{"doi":"10.2337/db25-0066","title":"Functional and Mechanistic Explanation for the Unique Clinical Success of the Glucokinase Activator Dorzagliatin in the Treatment of Type 2 Diabetes","abstract":"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-MK-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. ARTICLE HIGHLIGHTS: 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.","journal":"Diabetes","year":2025,"id":521058,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":725594,"name":"Yue Yuan","orcid":"0000-0003-3524-0576","position":1,"is_corresponding":false},{"id":1390906,"name":"Xu Yue","orcid":"0000-0002-8861-8192","position":2,"is_corresponding":false},{"id":1391341,"name":"Qiusha Zhu","orcid":null,"position":3,"is_corresponding":false},{"id":3944,"name":"Shaowen Wu","orcid":null,"position":4,"is_corresponding":false},{"id":1390907,"name":"Fang Zhao","orcid":"0009-0009-3714-698X","position":5,"is_corresponding":false},{"id":1390908,"name":"Xue Zhou","orcid":"0000-0002-3675-9479","position":6,"is_corresponding":false},{"id":240788,"name":"Meng Shi","orcid":"0000-0002-9716-0240","position":7,"is_corresponding":false},{"id":1391342,"name":"Dongna Han","orcid":null,"position":8,"is_corresponding":false},{"id":781755,"name":"Kim A. Sharp","orcid":"0000-0002-0338-0382","position":9,"is_corresponding":false},{"id":1390909,"name":"Li Chen","orcid":"0000-0002-6192-3752","position":10,"is_corresponding":false},{"id":704627,"name":"Changhong Li","orcid":"0000-0003-0513-1459","position":11,"is_corresponding":false},{"id":415494,"name":"Nicolai M. Doliba","orcid":"0000-0003-4598-9222","position":12,"is_corresponding":false},{"id":1391340,"name":"Jeff Roman","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T02:49:32.958846Z","pmid":"40272935","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}