Orally Available Small Molecule Regulates TXNIP Expression and Glucagon Action for the Treatment of Diabetes

Orally Available Small Molecule Regulates TXNIP Expression and Glucagon Action for the Treatment of 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 Article Orally Available Small Molecule Regulates TXNIP Expression and Glucagon Action for the Treatment of Diabetes Xiaolei Wang, Zhikuan Luo, Jun Han, Qiong Tian, Ruijun Jing, Ao Dong, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3766638/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 In the progression of diabetes, sustained glucagon secretion facilitates glucose production. Despite its significance, no treatments currently target this vital parameter. We employed the promoter sequence of thioredoxin-interacting protein (TXNIP) as a screening target, evaluated our in-house chemical library, and subsequently undertook high-throughput screening and optimization via various medicinal chemistry techniques. Our efforts led to the identification of SKL-1223, an orally administered, non-toxic small molecule capable of effectively regulating blood glucose levels in both streptozotocin-induced and obesity-induced (db/db) diabetic mice. Furthermore, our study elucidated the hypoglycemic effect of glucagon and its role in reducing hepatic glucose output. On a mechanistic level, SKL-1223 interacts with the E-box region of the TXNIP promoter, consequently suppressing TXNIP transcription and associated signaling pathways. Thus, our study introduces a novel compound, offering a fresh therapeutic avenue for diabetes beyond existing regimens. Biological sciences/Chemical biology/Small molecules Health sciences/Diseases/Endocrine system and metabolic diseases/Diabetes/Type 2 diabetes Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupportingInformation.pdf Figure S1 and Table S1,Figure S2 to Figure S4,Spectra Data of the Compounds,Chemical Synthesis Section,The HPLC trace for SKL-1201 and SKL-1223,The Copy of NMR Data 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-3766638","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":265887682,"identity":"3e0a0228-1c3a-4dc7-a6c0-7049a42ae709","order_by":0,"name":"Xiaolei Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIie3RMUvEMBTA8RcK7RLsmlvqV3hQKIjgfZVXDu6WIB0FB5FCXDxc72u4OfbI0KVya8fecosdAk4HHUydXEw7CuY/BALvxyMEwOf7syHABbDHrvu+0UwSAiuR5hMYCYRiFsH6XX/w4iYJo1Ld0aAhjiTC+c1Bmtv11Q5Xacj3qiWuYfHcI9s2v5OskhkaDHIlckuEBmwlBkw5yKHPkPAhV5dHVRBqWE6SVqadQW232DEiu0VMkGXbZ2yHtX1LXgqqNlw0p2K/dZDFi0w/+XCfxFF9NGa4TuKn1Wt3dhAYv+PnjY9H5QQAgZkY8Pl8vv/eFxQETtbf3THIAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8867-6528","institution":"State Key Laboratory of Applied Organic Chemistry, Department of Chemistry and School of Pharmacy, Lanzhou University","correspondingAuthor":true,"prefix":"","firstName":"Xiaolei","middleName":"","lastName":"Wang","suffix":""},{"id":265887683,"identity":"7780cbfb-fd07-4450-8d5d-24afdd44c424","order_by":1,"name":"Zhikuan Luo","email":"","orcid":"","institution":"State Key Laboratory of Applied Organic Chemistry, Department of Chemistry and School of Pharmacy, Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Zhikuan","middleName":"","lastName":"Luo","suffix":""},{"id":265887684,"identity":"9b23dbdc-447a-4d09-8d50-7d12fce000a3","order_by":2,"name":"Jun Han","email":"","orcid":"","institution":"State Key Laboratory of Applied Organic Chemistry, Department of Chemistry and School of Pharmacy, Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Han","suffix":""},{"id":265887685,"identity":"2c8b5d3a-7b5e-4211-8174-a896a11f1ec3","order_by":3,"name":"Qiong Tian","email":"","orcid":"","institution":"State Key Laboratory of Applied Organic Chemistry, Department of Chemistry and School of Pharmacy, Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Qiong","middleName":"","lastName":"Tian","suffix":""},{"id":265887686,"identity":"fa0b642e-4ec2-4cf5-bccd-b5402adda3b4","order_by":4,"name":"Ruijun Jing","email":"","orcid":"","institution":"State Key Laboratory of Applied Organic Chemistry, Department of Chemistry and School of Pharmacy, Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Ruijun","middleName":"","lastName":"Jing","suffix":""},{"id":265887687,"identity":"13bcc327-c4f7-4df0-be14-a3b6420dd3d7","order_by":5,"name":"Ao Dong","email":"","orcid":"","institution":"Yunnan University","correspondingAuthor":false,"prefix":"","firstName":"Ao","middleName":"","lastName":"Dong","suffix":""},{"id":265887688,"identity":"bce1302a-d46f-4910-bd52-344cc0646183","order_by":6,"name":"Lingzhi Li","email":"","orcid":"","institution":"Yunnan University","correspondingAuthor":false,"prefix":"","firstName":"Lingzhi","middleName":"","lastName":"Li","suffix":""},{"id":265887689,"identity":"81fae2b8-2afe-4a28-9e46-a8da8cff2ff8","order_by":7,"name":"Hongbin Jia","email":"","orcid":"","institution":"State Key Laboratory of Applied Organic Chemistry, Department of Chemistry and School of Pharmacy, Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Hongbin","middleName":"","lastName":"Jia","suffix":""},{"id":265887690,"identity":"7da5a2a5-b58a-46c4-b52a-3c10a8d094ab","order_by":8,"name":"Tinghong