Clinical implications of the glucokinase impaired function - GCK MODY today

Abstract

Heterozygous inactivating mutations of the glucokinase (GCK) gene are causing GCK-MODY, one of the most common forms of the Maturity Onset Diabetes of the Young (MODY). GCK-MODY is characterized by fasting hyperglycemia without apparent worsening with aging and low risk for chronic vascular complications. Despite the mild clinical course, GCK-MODY could be misdiagnosed as type 1 or type 2 diabetes. In the diagnostic process, the clinical suspicion is often based on the clinical diagnostic criteria for GCK-MODY and should be confirmed by DNA analysis. However, there are several issues in the clinical and also in genetic part that could complicate the diagnostic process. Most of the people with GCK-MODY do not require any pharmacotherapy. The exception are pregnant women with a fetus which did not inherit GCK mutation from the mother. Such a child has accelerated growth, and has increased risk for diabetic foetopathy. In this situation the mother should be treated with substitutional doses of insulin. Therefore, distinguishing GCK-MODY from gestational diabetes in pregnancy is very important. For this purpose, special clinical diagnostic criteria for clinical identification of GCK-MODY in pregnancy are used. This review updates information on GCK-MODY and discusses several currently not solved problems in the clinical diagnostic process, genetics, and treatment of this type of monogenic diabetes.

Fig. 1

Schematic representation of GCK isoform 1. The scheme is based on the data from the NCBI database. NG_008847.2 represents genomic sequence of the GCK gene. Boxes represent exons and blue line represents intronic regions. Coding region (CDS), marked by thick blue line, is 1 397 bp long (starts from 487bp of transcript and ends at the position of 1884bp). Thin green line indicates translated protein NP_000153.1. Amino-acid (aa) positions correspond to exon positions of the transcript. Upper amino-acid positions indicate the small and large hexokinase subdomain. Brown amino-acid positions mark the protein sites which were described as substrate binding sites.