Identification of pathogenic variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment.

BACKGROUND

Functionally disruptive variants in the glucokinase gene () cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry variants. We aimed to investigate whether carriers of rare variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with -diabetes.

METHODS

Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with -diabetes took part in a three-month treatment withdrawal.

RESULTS

Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l,  = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l,  = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months,  = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months,  = 0.5). Participants did not consistently fulfill best practice guidelines for screening nor clinical criteria for monogenic diabetes.

DISCUSSION

Carriers of pathogenic or likely pathogenic variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with -diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified -diabetes who are not identifiable through common genetic screening criteria.