Genotype-Phenotype Discrepancies in Family Members With a Novel Glucokinase Mutation: Insights Into GCK-MODY and Its Interplay With Insulin Resistance
This study was undertaken to investigate the diabetogenic potential of a novel GCK variant, c.77A>T, p.Q26L, found in two family members with marked differences in diabetic phenotypes. We aimed to understand the role of GCK-Q26L in glucose metabolism and to explore whether genetic backgrounds, including polygenic risk score for insulin resistance and type 2 diabetes, contribute to diabetes manifestations. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes.
Authors
- Jingting Qiao (ORCID: https://orcid.org/0000-0002-1245-5411)
- Minxian Wang (ORCID: https://orcid.org/0000-0002-3753-508X)
- Qing He (ORCID: https://orcid.org/0009-0000-1408-4098)
- Wenli Feng (ORCID: https://orcid.org/0000-0002-8089-9364)
- Yuanyuan Ye
- Jinyang Zhen
- Hongwei� Jiang (ORCID: https://orcid.org/0000-0003-3807-7989)
- Yu Fan (ORCID: https://orcid.org/0000-0002-5978-5004)
- Kunling Wang (ORCID: https://orcid.org/0000-0003-4895-1457)
- Ming Rong Liu (ORCID: https://orcid.org/0000-0003-2665-4072)
- Shanshan Chen (ORCID: https://orcid.org/0000-0001-9723-2403)
- Ziyue Zhang (ORCID: https://orcid.org/0000-0002-8219-8510)
- Hua Shu (ORCID: https://orcid.org/0000-0002-4131-3551)
- Ying Yang (ORCID: https://orcid.org/0000-0002-3751-2590)
- Yadi Huang
- Shuhui Ji (ORCID: https://orcid.org/0000-0002-0346-1836)
- Xiong Yang
- Zhao Hongqiang (ORCID: https://orcid.org/0009-0004-7820-0528)
- Xuan Liu (ORCID: https://orcid.org/0000-0003-1590-8276)
Institutions
- Chinese Academy of Sciences (CN)
- Beijing Institute of Genomics (CN)
- Tianjin Medical University General Hospital (CN)
- Wuhan University (CN)
- Hubei Provincial Center for Disease Control and Prevention (CN)
- Tianjin Institute of Pharmaceutical Research (China) (CN)
- Wuhan Prevention and Treatment Center for Occupational Diseases (CN)
- Sino-Danish Centre for Education and Research (CN)
- Zhongnan Hospital of Wuhan University (CN)
- First Affiliated Hospital of Henan University of Science and Technology (CN)
- Tianjin Hospital (CN)
- Shanghai Center For Bioinformation Technology (CN)
- Pingjin Hospital (CN)
Publication Details
- Journal
- Diabetes
- Published
- 2025-09-25
- DOI
- https://doi.org/10.2337/db24-1036
- Citations
- 3
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 6.02