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

Anette P Gjesing*, Line Engelbrechtsen, Anne Cathrine B Thuesen, Christian T Have, Mette Hollensted, Niels Grarup, Allan Linneberg, Jens Steen Nielsen, Lotte B Christensen, Reimar W Thomsen, Kristoffer E Johansson, Matteo Cagiada, Sarah Gersing, Rasmus Hartmann-Petersen, Kresten Lindorff-Larsen, Allan Vaag, Henrik T Sørensen, Ivan Brandslund, Henning Beck-Nielsen, Oluf PedersenJørgen Rungby, Torben Hansen*

*Corresponding author for this work

Abstract

AIMS: Rare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). 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 circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications 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.

Original languageEnglish
Article number110159
JournalDiabetes Research and Clinical Practice
Volume194
Pages (from-to)110159
ISSN0168-8227
DOIs
Publication statusPublished - 1 Dec 2022

Keywords

  • Complications
  • Glucokinase
  • Macrovascular
  • Microvascular
  • MODY
  • Monogenic diabetes

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