Lv","email":"","orcid":"","institution":"State Key Laboratory of Applied Organic Chemistry, Lanzhou University,","correspondingAuthor":false,"prefix":"","firstName":"Tinghong","middleName":"","lastName":"Lv","suffix":""},{"id":265887691,"identity":"48f0659a-1ff0-4ff0-871d-b379a794df78","order_by":9,"name":"Yunkun Dang","email":"","orcid":"","institution":"Yunnan University","correspondingAuthor":false,"prefix":"","firstName":"Yunkun","middleName":"","lastName":"Dang","suffix":""},{"id":265887692,"identity":"e2042a5e-ae54-4a77-bc8c-87fe193161b9","order_by":10,"name":"Fan Lai","email":"","orcid":"","institution":"State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Center for Life Science, Yunnan Key Labora-tory of Cell Metabolism and Diseases，School of Life Sciences, Yunn","correspondingAuthor":false,"prefix":"","firstName":"Fan","middleName":"","lastName":"Lai","suffix":""},{"id":265887693,"identity":"298b0ec3-f7ed-40b4-9f46-d56774ef45f5","order_by":11,"name":"Shili Chen","email":"","orcid":"","institution":"Shanghai Key Laboratory of Biliary Tract Disease Research","correspondingAuthor":false,"prefix":"","firstName":"Shili","middleName":"","lastName":"Chen","suffix":""},{"id":265887694,"identity":"3d5b2ac1-be5f-442c-af44-46e942534600","order_by":12,"name":"XuSheng Ma","email":"","orcid":"https://orcid.org/0000-0002-3879-8324","institution":"Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences","correspondingAuthor":false,"prefix":"","firstName":"XuSheng","middleName":"","lastName":"Ma","suffix":""},{"id":265887695,"identity":"329bb3d2-f66b-477d-abff-b983bb6cb233","order_by":13,"name":"Haixue Zheng","email":"","orcid":"","institution":"Chinese Academy of Agricultural Sciences","correspondingAuthor":false,"prefix":"","firstName":"Haixue","middleName":"","lastName":"Zheng","suffix":""}],"badges":[],"createdAt":"2023-12-17 09:35:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3766638/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3766638/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50678625,"identity":"a41fbe9b-38d7-4b0a-bcc1-5eae4cfe5860","added_by":"auto","created_at":"2024-02-05 16:09:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1394523,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3766638/v1_covered_7a0d6e11-f987-449c-8991-73acd2550389.pdf"},{"id":49345235,"identity":"7f11f0ff-f5ce-46bd-a8cc-0bec7a55fb45","added_by":"auto","created_at":"2024-01-09 04:25:41","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8421247,"visible":true,"origin":"","legend":"Figure S1 and Table S1,Figure S2 to Figure S4,Spectra Data of the Compounds,Chemical Synthesis Section,The HPLC trace for SKL-1201 and SKL-1223,The Copy of NMR Data","description":"","filename":"SupportingInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3766638/v1/3aee28d3777136a6bcbd7b98.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Orally Available Small Molecule Regulates TXNIP Expression and Glucagon Action for the Treatment of Diabetes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":false,"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-3766638/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3766638/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn the progression of diabetes, sustained glucagon secretion facilitates glucose production. Despite its significance, no treatments currently target this vital parameter. We employed the promoter sequence of thioredoxin-interacting protein (TXNIP) as a screening target, evaluated our in-house chemical library, and subsequently undertook high-throughput screening and optimization via various medicinal chemistry techniques. Our efforts led to the identification of SKL-1223, an orally administered, non-toxic small molecule capable of effectively regulating blood glucose levels in both streptozotocin-induced and obesity-induced (db/db) diabetic mice. Furthermore, our study elucidated the hypoglycemic effect of glucagon and its role in reducing hepatic glucose output. On a mechanistic level, SKL-1223 interacts with the E-box region of the TXNIP promoter, consequently suppressing TXNIP transcription and associated signaling pathways. Thus, our study introduces a novel compound, offering a fresh therapeutic avenue for diabetes beyond existing regimens.\u003c/p\u003e","manuscriptTitle":"Orally Available Small Molecule Regulates TXNIP Expression and Glucagon Action for the Treatment of Diabetes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-09 04:25:36","doi":"10.21203/rs.3.rs-3766638/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":"82a4c744-0936-44f8-afb0-61d163b5d70d","owner":[],"postedDate":"January 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":28009978,"name":"Biological sciences/Chemical biology/Small molecules"},{"id":28009979,"name":"Health sciences/Diseases/Endocrine system and metabolic diseases/Diabetes/Type 2 diabetes"}],"tags":[],"updatedAt":"2026-03-02T04:10:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-09 04:25:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3766638","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3766638","identity":"rs-3766638","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}