Heterozygous Hnf1a Mutation in Mice Reveals Multiple Pathogenic Mechanisms of HNF1A-MODY

Heterozygous Hnf1a Mutation in Mice Reveals Multiple Pathogenic Mechanisms of HNF1A-MODY | 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 Article Heterozygous Hnf1a Mutation in Mice Reveals Multiple Pathogenic Mechanisms of HNF1A-MODY Caroline Bonner, Ana Acosta-Montalvo, Isaline Louvet, Chiara Saponaro, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6369014/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 Heterozygous mutations in HNF1A cause HNF1A-MODY, the most common form of monogenic diabetes, characterized by age-dependent onset and progression. Despite HNF1A 's established role in beta cell function, the mechanisms underlying disease progression remain poorly understood, with conventional mouse models failing to recapitulate the gradual metabolic deterioration observed in patients. We developed mice with a heterozygous deletion of the Hnf1a transactivation domain ( Hnf1a +/Δe4–10 ) that successfully models the temporal progression of HNF1A-MODY. Like their human counterparts, these mutant mice were normoglycemic at birth, with metabolic abnormalities emerging progressively with age. Male mutant mice, but not females, exhibited a sequential cascade of metabolic dysfunction: testosterone deficiency emerged during puberty (8–12 weeks), preceding fasting hyperglycemia in young adulthood (12–16 weeks), followed by glycosuria and glucose intolerance in mature adults (25–35 weeks) that worsened with advanced age (> 45 weeks). Aging mutant mice displayed elevated fasting glucagon levels, increased endogenous glucose production, and hepatic fat accumulation, while maintaining normal plasma insulin levels compared to wild-type siblings. Isolated islets revealed reduced Androgen Receptor expression not observed in liver tissue, complex hormonal dysregulation, dysregulated glucose-stimulated insulin secretion (GSIS) and defective glucagon suppression, with preserved sulfonylurea sensitivity. Parallel knockdown studies in human islets demonstrated HNF1A' s critical role in alpha cell function, where haploinsufficiency reduced SGLT2 protein expression while increasing glucagon content and secretion. These findings establish HNF1A as a master regulator of multiple hormonal pathways and identify testosterone deficiency as a potential trigger for disease onset in males, suggesting therapeutic strategies for HNF1A-MODY that extend beyond insulin-centric approaches. Biological sciences/Genetics/Mutation Biological sciences/Physiology/Metabolism/Metabolic diseases 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-6369014","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":441049698,"identity":"444e3dc3-9531-4ccf-9e57-f14c268379ab","order_by":0,"name":"Caroline Bonner","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie3QsWqDQBjA8e8o6HKN64Gir3BBCH2cz0WXBoQuDqU9EezYNXkLHyFBcLK70FAuFJzzAKH0opAUcmbucP/BO4Uf33kAJtN/TXL1YOPeByACIGXeTL0dpgj+IeFIOKOW2q0mCVxIJIaFwyRx3j72EtOdD27RfKfZV1J9FiUD/kAtW5AiuyasTUKOvA/Ba5Jw1T4tq932RNTB6Ibk7TXhEFsMeR0J9rhw70tcVl1UhMcTYWjvhYY4/UBeR/KDCVeED1MCSXIdYeMUhIEIREVyORAGWsK6/k79Sz0vvSZ2aYPz9ZnQKNcR5z0m8nCsA0fdmEufMZh1idxA9uI7dr3VkXOW5hu5BUwmk8l0o19F7Fuy40DFZAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4430-8280","institution":"Institut Pasteur de Lille","correspondingAuthor":true,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Bonner","suffix":""},{"id":441049699,"identity":"87d2d21e-da0b-4a7a-b262-72725bd81b54","order_by":1,"name":"Ana Acosta-Montalvo","email":"","orcid":"","institution":"Univ. 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Despite \u003cem\u003eHNF1A\u003c/em\u003e's established role in beta cell function, the mechanisms underlying disease progression remain poorly understood, with conventional mouse models failing to recapitulate the gradual metabolic deterioration observed in patients. We developed mice with a heterozygous deletion of the \u003cem\u003eHnf1a\u003c/em\u003e transactivation domain (\u003cem\u003eHnf1a\u003c/em\u003e\u003csup\u003e\u003cem\u003e+/Δe4\u0026ndash;10\u003c/em\u003e\u003c/sup\u003e) that successfully models the temporal progression of HNF1A-MODY. Like their human counterparts, these mutant mice were normoglycemic at birth, with metabolic abnormalities emerging progressively with age. Male mutant mice, but not females, exhibited a sequential cascade of metabolic dysfunction: testosterone deficiency emerged during puberty (8\u0026ndash;12 weeks), preceding fasting hyperglycemia in young adulthood (12\u0026ndash;16 weeks), followed by glycosuria and glucose intolerance in mature adults (25\u0026ndash;35 weeks) that worsened with advanced age (\u0026gt;\u0026thinsp;45 weeks). Aging mutant mice displayed elevated fasting glucagon levels, increased endogenous glucose production, and hepatic fat accumulation, while maintaining normal plasma insulin levels compared to wild-type siblings. Isolated islets revealed reduced Androgen Receptor expression not observed in liver tissue, complex hormonal dysregulation, dysregulated glucose-stimulated insulin secretion (GSIS) and defective glucagon suppression, with preserved sulfonylurea sensitivity. Parallel knockdown studies in human islets demonstrated \u003cem\u003eHNF1A'\u003c/em\u003es critical role in alpha cell function, where haploinsufficiency reduced SGLT2 protein expression while increasing glucagon content and secretion. These findings establish \u003cem\u003eHNF1A\u003c/em\u003e as a master regulator of multiple hormonal pathways and identify testosterone deficiency as a potential trigger for disease onset in males, suggesting therapeutic strategies for HNF1A-MODY that extend beyond insulin-centric approaches.\u003c/p\u003e","manuscriptTitle":"Heterozygous Hnf1a Mutation in Mice Reveals Multiple Pathogenic Mechanisms of HNF1A-MODY","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-15 13:31:17","doi":"10.21203/rs.3.rs-6369014/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":"6e0dad1c-3133-487a-b2a8-07a6399d9ca7","owner":[],"postedDate":"April 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46958991,"name":"Biological sciences/Genetics/Mutation"},{"id":46958992,"name":"Biological sciences/Physiology/Metabolism/Metabolic diseases"}],"tags":[],"updatedAt":"2025-04-21T04:50:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-15 13:31:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6369014","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6369014","identity":"rs-6369014","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}