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

Anne Cathrine Baun Thuesen; Rasmus Tanderup Jensen; Henrik Maagensen; Maja Refshauge Kristiansen; Henrik Toft Sørensen; Allan Vaag; Henning Beck-Nielsen; Oluf B Pedersen; Niels Grarup; Jens Steen Nielsen; Jørgen Rungby; Anette Prior Gjesing; Heidi Storgaard; Tina Vilsbøll; Torben Hansen

doi:10.1016/j.ymgmr.2023.100972

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

Mol Genet Metab Rep. 2023 Mar 29:35:100972. doi: 10.1016/j.ymgmr.2023.100972. eCollection 2023 Jun.

Authors

Anne Cathrine Baun Thuesen^{1

2}, Rasmus Tanderup Jensen¹, Henrik Maagensen², Maja Refshauge Kristiansen³, Henrik Toft Sørensen⁴, Allan Vaag^{2

5}, Henning Beck-Nielsen³, Oluf B Pedersen¹, Niels Grarup¹, Jens Steen Nielsen^{3

6}, Jørgen Rungby^{2

7}, Anette Prior Gjesing¹, Heidi Storgaard², Tina Vilsbøll^{2

7}, Torben Hansen¹

Affiliations

¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.
³ Steno Diabetes Center Odense, the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), Odense University Hospital, Odense, Denmark.
⁴ Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
⁵ Department for Translational Type 2 Diabetes Research, Lund University Diabetes Center, Lund University, Sweden.
⁶ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Abstract

Background: Functionally disruptive variants in the glucokinase gene (GCK) 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 GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes.

Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-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, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 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, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes.

Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-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 GCK-diabetes who are not identifiable through common genetic screening criteria.

Keywords: Diagnosis; MODY (maturity-onset diabetes of the young); T2D (type 2 diabetes); Treatment.