Genotype‐Dependent Functional and Pharmacological Profiling of Rare GCK Variants Reveals Implications for Precision Management of Monogenic Diabetes
4 affiliations
- 1NHC 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 & Peking Union Medical College Beijing China
- 2Nanjing AscendRare Pharmaceutical Technology Co., Ltd. Nanjing Jiangsu China
- 3Clinical Biobank, National Infrastructures for Translational Medicine, Institute of Clinical Medicine Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
- 4Department of Endocrinology The 305 Hospital of PLA Beijing China
Abstract
Aims: Rare GCK 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 β‐cells and hepatocytes, defining the functional properties of individual variants may improve molecular diagnosis and inform the interpretation of potential therapeutic responses in GCK‐maturity‐onset diabetes of the young (GCK‐MODY, also called MODY2).
Materials and Methods: We established a recombinant protein‐based functional platform to investigate two rare GCK variants, p.Leu88Pro and p.Val374Glu, identified in Chinese families with GCK‐MODY. Wild‐type and mutant GCK proteins were expressed and purified using a GST‐tagged prokaryotic system. Functional consequences were assessed by glucose‐response kinetics, pharmacological modulation with dorzagliatin, thermal stability analysis and structural stability prediction.
Results: The p.Leu88Pro variant demonstrated impaired glucose sensing, with an increased S0.5 value, together with reduced stability and a marked predicted destabilizing effect. The p.Val374Glu variant retained near‐normal glucose‐response kinetics under basal conditions but exhibited reduced thermal stability. Dorzagliatin markedly reduced the S0.5 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.
Conclusions: Rare GCK variants can cause heterogeneous biochemical defects and show differential responses to pharmacological activation. Integrating glucose‐response kinetics, protein stability assessment and drug‐response profiling provides complementary functional evidence for variant interpretation and highlights the molecular heterogeneity of GCK‐MODY and the potential for genotype‐dependent pharmacological responses.
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BibTeX
@article{bai2026genotypedependent,
title = {{Genotype‐Dependent Functional and Pharmacological Profiling of Rare GCK Variants Reveals Implications for Precision Management of Monogenic Diabetes}},
author = {Haoyu Bai and Jie Yu and Qiusha Zhu and Xue Zhou and Ting Xie and Tong Wang and Jing Ren and Chuhan Shao and Qian Zhang and Changhong Li and Xinhua Xiao},
journal = {Diabetes, Obesity \& Metabolism},
year = {2026},
month = sep,
doi = {10.1111/dom.71398},
url = {https://doi.org/10.1111/dom.71398},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Genotype‐Dependent Functional and Pharmacological Profiling of Rare GCK Variants Reveals Implications for Precision Management of Monogenic Diabetes
AU - Haoyu Bai
AU - Jie Yu
AU - Qiusha Zhu
AU - Xue Zhou
AU - Ting Xie
AU - Tong Wang
AU - Jing Ren
AU - Chuhan Shao
AU - Qian Zhang
AU - Changhong Li
AU - Xinhua Xiao
PY - 2026
DA - 2026/09/28
JO - Diabetes, Obesity & Metabolism
DO - 10.1111/dom.71398
UR - https://doi.org/10.1111/dom.71398
AB - Aims: Rare GCK 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 β‐cells and hepatocytes, defining the functional properties of individual variants may improve molecular diagnosis and inform the interpretation of potential therapeutic responses in GCK‐maturity‐onset diabetes of the young (GCK‐MODY, also called MODY2). Materials and Methods: We established a recombinant protein‐based functional platform to investigate two rare GCK variants, p.Leu88Pro and p.Val374Glu, identified in Chinese families with GCK‐MODY. Wild‐type and mutant GCK proteins were expressed and purified using a GST‐tagged prokaryotic system. Functional consequences were assessed by glucose‐response kinetics, pharmacological modulation with dorzagliatin, thermal stability analysis and structural stability prediction. Results: The p.Leu88Pro variant demonstrated impaired glucose sensing, with an increased S0.5 value, together with reduced stability and a marked predicted destabilizing effect. The p.Val374Glu variant retained near‐normal glucose‐response kinetics under basal conditions but exhibited reduced thermal stability. Dorzagliatin markedly reduced the S0.5 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. Conclusions: Rare GCK variants can cause heterogeneous biochemical defects and show differential responses to pharmacological activation. Integrating glucose‐response kinetics, protein stability assessment and drug‐response profiling provides complementary functional evidence for variant interpretation and highlights the molecular heterogeneity of GCK‐MODY and the potential for genotype‐dependent pharmacological responses.
SN - 1462-8902
SN - 1463-1326
ER -