RESUMO
AIM: To investigate the frequency and spectrum of glucokinase (GCK) mutations in a cohort of adults from an island population having a high prevalence of diabetes mellitus (DM). METHODS: A single-centre cohort study was conducted, including 145 non-obese adults of Maltese-Caucasian ethnicity with impaired fasting glycaemia (IFG) or non-autoimmune diabetes diagnosed before the age of 40 years. Bidirectional sequencing of the GCK coding regions was performed. Genotype-phenotype associations and familial segregation were explored and the effects of missense variants on protein structure were evaluated using computational analysis. RESULTS: Three probands with pathogenic/likely pathogenic GCK variants in the heterozygous state having clinical features consistent with GCK-diabetes were detected. The missense variants have structurally destabilising effects on protein structure. GCK variant carriers exhibited a significantly lower body mass index and serum triglyceride levels when compared to GCK variant non-carriers. CONCLUSIONS: The frequency of GCK-diabetes is approximately 2% in non-obese Maltese adults with diabetes or prediabetes. This study broadens the mutational spectrum of GCK and highlights clinical features that could be useful in discriminating GCK-DM from type 2 DM or prediabetes. It reinforces the need for increased molecular testing in young adults with diabetes having a suspected monogenic aetiology.
