{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T01:35:28Z","timestamp":1790386528998,"version":"4.1.0"},"reference-count":54,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100031158","name":"Diabetes Research Center, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania","doi-asserted-by":"publisher","award":["P30DK19525"],"award-info":[{"award-number":["P30DK19525"]}],"id":[{"id":"10.13039\/100031158","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK136564"],"award-info":[{"award-number":["R01DK136564"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Glucokinase (GK) activators (GKAs) are a long-sought therapeutic modality for the treatment of type 2 diabetes. However, GKAs have failed in clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with those of the unsuccessful GKA MK-0941 (Merck Pharmaceuticals), which is well characterized both clinically and mechanistically. Dorzagliatin improved glucose-stimulated insulin secretion in a dose- and glucose-dependent manner, in contrast to MK-0941, which induced maximal insulin secretion at low doses and glucose concentrations. To understand these functional differences, the atomic resolution structure of the dorzagliatin-GK complex was determined and compared with the GK\u2013MK-0941 structure. MK-0941 bound to a pocket accessible in both open and closed conformations; had a strong interaction with Y214, the mutation of which produces the most clinically severe activating mutation; and produced a high energy barrier for the open-to-closed transition. In contrast, dorzagliatin only bound favorably to the closed form of GK, interacting primarily with R63 and causing a low energy barrier for the open-to-closed transition. This provides the molecular rationale for the clinical success of dorzagliatin, which can guide the future development of next-generation allosteric activators of GK.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>The type 2 diabetes (T2D) treatment dorzagliatin has achieved singular success among its drug class, known as glucokinase (GK) activators (GKAs). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies revealed the unique mechanism by which dorzagliatin activates GK. Dorzagliatin dose-dependently reduces the glucose threshold for stimulation of insulin secretion and binds preferably to the closed form of GK, preventing overstimulation of the enzyme. A renewed interest in GKAs, coupled with modern tools to assess their molecular interactions with GK, should guide the future development of novel GKA treatments for T2D.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0066","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T11:45:35Z","timestamp":1746618335000},"page":"1374-1384","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":7,"title":["Functional and Mechanistic Explanation for the Unique Clinical Success of the Glucokinase Activator Dorzagliatin in the Treatment of Type 2 Diabetes"],"prefix":"10.2337","volume":"74","author":[{"given":"Jeff","family":"Roman","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania 1 , Philadelphia, 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