Underestimated risk of secondary complications in pathogenic and glucose-elevating GCK variant carriers with type 2 diabetes
Open accessAbstract
Natural HbA1c levels in GCK Maturity-onset diabetes of the young (GCK-MODY) patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Treatments to lower HbA1c levels show reduced effectiveness in these individuals, yet in case studies to date, GCK-MODY patients often evade secondary T2D complications. Given these deviations, genetic screening of GCK may be clinically useful, but population studies are needed to more broadly understand T2D-related complications in GCK variant carriers. To identify GCK variant carriers at the population level, we used both ACMG/AMP variant interpretation for GCK-MODY pathogenicity and a state-of-the-art variant interpretation strategy based on functional and statistical evidence to predict glucose elevations. Presence of pathogenic and glucose-elevating GCK variants was assessed in two cohorts (n~535,000). We identified 442 individuals with GCK variants predicted to increase glucose (~1/1200), with 150 (34%) of these individuals harboring variants reaching a pathogenic interpretation. In a retrospective analysis, we show that in addition to elevated HbA1c, pathogenic variant carriers are 10x as likely, and all other glucose-elevating GCK variant carriers are 3x as likely, to receive a T2D diagnosis compared to non-GCK carriers. Surprisingly, carriers of pathogenic and glucose-elevating GCK variants with T2D develop T2D-related complications at rates more than double that of individuals without T2D, comparable to non-GCK individuals with T2D. This population-level assessment shows secondary complications in individuals with pathogenic and glucose-elevating GCK variants and T2D and suggests that genotyping for these variants should be considered in a precision medicine approach for T2D treatment and prevention. This study investigates the role of the GCK gene in Type 2 Diabetes (T2D). Variations in the GCK gene are known to cause a form of diabetes that is characterized by early onset and stable blood sugar levels, with a low risk of the type of complications often experienced by people with other causes of T2D. However, our study of a large number of people living in both the United Kingdom and the United States shows that some specific variations in the GCK gene give people a higher risk of developing T2D with the typical secondary complications. This suggests that knowledge of GCK variation in a person should be considered when optimizing T2D prevention and treatment strategies. Schiabor Barrett et al evaluate variants in GCK, a gene associated with Monogenic Diabetes of the Young (MODY), in two population cohorts with healthcare records. They find that participants with pathogenic MODY and other glucose-elevating variants are at risk for Type 2 Diabetes (T2D) and those with T2D show secondary complications of T2D.
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- [40]Creators Schiabor Barrett, K. Analysis Code for ‘Underestimated Risk of Secondary Complications in Pathogenic and Glucose-Elevating GCK Variant Carriers with Type 2 Diabetes’. 10.5281/zenodo.12774460. PMC11579005 39567669 · DOI
- [41]Gersing, S. et al. A multiplexed assay of human glucokinase reveals thousands of potential disease variants with both decreased and increased activity. bioRxiv 2022.05.04.490571 10.1101/2022.05.04.490571. (2022). · DOI
- [45]Creators Schiabor Barrett, Kelly Contributors Researcher: Schiabor Barrett, Kelly. GCK Variants and Their Annotations for ‘Underestimated Risk of Secondary Complications in Pathogenic and Glucose-Elevating GCK Variant Carriers with Type 2 Diabetes’. 10.5281/zenodo.12775172. PMC11579005 39567669 · DOI
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Arosemena, M., Chopra, K., Salguero, M. V., Reyes, D., Naylor, R. N., Wroblewski, K., Tasali, E., & Philipson, L. H. (2026) · Diabetes · doi:10.2337/db24-0787 · Cited by 2 · see citing works
“…studies have shown differences in cardiovascular risk for MODY, with GCK-MODY having a lower risk of coronary artery disease compared with type 2 diabetes (25) and a lower risk of diabetes-related complications overall, except for in individuals who could have superimposed type 2 diabetes (26).”
- Authors
- Schiabor Barrett, K. M., Telis, N., McEwen, L. M., Burrows, E. K., Khuder, B., Judge, D. P., Pawloski, P. A., Grzymski, J. J., Washington, N. L., Bolze, A., & Cirulli, E. T.
- Affiliations
- Helix (United States) (US)
- Medical University of South Carolina (US)
- HealthPartners (US)
- University of Nevada, Reno (US)
- ORCID
- Venue
- Communications Medicine
- Published
- 2024-11-20
- Volume
- 4
- Issue
- 1
- Pages
- 239-239
- ISSN
- 2730-664X (ISSN-L)
- PMC
- PMC11579005
- OpenAlex
- W4404536585
- Cited by
- 8
- References
- 39
- Citations by year
- 2026: 4 · 2025: 4
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Communications Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- University of South Carolina
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- GCK gene, GCK-MODY, type 2 diabetes, pathogenic variants, secondary complications, HbA1c, variant interpretation, genetic screening, precision medicine, diabetes prevention, diabetes treatment, population cohort, ACMG/AMP guidelines, genotype-phenotype correlation, diabetes risk stratification, UK Biobank
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