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

Abstract

Natural HbA1c levels inGCK-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 ofGCKmay be clinically useful, but population studies are needed to more precisely quantify T2D-related outcomes inGCKvariant 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) forGCKrisk variants and examined rates of T2D and T2D-complications from seven disease categories.We identified 439 individuals withGCKvariants predicted to increase glucose (~1/1200). Aligning with their glucose elevations,GCK-MODY variant carriers were 12x as likely, and all otherGCKrisk carriers 4x as likely, to receive a T2D diagnosis, compared to non-GCKcarriers. Surprisingly,GCKrisk carriers with T2D develop a range of T2D-related complications at rates comparable to non-GCKT2D patients. Although the penetrance for secondary complications is lower than that for glucose elevations,GCKrisk carriers remain at elevated risk of T2D and secondary complications.