{"data":{"id":"10.5061/dryad.5qfttdz9v","type":"dois","attributes":{"doi":"10.5061/dryad.5qfttdz9v","prefix":"10.5061","suffix":"dryad.5qfttdz9v","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Daniel, Fuster","nameType":"Personal","givenName":"Fuster","familyName":"Daniel","affiliation":["University of Bern"],"nameIdentifiers":[{"schemeUri":"https://orcid.org","nameIdentifier":"https://orcid.org/0000-0001-7220-1803","nameIdentifierScheme":"ORCID"}]}],"titles":[{"title":"Thiazides attenuate insulin secretion through inhibition of mitochondrial carbonic anhydrase 5b in β-islet cells in mice"}],"publisher":"Dryad","container":{},"publicationYear":2023,"subjects":[{"subject":"FOS: Basic medicine","schemeUri":"https://web-archive.oecd.org/2012-06-15/138575-38235147.pdf","subjectScheme":"fos"},{"subject":"FOS: Basic medicine","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"}],"contributors":[{"name":"University Hospital of Bern","affiliation":[],"contributorType":"Sponsor","nameIdentifiers":[]}],"dates":[{"date":"2023-03-20T13:08:30Z","dateType":"Submitted"},{"date":"2023-03-27T00:00:00Z","dateType":"Issued"},{"date":"2023-03-27T00:00:00Z","dateType":"Available"}],"language":"en","types":{"ris":"DATA","bibtex":"misc","citeproc":"dataset","schemaOrg":"Dataset","resourceType":"dataset","resourceTypeGeneral":"Dataset"},"relatedIdentifiers":[{"relationType":"IsCitedBy","relatedIdentifier":"10.1681/asn.0000000000000122","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":["4787808 bytes"],"formats":[],"version":"3","rightsList":[{"rights":"Creative Commons Zero v1.0 Universal","rightsUri":"https://creativecommons.org/publicdomain/zero/1.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc0-1.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"Background: Thiazides are associated with glucose intolerance and new\n onset diabetes mellitus. Previous studies demonstrated that thiazides\n attenuate insulin secretion, but the molecular mechanisms remain elusive.\n We hypothesized that thiazides attenuate insulin secretion via one of the\n known molecular thiazide targets in β-cells. Methods: We performed static\n insulin secretion experiments with islets of wild-type, NCC (SLC12A3) and\n NDCBE (SLC4A8) knock-out (KO) mice and with murine Min6 cells with\n individual knock-down of carbonic anhydrase (CA) isoforms to identify the\n molecular target of thiazides in β-cells. CA5b KO mice were then used to\n assess the role of the putative thiazide target CA5b in β-cell function\n and in mediating thiazide sensitivity in vitro and in vivo. Results:\n Thiazides inhibited glucose- and sulfonylurea-stimulated insulin secretion\n in islets and Min6 cells at pharmacologically relevant concentrations.\n Inhibition of insulin secretion by thiazides was CO2/HCO3--dependent, not\n additive to unselective CA inhibition with acetazolamide and independent\n of extracellular potassium. In contrast, insulin secretion was unaltered\n in islets of mice lacking the known molecular thiazide targets NCC or\n NDCBE. CA expression profiling with subsequent knock-down of individual CA\n isoforms suggested mitochondrial CA5b as molecular target. In support of\n these findings, thiazides significantly attenuated Krebs cycle anaplerosis\n through reduction of mitochondrial oxaloacetate synthesis. CA5b KO mice\n were resistant to thiazide-induced glucose intolerance, and thiazides did\n not alter insulin secretion in CA5b KO islets. Conclusions: In summary,\n our study reveals that thiazides attenuate insulin secretion via\n inhibition of the mitochondrial CA5b isoform in β-cells.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[{"schemeUri":"https://ror.org","funderName":"Swiss National Science Foundation","awardNumber":"# grant 31003A_172974","funderIdentifier":"https://ror.org/00yjd3n13","funderIdentifierType":"ROR"},{"schemeUri":"https://ror.org","funderName":"Swiss National Science Foundation","awardNumber":"NCCR TransCure","funderIdentifier":"https://ror.org/00yjd3n13","funderIdentifierType":"ROR"},{"schemeUri":"https://ror.org","funderName":"Swiss National Science Foundation","awardNumber":"NCCR Kidney.CH","funderIdentifier":"https://ror.org/00yjd3n13","funderIdentifierType":"ROR"},{"schemeUri":"https://ror.org","funderName":"Novartis (Switzerland)","awardNumber":"# 15B121","funderIdentifier":"https://ror.org/02f9zrr09","funderIdentifierType":"ROR"},{"schemeUri":"https://ror.org","funderName":"Stiftung Prof. Dr. Max Cloëtta","awardNumber":"Medical Research Position Award","funderIdentifier":"https://ror.org/05pn6h396","funderIdentifierType":"ROR"}],"xml":"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