{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:51:36Z","timestamp":1791571896562,"version":"4.3.4"},"reference-count":46,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"41","funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008695","name":"Japan Foundation for Applied Enzymology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019432","name":"Fujiwara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019432","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K19287"],"award-info":[{"award-number":["24K19287"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003837","name":"Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008644","name":"Japan Diabetes Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008644","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:p>\n                    Intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling is essential for glucose-induced insulin secretion (GIIS) and hepatic glucose production (HGP), yet how Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics are coordinated across organs remains unclear. Carbonic anhydrase VIII (CA8), an endogenous inhibitor of inositol 1,4,5-trisphosphate receptor 1 (IP3R1), was identified as a shared regulator of pancreatic and hepatic glucose metabolism. Using\n                    <jats:italic toggle=\"yes\">\n                      Car8\n                      <jats:sup>wdl<\/jats:sup>\n                    <\/jats:italic>\n                    mice, we showed that CA8 deficiency enhanced GIIS and HGP in vivo and ex vivo. In islets and hepatocytes, CA8 loss augments Ca\n                    <jats:sup>2+<\/jats:sup>\n                    oscillations, an effect abolished by IP3R inhibition or\n                    <jats:italic toggle=\"yes\">Car8<\/jats:italic>\n                    reexpression. Enhanced HGP persists independently of glucagon receptor, PLC, or PKA signaling and occurs without increased IP\n                    <jats:sub>1<\/jats:sub>\n                    , indicating heightened IP3R1 sensitivity rather than increased IP\n                    <jats:sub>3<\/jats:sub>\n                    production. In hepatocytes, chronic glucagon exposure attenuated acute glucagon responsiveness in a CA8-dependent manner. In obese diabetic mice, CA8 increased in islets but decreased in hepatocytes; hepatic CA8 restoration reduced excessive HGP. Collectively, these findings identify CA8 as a cross-organ regulator of IP3R1-dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling with translational relevance to diabetes.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh4948","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:06:59Z","timestamp":1791569219000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Carbonic anhydrase VIII regulates IP3R1-dependent Ca\n                    <sup>2+<\/sup>\n                    signaling to coordinate insulin secretion and hepatic glucose production"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9097-3938","authenticated-orcid":true,"given":"Muhammad","family":"Fauzi","sequence":"first","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3844-1138","authenticated-orcid":true,"given":"Takaaki","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Usui","sequence":"additional","affiliation":[{"name":"Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5610-4659","authenticated-orcid":true,"given":"Ainur","family":"Botagarova","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8185-673X","authenticated-orcid":true,"given":"Daisuke","family":"Otani","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3690-102X","authenticated-orcid":true,"given":"Kentarou","family":"Sakaki","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4070-6724","authenticated-orcid":true,"given":"Shinsuke","family":"Tokumoto","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8808-1893","authenticated-orcid":true,"given":"Toshinori","family":"Imaizumi","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisato","family":"Tatsuoka","sequence":"additional","affiliation":[{"name":"Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7107-2752","authenticated-orcid":true,"given":"Masahito","family":"Ogura","sequence":"additional","affiliation":[{"name":"Department of Diabetes, National Hospital Organization Kyoto Medical Center, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4358-6331","authenticated-orcid":true,"given":"Jonathan","family":"Campbell","sequence":"additional","affiliation":[{"name":"Duke Molecular Physiology Institute, Duke University, Durham, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuya","family":"Inagaki","sequence":"additional","affiliation":[{"name":"Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5334-7687","authenticated-orcid":true,"given":"Daisuke","family":"Yabe","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.1999.00003.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(85)90579-0"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1010825"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.12.3048"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.13435"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2018.10.016"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","unstructured":"J. B. Parys H. De Smedt \u201cInositol 1 4 5-trisphosphate and its receptors \u201d in Calcium Signaling Md. S. Islam Ed. (Springer Netherlands 2012) vol. 740 of Advances in Experimental Medicine and Biology pp. 255\u2013279.","DOI":"10.1007\/978-94-007-2888-2_11"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52048-1"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2074-6"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2012.95"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.15263"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20030110"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0118273"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00312.2020"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ads2905"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4160(03)00026-5"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01034-9"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0993"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.2337\/db17-1521"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1811129115"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50660-y"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102265"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1153-1"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aad6281"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108294"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2430039"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1057"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.10.016"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2023.01.012"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1127"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.020"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-44324-y"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198507253130405"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2011.01454.x"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.07.075"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.105.044487"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jhered.a106073"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-010-1729-5"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-4-8"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3252"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.920"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3300947"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1385\/MB:26:2:165"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.15.10930"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.180695"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.556050"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeh4948","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:08:04Z","timestamp":1791569284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeh4948"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":46,"journal-issue":{"issue":"41","published-print":{"date-parts":[[2026,10,9]]}},"alternative-id":["10.1126\/sciadv.aeh4948"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeh4948","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"assertion":[{"value":"2026-03-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeh4948"}}