by":"auto","created_at":"2021-11-16 17:19:08","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1287894,"visible":true,"origin":"","legend":"","description":"","filename":"renamed0d20c.pdf","url":"https://assets-eu.researchsquare.com/files/rs-903256/v1_covered.pdf"},{"id":13912659,"identity":"06b82cdf-5fa2-4057-908c-5d6dcd5aa5ba","added_by":"auto","created_at":"2021-09-23 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PDF\u003c/a\u003e."}],"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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Wolfram syndrome, Wfs1, GLP1 receptor agonist, liraglutide, rat model, neurodegeneration, optic nerve atrophy, hearing loss, visual acuity, diabetes","lastPublishedDoi":"10.21203/rs.3.rs-903256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-903256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eWolfram syndrome (WS), also known as a DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, Optic nerve Atrophy and Deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 ( WFS1 ) gene. Previous studies revealed that glucagonlike peptide-1 receptor agonist (GLP1 RA) anti-diabetic drugs are effective in delaying and restoring glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats, reducing neuroinflammation, retinal ganglion cell death and optic nerve degeneration. \u003c/p\u003e\u003cp\u003eWS is an early-onset, chronical condition and, therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression in WS patients. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide (0.4mg/kg/day) up to the age of 18 months and changes in diabetes markers, visual acuity, hearing sensitivity were monitored in vivo over the course of the 16-month treatment period. \u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003eEarly and chronic (16-month) intervention with the GLP-1 RA liraglutide delayed the development of glucose intolerance in WS rats. At the end of the experiment, 91% of saline- and 55% of liraglutide-treated WS rats needed daily insulin supplementation. Liraglutide administration was effective in maintaining visual acuity in WS rats by stalling the progression of cataract, degeneration of retinal ganglion cells and of optic nerve atrophy. Prolonged liraglutide therapy could not prevent sensorineural hearing loss at low frequencies. \u003c/p\u003e\u003cp\u003eConclusion\u003c/p\u003e\u003cp\u003eThe rat model of WS used in this study is an excellent predictive model for preclinical trials as it closely recapitulates the relative onset and severity of the main symptoms of WS observed in human patients. We found that a 16-month treatment with GLP1 receptor agonist liraglutide delays or prevents the onset of diabetes and protects against vision loss in a rat model of Wolfram syndrome. Therefore, early diagnosis and prophylactic treatment with the GLP-1R agonist liraglutide may also prove to be a promising treatment option for Wolfram syndrome patients by increasing the quality of life of WS patients.\u003c/p\u003e","manuscriptTitle":"Early intervention and lifelong treatment with GLP1 receptor agonist liraglutide in a Wolfram Syndrome rat model with an emphasis on visual neurodegeneration, sensorineural hearing loss and diabetic phenotype","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-09-23 14:56:39","doi":"10.21203/rs.3.rs-903256/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d8346f81-a5f7-49d5-bf27-7be9dbcc2ae4","owner":[],"postedDate":"September 23rd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":7384853,"name":"Plant Physiology and Morphology"},{"id":7384854,"name":"Translational Medicine"}],"tags":[],"updatedAt":"2021-11-16T17:18:57+00:00","versionOfRecord":{"articleIdentity":"rs-903256","link":"https://doi.org/10.3390/cells10113193","journal":{"identity":"cells","isVorOnly":true,"title":"Cells"},"publishedOn":"2021-11-16 17:18:57","publishedOnDateReadable":"November 16th, 2021"},"versionCreatedAt":"2021-09-23 14:56:39","video":"","vorDoi":"10.3390/cells10113193","vorDoiUrl":"https://doi.org/10.3390/cells10113193","workflowStages":[]},"version":"v1","identity":"rs-903256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-903256","identity":"rs-903256","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}