Functional and Mechanistic Explanation for the Unique Clinical Success of the Glucokinase Activator Dorzagliatin in the Treatment of Type 2 Diabetes
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.
Authors
- Xu Yue (ORCID: https://orcid.org/0000-0002-8861-8192)
- Meng Shi (ORCID: https://orcid.org/0000-0002-9716-0240)
- Jeff Roman
- Nicolai M. Doliba (ORCID: https://orcid.org/0000-0003-4598-9222)
- Xue Zhou (ORCID: https://orcid.org/0000-0002-3675-9479)
- Kim A. Sharp (ORCID: https://orcid.org/0000-0002-0338-0382)
- Didi Han (ORCID: https://orcid.org/0000-0002-6975-2783)
- Qiusha Zhu
- Yue Yuan
- Li Chen (ORCID: https://orcid.org/0009-0001-9154-9060)
- Fang Zhao (ORCID: https://orcid.org/0009-0009-3714-698X)
- Shaowen Wu
- Changhong Li
Institutions
- China Pharmaceutical University (CN)
- Hua Medicine (China) (CN)
- University of Pennsylvania (US)
Publication Details
- Journal
- Diabetes
- Published
- 2025-04-24
- DOI
- https://doi.org/10.2337/db25-0066
- Citations
- 2
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 4.01
Funders
- University of Pennsylvania
- Human Islet Research Network
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases