{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:17:20Z","timestamp":1788891440021,"version":"build-2803163510"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005089","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7232230"],"award-info":[{"award-number":["7232230"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470900"],"award-info":[{"award-number":["82470900"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070890"],"award-info":[{"award-number":["82070890"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Berberine (BBR) is a well\u2010established natural product lowing glucose and promoting insulin secretion in mice and diabetic patients. However, the bioavailability of BBR is low and the target remains unclear. Here, a BBR analog dihydroberberine (DHB) showed higher bioavailability in promoting insulin secretion by targeting glucokinase (GCK) that has been reported as a powerful regulator of diabetes by promoting insulin secretion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>To evaluate the effects and mechanisms of drugs in MIN6 and INS\u20101 cells, cell viability, glucose\u2010stimulated insulin secretion (GSIS) and the expression of genes associated with insulin secretion and cell function were assessed. Glucose tolerance, insulin secretion and insulin tolerance experiment were conducted to confirm the effects of DHB in vivo. Molecular docking, CETSAs, and knockdown experiments were used to predict and validate the target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>DHB promoted glucose\u2010stimulated insulin secretion (GSIS) in INS\u20101 and MIN6 cells. DHB might be one of the most effective BBR analog, as validated by the improved oral glucose tolerance test (GTT) and insulin released test (IRT) assays in mice. In addition, molecular docking and cellular thermal shift assay (CETSA) revealed that DHB formed compact complexes with GCK. Importantly, the effects of DHB were significantly diminished in INS\u20101 cells upon deprivation of GCK in siRNA knockdown assay, supporting that GCK is required for DHB promoting glucose\u2010stimulated insulin secretion (GSIS) and preventing cell apoptosis in pancreatic \u03b2\u2010cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest DHB might be one of the most effective compound via regulating GCK.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.70171","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T07:30:29Z","timestamp":1760340629000},"page":"151-165","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dihydroberberine normalizes insulin secretion by regulating glucokinase"],"prefix":"10.1111","volume":"28","author":[{"given":"Chenyang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuelian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine (TCM) Regulating Metabolic Diseases Key Laboratory of Sichuan Province Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianrui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Beijing Friendship Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengran","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8051-5260","authenticated-orcid":false,"given":"Gang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xisong","family":"Ke","sequence":"additional","affiliation":[{"name":"Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6744-7833","authenticated-orcid":false,"given":"Jing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00181.2024"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurjpc\/zwae151"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00510-4"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2021.2025362"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/1753-0407.13380"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-020-01278-z"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2008.01.013"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu13072373"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.7.673"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104722"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2016.02.001"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.7589"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2021.1974001"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu14010124"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2020.1755413"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202302194RR"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2024.101885"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-024-00971-z"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2021.153631"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01103-1"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176275"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/1753-0407.12937"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026620666201022144405"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/np400607k"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077969"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/03602532.2017.1306544"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2021.154734"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-017-0694-z"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2008.09.015"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.9.2602"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241813782"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.17305\/bjbms.2016.919"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.976465"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389557523666230823151927"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2019.01.011"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1470"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25010571"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15179"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01802-6"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36946-7"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.2337\/db22-0708"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(18)30133-5"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/lifemeta\/load031"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1200"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2022.12.007"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13327"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/dom.70171","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/full-xml\/10.1111\/dom.70171","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/dom.70171","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:57:28Z","timestamp":1772989048000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/10.1111\/dom.70171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1111\/dom.70171"],"URL":"https:\/\/doi.org\/10.1111\/dom.70171","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/DOM.70171\/v1\/review3","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v1\/review4","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v1\/review5","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v1\/review6","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v2\/review4","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v2\/review3","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70171\/v2\/decision1","asserted-by":"object"}]},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]},"assertion":[{"value":"2025-07-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}