Patients with Type 2 Diabetes and a GCK variant are still at risk for T2D-related secondary complications

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.