Can insulin resistance be explained by increased chain splitting of insulin before its action?

Can insulin resistance be explained by increased chain splitting of insulin before its action? | 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 Letter Can insulin resistance be explained by increased chain splitting of insulin before its action? Jeppe Sturis, Christian Cramer, František Hubálek, Christian Brand, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4998078/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 Despite decades of intense research, the mechanisms underlying insulin resistance are still poorly understood. What if a major cause of insulin resistance is not related to defects in the target tissues and/or insulin receptor signaling, but rather to a reduced survival of endogenously secreted insulin on its way to activating the receptor on the cell surface of the target tissues? Here, we present data and lay out arguments in support of this novel hypothesis which is fundamentally different from the common view that insulin resistance is caused by the body's cells becoming less sensitive to insulin. Biological sciences/Physiology/Metabolism/Metabolic diseases/Pre-diabetes Biological sciences/Physiology/Metabolism/Metabolic diseases/Diabetes/Type 2 diabetes Full Text Additional Declarations There is NO Competing Interest. 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-4998078","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Letter","associatedPublications":[],"authors":[{"id":348413366,"identity":"7b152f3b-711c-4404-b297-fb046ed8cb94","order_by":0,"name":"Jeppe Sturis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYBAC9v7z3yQ+wHg8BgwGBLUwzkhsk5xBohbGNmkeuBYGYrXY7rBJ7JduPvbhTUGdMQP74aMb8GrpP9gmnXsmLXHmnGPJM+cYHDZj4ElLu4FXS0MiUEvbYWODGznGzDwGB2wYJHjMCGuxRGipI6xFEKSFse2wHFQLsxlBLdISic2GvW1pcpIz0pIZgX4xZiPkFz7+g40PfrbZ8PBLJB9mePOnzrCf/fAxvFowARtpykfBKBgFo2AUYAMA4uBD2aGqkpcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-9938-5278","institution":"Novo Nordisk (Denmark)","correspondingAuthor":true,"prefix":"","firstName":"Jeppe","middleName":"","lastName":"Sturis","suffix":""},{"id":348413367,"identity":"f9694381-c4c9-43df-9640-14126bd065d2","order_by":1,"name":"Christian Cramer","email":"","orcid":"https://orcid.org/0000-0001-9455-4212","institution":"Novo Nordisk A/S","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Cramer","suffix":""},{"id":348413368,"identity":"94d79c96-3007-43ba-8961-9c9c780a246a","order_by":2,"name":"František Hubálek","email":"","orcid":"","institution":"Novo Nordisk A/S","correspondingAuthor":false,"prefix":"","firstName":"František","middleName":"","lastName":"Hubálek","suffix":""},{"id":348413369,"identity":"6885448c-b204-4d1c-8b70-f11842c125a3","order_by":3,"name":"Christian Brand","email":"","orcid":"","institution":"Novo Nordisk A/S","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Brand","suffix":""},{"id":348413370,"identity":"227db497-b135-428e-8884-4c99615fc73f","order_by":4,"name":"Hans Helleberg","email":"","orcid":"","institution":"Novo Nordisk A/S","correspondingAuthor":false,"prefix":"","firstName":"Hans","middleName":"","lastName":"Helleberg","suffix":""},{"id":348413371,"identity":"da9e4eca-363d-4f7b-a629-c32c3a4d0563","order_by":5,"name":"Peter Kurtzhals","email":"","orcid":"","institution":"Novo Nordisk A/S","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Kurtzhals","suffix":""}],"badges":[],"createdAt":"2024-08-29 13:31:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4998078/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4998078/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64773014,"identity":"dd9d50fc-9969-4917-b811-f35114216c09","added_by":"auto","created_at":"2024-09-18 15:11:35","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":507808,"visible":true,"origin":"","legend":"","description":"","filename":"Caninsulinresistancebeexplainedbyincreasedchainsplittingofinsulinbeforeitsactionfinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4998078/v1_covered_ea71f2ad-4ac6-41c5-aa68-945daf2d598d.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Can insulin resistance be explained by increased chain splitting of insulin before its action?","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-4998078/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4998078/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Despite decades of intense research, the mechanisms underlying insulin resistance are still poorly understood. 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