Telmisartan Potentiates Insulin Secretion Via Ion Channels, Independent of The AT1 Receptor and PPARγ.

Telmisartan Potentiates Insulin Secretion Via Ion Channels, Independent of The AT1 Receptor and PPARγ. | 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 Original investigation Telmisartan Potentiates Insulin Secretion Via Ion Channels, Independent of The AT1 Receptor and PPARγ. Tao Liu, Lijuan Cui, Huan Xue, Xiaohua Yang, Mengmeng Liu, Linping Zhi, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-237604/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 and aim: Angiotensin II type 1 (AT1) receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the direct effects of ARBs on insulin secretion remain unclear. In this study, we aimed to investigate the insulinotropic effect of ARBs and the underlying electrophysiological mechanism. Methods: Islets isolated from Wistar rats or db/db mice were incubated with drugs under different glucose conditions for 30 minutes, then supernatant liquid was collected for insulin secretion. Intracellular Ca2+ ([Ca2+]i) levels of β-cells were measured by calcium imaging technology. Patch-clamp technology was applied to detect effects on action potential duration (APD), Voltage-dependent potassium (Kv) channels, and voltage-gated calcium channels (VGCC). In our in vivo experiment, the 8-week-old and 11-week-old db/db mice were separately administered acute oral acute oral telmisartan treatment (15 mg/kg), then the oral glucose tolerance test (OGTT) was performed to observe the insulinotropic effect of telmisartan at 2 hours following drug intake. Results: Only telmisartan among the three ARBs（telmisartan, valsartan, and irbesartan）exhibited an insulin secretagogue role in rat islets. Independent of AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ), telmisartan exerted effects on ion channels including Kv channels and L-type VGCCs to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. Furthermore, we identified that telmisartan directly inhibited Kv2.1 channel on a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of db/db mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in OGTT. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from db / db mice. Conclusions: Our results establish an important insulinotropic function of telmisartan distinct from other ARBs in the treatment of diabetes. Cardiac & Cardiovascular Systems Telmisartan Insulin secretion AT1 receptor PPARγ Kv channel L-type VGCC Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Full Text 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-237604","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Original investigation","associatedPublications":[],"authors":[{"id":13132804,"identity":"2519b713-51c2-4310-8ee3-36cd23d1ded0","order_by":0,"name":"Tao Liu","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Liu","suffix":""},{"id":13132805,"identity":"8b5d8934-0ace-4acc-bb17-331e6b92c5dc","order_by":1,"name":"Lijuan Cui","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lijuan","middleName":"","lastName":"Cui","suffix":""},{"id":13132806,"identity":"52873478-d9f6-48c3-8496-04995cff37f4","order_by":2,"name":"Huan Xue","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Huan","middleName":"","lastName":"Xue","suffix":""},{"id":13132807,"identity":"13ae321a-05a5-4f3c-b698-65d1ed2a8130","order_by":3,"name":"Xiaohua Yang","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaohua","middleName":"","lastName":"Yang","suffix":""},{"id":13132808,"identity":"1f20db16-40f0-4308-9be9-de7eae6294de","order_by":4,"name":"Mengmeng Liu","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mengmeng","middleName":"","lastName":"Liu","suffix":""},{"id":13132809,"identity":"34bdff40-0b04-4068-8eeb-a161111c62bc","order_by":5,"name":"Linping Zhi","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Linping","middleName":"","lastName":"Zhi","suffix":""},{"id":13132810,"identity":"83616d3d-a55a-4e78-997c-9e065205da5c","order_by":6,"name":"Huanhuan Yang","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Huanhuan","middleName":"","lastName":"Yang","suffix":""},{"id":13132811,"identity":"d7d5ac6a-a081-4a60-a6b6-496965d44471","order_by":7,"name":"Zhihong Liu","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhihong","middleName":"","lastName":"Liu","suffix":""},{"id":13132812,"identity":"c228b2a9-64a5-47ff-a554-5fc24ac662cf","order_by":8,"name":"Min Zhang","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Zhang","suffix":""},{"id":13132813,"identity":"ff618441-0cf9-450f-8ea2-bae5a0002298","order_by":9,"name":"Qing Guo","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Guo","suffix":""},{"id":13132814,"identity":"c8b76209-5b44-43eb-81f1-fee5773d54f3","order_by":10,"name":"Peifeng He","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Peifeng","middleName":"","lastName":"He","suffix":""},{"id":13132815,"identity":"d76f7ae1-02d4-41c5-92cc-6e2d083185b4","order_by":11,"name":"Yunfeng Liu","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yunfeng","middleName":"","lastName":"Liu","suffix":""},{"id":13132816,"identity":"ab1a2125-40f7-43cc-872a-62996d166a86","order_by":12,"name":"Yi Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYDACZgY2EGXHxt984MCHHyRoSeaTOJZ4cGYPcfaAtTDOY8gxPszBRoR6g+Pszx783FHLzMZw5sNhBh4GeX6xAwS0HGZIN+w9c5yPjbl3w+ECCwbDmbMTCGo5JsHbdgxoy9kNh2fwMCQY3CaohbFN8m/bMcY2hpwHh3nYiNLCzCbN21YD0sJAnBbJw2xs0rJtB5LZJI4ZAANZgrBf+M4ffyb5tq3OTr6/+fGHDz9s5PmlCWhROACmDsP4EviVg4B8A5iqI6xyFIyCUTAKRi4AAMI4Rbqjv8RGAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-0305-3127","institution":"Shanxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yi","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2021-02-12 16:54:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-237604/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-237604/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":6410063,"identity":"e57487e6-92bf-4f91-be68-48f4391f79ef","added_by":"auto","created_at":"2021-02-26 21:30:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46974,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig01.