Patients with Type 2 Diabetes and a GCK variant are still at risk for T2D-related secondary complications
Authors:
- Kelly M. Schiabor BarrettKBKelly M. Schiabor Barrett
- Natalie TelisNTNatalie Telis
- Lisa M. McEwenLMLisa M. McEwen
- Evanette K. BurrowsEBEvanette K. Burrows
- Daniel P. JudgeDJDaniel P. Judge
- Pamala A. PawloskiPPPamala A. Pawloski
- Joseph J. GrzymskiJGJoseph J. Grzymski
- Nicole L. WashingtonNWNicole L. Washington
- Alexandre BolzeABAlexandre Bolze
- Elizabeth T. CirulliECElizabeth T. Cirulli
Preprint
Abstract
Natural HbA1c levels in GCK -MODY patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Standard treatments to lower HbA1c levels are ineffective in these individuals, yet in case studies to date, GCK -MODY patients often evade secondary T2D complications. Given these deviations from a more typical T2D disease course, genetic screening of GCK may be clinically useful, but population studies are needed to more precisely quantify T2D-related outcomes in GCK variant carriers. Using a state-of-the-art variant interpretation strategy based on glucose elevations, we genotyped all individuals in two real-world cohorts (n~535,000) for GCK risk variants and examined rates of T2D and T2D-complications from seven disease categories. We identified 439 individuals with GCK variants predicted to increase glucose (~1/1200). Aligning with their glucose elevations, GCK -MODY variant carriers were 12x as likely, and all other GCK risk carriers 4x as likely, to receive a T2D diagnosis, compared to non- GCK carriers. Surprisingly, GCK risk carriers with T2D develop a range of T2D-related complications at rates comparable to non- GCK T2D patients. Although the penetrance for secondary complications is lower than that for glucose elevations, GCK risk carriers remain at elevated risk of T2D and secondary complications.Keywords
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