{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:55:53Z","timestamp":1790654153867,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870545"],"award-info":[{"award-number":["81870545"]}],"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":["81870579"],"award-info":[{"award-number":["81870579"]}],"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":["82170854"],"award-info":[{"award-number":["82170854"]}],"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":["82570971"],"award-info":[{"award-number":["82570971"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009592","name":"Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park","doi-asserted-by":"publisher","award":["Z201100005520011"],"award-info":[{"award-number":["Z201100005520011"]}],"id":[{"id":"10.13039\/501100009592","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005089","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7202163"],"award-info":[{"award-number":["7202163"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      Rare\n                      <jats:italic>GCK<\/jats:italic>\n                      variants contribute to heterogeneous forms of monogenic diabetes, yet the molecular basis underlying their diverse functional consequences and pharmacological responsiveness remains incompletely understood. As glucokinase (GCK) serves as a central glucose sensor in pancreatic \u03b2\u2010cells and hepatocytes, defining the functional properties of individual variants may improve molecular diagnosis and inform the interpretation of potential therapeutic responses in GCK\u2010maturity\u2010onset diabetes of the young (GCK\u2010MODY, also called MODY2).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      We established a recombinant protein\u2010based functional platform to investigate two rare\n                      <jats:italic>GCK<\/jats:italic>\n                      variants, p.Leu88Pro and p.Val374Glu, identified in Chinese families with GCK\u2010MODY. Wild\u2010type and mutant GCK proteins were expressed and purified using a GST\u2010tagged prokaryotic system. Functional consequences were assessed by glucose\u2010response kinetics, pharmacological modulation with dorzagliatin, thermal stability analysis and structural stability prediction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The p.Leu88Pro variant demonstrated impaired glucose sensing, with an increased S\n                      <jats:sub>0.5<\/jats:sub>\n                      value, together with reduced stability and a marked predicted destabilizing effect. The p.Val374Glu variant retained near\u2010normal glucose\u2010response kinetics under basal conditions but exhibited reduced thermal stability. Dorzagliatin markedly reduced the S\n                      <jats:sub>0.5<\/jats:sub>\n                      of p.Val374Glu with limited effects on maximal catalytic activity. Structural stability analysis further indicated reduced protein stability for both variants, with a greater predicted destabilizing effect for p.Leu88Pro than for p.Val374Glu.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Rare\n                      <jats:italic>GCK<\/jats:italic>\n                      variants can cause heterogeneous biochemical defects and show differential responses to pharmacological activation. Integrating glucose\u2010response kinetics, protein stability assessment and drug\u2010response profiling provides complementary functional evidence for variant interpretation and highlights the molecular heterogeneity of GCK\u2010MODY and the potential for genotype\u2010dependent pharmacological responses.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71398","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:13:39Z","timestamp":1790651619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotype\u2010Dependent Functional and Pharmacological Profiling of Rare\n                    <scp>\n                      <i>GCK<\/i>\n                    <\/scp>\n                    Variants Reveals Implications for Precision Management of Monogenic Diabetes"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1078-8434","authenticated-orcid":false,"given":"Haoyu","family":"Bai","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2304-058X","authenticated-orcid":false,"given":"Jie","family":"Yu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiusha","family":"Zhu","sequence":"additional","affiliation":[{"name":"Nanjing AscendRare Pharmaceutical Technology Co., Ltd.  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhou","sequence":"additional","affiliation":[{"name":"Nanjing AscendRare Pharmaceutical Technology Co., Ltd.  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Xie","sequence":"additional","affiliation":[{"name":"Clinical Biobank, National Infrastructures for Translational Medicine, Institute of Clinical Medicine Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology The 305 Hospital of PLA  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ren","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-3815","authenticated-orcid":false,"given":"Chuhan","family":"Shao","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhong","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing AscendRare Pharmaceutical Technology Co., Ltd.  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-7766","authenticated-orcid":false,"given":"Xinhua","family":"Xiao","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2024.12.007"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci117064"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658\u2010024\u201000640\u20103"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21110"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010024\u201003238\u20102"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00592\u2010018\u20101179\u2010y"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0065326"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s001250050666"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.283980"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13300\u2010020\u201000864\u20104"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa710"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010019\u20100698\u20107"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010023\u201002935\u20108"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.2337\/db25\u20100066"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.2337\/db22\u20100708"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki387"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz184"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaf064"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu426"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2004.02.005"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.7473"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08\u20101792"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13072"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2019.01.011"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms27010156"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.13406\/j.cnki.cyxb.004021"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1826357"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12772"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.13426"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607987200"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dom.71398","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/dom.71398","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dom.71398","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:13:43Z","timestamp":1790651623000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/10.1111\/dom.71398"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":31,"alternative-id":["10.1111\/dom.71398"],"URL":"https:\/\/doi.org\/10.1111\/dom.71398","archive":["Portico"],"relation":{},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]},"assertion":[{"value":"2026-08-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"dom.71398"}}