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/c55f095b873d163022bd3459.png"},{"id":6410306,"identity":"13473be1-d0c9-4ec8-825b-c426a2649f68","added_by":"auto","created_at":"2021-02-26 21:33:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":149517,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig02.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/34152c9771ac3a37c265fd91.png"},{"id":6410062,"identity":"47274372-9f8e-4b41-a38c-5fec035341d1","added_by":"auto","created_at":"2021-02-26 21:30:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34464,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig03.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/5b2aef020de3e2f27f4ff9ba.png"},{"id":6409477,"identity":"6be2c81e-b7db-45ca-9769-31d00df6488b","added_by":"auto","created_at":"2021-02-26 21:27:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":64778,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig04.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/f02626720ff83e20602f6d3c.png"},{"id":6409475,"identity":"53a2f846-55d3-4b86-a834-9f1133d70229","added_by":"auto","created_at":"2021-02-26 21:27:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":126665,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig05.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/096914d813e2cd8da57cbf1e.png"},{"id":6409471,"identity":"25908c75-f13d-407c-a7fa-122977a39ee4","added_by":"auto","created_at":"2021-02-26 21:27:38","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":283695,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig06.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/e0fde0a6cf0687003e232675.png"},{"id":6410060,"identity":"0525891f-421b-4f01-9954-875c6410fde3","added_by":"auto","created_at":"2021-02-26 21:30:38","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":108542,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig07.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/02fda0a96eceffb2b3ea6605.png"},{"id":6409473,"identity":"d06ff84c-962a-4482-8835-4e78b44b650b","added_by":"auto","created_at":"2021-02-26 21:27:38","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":82881,"visible":true,"origin":"","legend":"See the Manuscript Files section for the complete figure caption.","description":"","filename":"Fig08.png","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/12d562393bb7f783cd457f01.png"},{"id":13672568,"identity":"1d725eec-bcd1-420e-9b53-ffb5035ba8ff","added_by":"auto","created_at":"2021-09-17 11:14:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1051916,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-237604/v1/338b4b50-840a-4134-aac5-e9b5ded13e4b.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eTelmisartan Potentiates Insulin Secretion Via Ion Channels, Independent of The AT1 Receptor and PPARγ.\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-237604/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"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":"Telmisartan, Insulin secretion, AT1 receptor, PPARγ, Kv channel, L-type VGCC","lastPublishedDoi":"10.21203/rs.3.rs-237604/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-237604/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and aim: \u003c/strong\u003eAngiotensin II type 1 (AT1) receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the direct effects of ARBs on insulin secretion remain unclear. In this study, we aimed to investigate the insulinotropic effect of ARBs and the underlying electrophysiological mechanism. \u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eIslets isolated from Wistar rats or \u003cem\u003edb/db \u003c/em\u003emice were incubated with drugs under different glucose conditions for 30 minutes, then supernatant liquid was collected for insulin secretion. Intracellular Ca2+ ([Ca2+]i) levels of β-cells were measured by calcium imaging technology. Patch-clamp technology was applied to detect effects on action potential duration (APD), Voltage-dependent potassium (Kv) channels, and voltage-gated calcium channels (VGCC). In our in vivo experiment, the 8-week-old and 11-week-old \u003cem\u003edb/db \u003c/em\u003emice were separately administered acute oral acute oral telmisartan treatment (15 mg/kg), then the oral glucose tolerance test (OGTT) was performed to observe the insulinotropic effect of telmisartan at 2 hours following drug intake.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOnly telmisartan among the three ARBs（telmisartan, valsartan, and irbesartan）exhibited an insulin secretagogue role in rat islets. Independent of AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ), telmisartan exerted effects on ion channels including Kv channels and L-type VGCCs to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. Furthermore, we identified that telmisartan directly inhibited Kv2.1 channel on a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of \u003cem\u003edb/db \u003c/em\u003emice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in OGTT. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from \u003cem\u003edb\u003c/em\u003e/\u003cem\u003edb \u003c/em\u003emice. \u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur results establish an important insulinotropic function of telmisartan distinct from other ARBs in the treatment of diabetes. \u003c/p\u003e","manuscriptTitle":"Telmisartan Potentiates Insulin Secretion Via Ion Channels, Independent of The AT1 Receptor and PPARγ.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-02-26 21:27:35","doi":"10.21203/rs.3.rs-237604/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":"6243b512-7f99-40bb-a464-b0342c970ecc","owner":[],"postedDate":"February 26th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2653498,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2021-02-26T21:30:37+00:00","versionOfRecord":[],"versionCreatedAt":"2021-02-26 21:27:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-237604","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-237604","identity":"rs-237604","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}