Metabolic Dysfunction and Cognitive Decline in a Rat Model of Type 2 Diabetes

Metabolic Dysfunction and Cognitive Decline in a Rat Model of Type 2 Diabetes | 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 Metabolic Dysfunction and Cognitive Decline in a Rat Model of Type 2 Diabetes Bayan Alsamarah, Khawla Nuseir, Rasha Khader This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9111343/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Diabetes Mellitus (DM) comprises a group of metabolic disorders. Type 2 DM (T2DM), strongly associated with obesity and dietary habits, represents a major global health challenge. Cognitive impairment is a recognized complication of poorly controlled DM; however, its underlying mechanisms remain incompletely understood. This study aimed to investigate T2DM-induced cognitive dysfunction using a rat model that closely mimics human T2DM. Methods Forty-eight male and female Sprague–Dawley rats were allocated into two groups: high-fat diet (HFD) group combined with low-dose streptozotocin (STZ) and a regular diet (RD) control group. The two groups further stratified into four groups according to sex. HFD rats received a diet rich in fat and fructose water for 21 weeks, followed by an intraperitoneal STZ injection (40 mg/kg). Body weight and metabolic parameters, including fasting blood glucose (FBG), fasting insulin (FI), and insulin resistance (HOMA2-IR), were assessed. Behavioral tests were performed after 15 weeks to evaluate cognitive and related functions. At the end of the experiment, hippocampal and serum levels of oxidative stress and neurodegeneration markers (Brain derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), β-amyloid, Matrix metaloprotenase 9 (MMP9), Phosphorylated tau (P-tau) and Advanced glycation end products (AGEs) were analyzed. Results Results demonstrated that HFD significantly increased body weight ( p < 0.0001), FBG ( p < 0.0001), and insulin resistance ( p < 0.0001), accompanied by cognitive impairment as evidenced by behavioral testing (spatial learning and memory, p =0.0011). Biomarker analysis further supported the presence of hippocampal oxidative stress and neurodegenerative changes (BDNF, MMP9, P.tau, β-amyloid, p <0.05). Conclusion These findings highlight the detrimental impact of diet-induced metabolic dysfunction on cognitive health and provide insights into potential mechanisms linking T2DM and cognitive decline. Streptozocin Radial Arm Water Maze High Fat Diet Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementary.docx Cite Share Download PDF Status: Posted 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-9111343","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":611631592,"identity":"0b6c5cc9-9d82-4868-ad8d-eadf28413547","order_by":0,"name":"Bayan Alsamarah","email":"","orcid":"","institution":"Jordan University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Bayan","middleName":"","lastName":"Alsamarah","suffix":""},{"id":611631593,"identity":"952de5ca-8255-46fe-bf6e-04bdd05f4433","order_by":1,"name":"Khawla Nuseir","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYBACCRjFz3AAzGJsYGBIIE6LZANQywEStDAwGIAsgWrBDyTbc49J/qiwyDc+eMb48wcGG9kNBxgePsCnRZrnXZo0zxkJy20HzphJHGBIMwZqSTbAp0VOIsdMmrFNwsAMqAXosMOJQC1pEoS0SP78J2Fg3HDG+MMBhv+EtUgDtUjwNkgYGDCcMQA67ABhLZI9b4yteY5JAJUfK5M4Y5BsPPMwAb9IHM8xvPmjps6Af8bhzR8qKuxk+473JD7ApwURb0BXAWMHiJl5EnCpRdPC3wATYT9AQMsoGAWjYBSMMAAAlXZL525IhOwAAAAASUVORK5CYII=","orcid":"","institution":"Jordan University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Khawla","middleName":"","lastName":"Nuseir","suffix":""},{"id":611631594,"identity":"67e21eef-1e64-4a69-9493-ebd6a5da338c","order_by":2,"name":"Rasha Khader","email":"","orcid":"","institution":"Jordan University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Rasha","middleName":"","lastName":"Khader","suffix":""}],"badges":[],"createdAt":"2026-03-13 07:08:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9111343/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9111343/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107130265,"identity":"e40241aa-e3e1-4819-9190-015ccc72071c","added_by":"auto","created_at":"2026-04-17 06:58:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":506851,"visible":true,"origin":"","legend":"","description":"","filename":"DMCognitiveDef.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9111343/v1_covered_84a8c2c1-0c78-457d-9148-72ea73e1d260.pdf"},{"id":105503582,"identity":"fc20b857-d2ef-4c29-b359-f1734c6c2928","added_by":"auto","created_at":"2026-03-26 18:12:41","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":54478,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-9111343/v1/95c8adf0db632575311ff878.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Metabolic Dysfunction and Cognitive Decline in a Rat Model of Type 2 Diabetes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"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":"Streptozocin, Radial Arm Water Maze, High Fat Diet","lastPublishedDoi":"10.21203/rs.3.rs-9111343/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9111343/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiabetes Mellitus (DM) comprises a group of metabolic disorders. Type 2 DM (T2DM), strongly associated with obesity and dietary habits, represents a major global health challenge. Cognitive impairment is a recognized complication of poorly controlled DM; however, its underlying mechanisms remain incompletely understood. This study aimed to investigate T2DM-induced cognitive dysfunction using a rat model that closely mimics human T2DM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForty-eight male and female Sprague–Dawley rats were allocated into two groups: high-fat diet (HFD) group combined with low-dose streptozotocin (STZ) and a regular diet (RD) control group. The two groups further stratified into four groups according to sex. HFD rats received a diet rich in fat and fructose water for 21 weeks, followed by an intraperitoneal STZ injection (40 mg/kg). Body weight and metabolic parameters, including fasting blood glucose (FBG), fasting insulin (FI), and insulin resistance (HOMA2-IR), were assessed. Behavioral tests were performed after 15 weeks to evaluate cognitive and related functions. At the end of the experiment, hippocampal and serum levels of oxidative stress and neurodegeneration markers (Brain derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), β-amyloid, Matrix metaloprotenase 9 (MMP9), Phosphorylated tau (P-tau) and Advanced glycation end products (AGEs) were analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults demonstrated that HFD significantly increased body weight (\u003cem\u003ep\u003c/em\u003e\u0026lt; 0.0001), FBG (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001), and insulin resistance (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001), accompanied by cognitive impairment as evidenced by behavioral testing (spatial learning and memory, \u003cem\u003ep\u003c/em\u003e=0.0011). Biomarker analysis further supported the presence of hippocampal oxidative stress and neurodegenerative changes (BDNF, MMP9, P.tau, β-amyloid, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese findings highlight the detrimental impact of diet-induced metabolic dysfunction on cognitive health and provide insights into potential mechanisms linking T2DM and cognitive decline.\u003c/p\u003e","manuscriptTitle":"Metabolic Dysfunction and Cognitive Decline in a Rat Model of Type 2 Diabetes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-26 18:12:30","doi":"10.21203/rs.3.rs-9111343/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":"4ade8311-c757-4250-a52d-e463e898afd3","owner":[],"postedDate":"March 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-17T06:55:43+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-26 18:12:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9111343","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9111343","identity":"rs-9111343","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}