14-fold increased prevalence of rare glucokinase gene variant carriers in unselected Danish patients with newly diagnosed type 2 diabetes

Aims: Rare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCKMODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants. Methods: This is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years. Results: Twenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10(-6)]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumoference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular comoplications during follow-up. Conclusions: Approximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients.

Automated summary

This study investigated the prevalence and phenotypic characteristics of GCK gene variants in patients with and without diabetes. The results showed that patients with type 2 diabetes carrying GCK variants had lower waist circumference, hip circumference, and BMI compared to non-carriers. Some GCK variant carriers also experienced microvascular complications during follow-up. This subset of diabetes patients may benefit from treatment cessation.