The mean (SD) insulin requirement in the final trimester of pregnancy among mothers with deletion mutation (0.48 (0.13) U/kg) was higher than that of mothers with other mutations (0.20 (0.13) U/kg) (P=0.07). Permanent neonatal diabetes was diagnosed in one case with homozygous deletion mutation, and glycemic control was achieved with insulin pump treatment. GCK-MODY was diagnosed in two cases with homozygous missense mutation, and medical treatment was not required in these.

Patients with GCK-MODY are mostly asymptomatic. The fasting blood glucose level and HbA1c level at first admission in the present study was consistent with the literature [6]. Pharmacological therapy is not recommended in GCK-MODY, except during pregnancy, because of the low effect of blood glucose lowering therapy and the absence of complications in diabetics with this mutation [8].

Most GCK-MODY mutations consist of missense (65%), nonsense, frameshift or splice site mutations [2]. Rare causes include GCK pancreatic islet promoter mutations [9] and partial or complete gene deletions [10]. Consistent with the previous literature, the most common GCK mutation in the present study was missense mutation. High blood glucose is reported to induce glucokinase through post-translation mechanisms, and the clinical phenotype is therefore similar in cases with GCK-MODY irrespective of the severity of the mutations [11]. However, recent studies have demonstrated that the phenotype may significantly differ in patients with GCK-MODY depending on the type of the mutation [12]. Fasting blood sugar in our deletion mutation group was significantly higher than in patients with other mutations, a finding consistent with previous studies revealing a relationship between genotype and phenotype. Velho, et al. [13] reported that missense mutations exhibit varying effects on glucokinase activity, and that glucose affinity can be affected, ranging from a small change to complete inactivity. In contrast, we found that children with heterozygous missense mutation GCK-MODY exhibited similar phenotype characteristics to those of children with GCK-MODY with other mutations, and that they presented with mild fasting hyperglycemia. Although homozygous mutations in the GCK gene are known to cause permanent neonatal diabetes, few cases with this mutation are diagnosed with mild fasting hyperglycemia, and protein instability has been implicated in this difference in phenotypes [14].

Maternal hyperglycemia during pregnancy is the primary risk factor for fetal macrosomia caused by fetal hyperinsulinism [15]. However, if the fetus inherits the GCK mutation from the mother, aggressive insulin treatment directed toward maternal euglycemia may cause fetal growth retardation [16]. In our study, the mean birthweight of the patients with deletion mutation inherited from the mothers was significantly lower than that of patients with nonsense and missense mutations inherited from mothers. The need for blood glucose-lowering treatment in pregnant women with GCK-MODY with gene deletion may explain the lower birth weight in the infants with the same mutation.

In conclusion, our study shows that patients with deletion mutation inherited from mothers had lower birth weight and higher fasting blood glucose, but similar HbA1c values, compared to patients with other inherited mutations, and that homozygous gene mutations in the GCK gene result in phenotypic characteristics ranging from neonatal diabetes to GCK-MODY.

Ethical clearance: Institutional ethics committee of Malatya Clinical Research Institute; No. 23536505-604.02, dated March 13, 2019.

Contributors: All authors approved the final version of manuscript, and are accountable for all aspects related to the study.

Funding: None; Competing interest: None stated.

1. Irgens HU, Molnes J, Johansson BB, Ringdal M, Skrivarhaug T, Undlien DE, et al. Prevalence of monogenic diabetes in the population-based Norwegian Childhood Diabetes Registry. Diabetologia. 2013;56: 1512-9.

2. Valentínová L, Beer NL, Staník J, Tribble ND, van de Bunt M, Huèková M, et al. Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia.　PLoS One.　2012;7: e34541.

3. Chakera AJ, Spyer G, Vincent N, Ellard S, Hattersley AT, Dunne FP. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: The Atlantic Diabetes in Pregnancy Cohort.　Diabetes Care.　2014;37:1230-6.

4. Anik A, Catli G, Abaci A, Sarý E, Yeþilkaya E, Korkmaz HA, et al. Molecular diagnosis of maturity-onset diabetes of the young [MODY] in Turkish children by using targeted next-generation sequencing.　J Pediatr Endocrinol Metab.　2015;28:1265-71.

5. Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, et al. Update on mutations in glucokinase [GCK], which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009;30:1512-26.

6. Steele AM, Wensley KJ, Ellard S, Murphy R, Shepherd M, Colclough K, et al. Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: Observational case control studies. PLoS One. 2013;8:e65326.

7. Feigerlová E, Pruhová S, Dittertová L, Lebl J, Pinterová D, Kolostová K, et al. Aetiological heterogeneity of asympto-matic hyperglycaemia in children and adolescents. Eur J Pediatr.　2006;165:446-52.

8. Stride A, Shields B, Gill-Carey O, Chakera AJ, Colclough K, Ellard S, et al. Cross sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57:54-6.

9. Gasperíková D, Tribble ND, Staník J, Hucková M, Misovicová N, van de Bunt M, et al. Identiûcation of a novel beta-cell glucokinase [GCK] promoter mutation [-71G.C] that modulates GCK gene expression through loss of allele-specific Spl binding causing mild fasting hyperglycemia in humans. Diabetes. 2009;58:1929-35.

10. Ellard S, Thomas K, Edghill EL, Owens M, Ambye L, Cropper J, et al. Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young. Diabetologia. 2007;50:2313-7.

11. Stride A, Vaxillaire M, Tuomi T, Barbetti F, Njølstad PR, Hansen T, et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia. 2002;45:427-5.

12. Cuesta-Muñoz AL, Tuomi T, Cobo-Vuilleumier N, Koskela H, Odili S, Stride A, et al. Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene [GCK-MODY]. Diabetes Care. 2010;33:290-2.

13. Velho G, Blanché H, Vaxillaire M, Bellanné-Chantelot C, Pardini VC, Timsit J, et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997;40:217-24.

14. Raimondo A, Chakera AJ, Thomsen SK, Colclough K, Barrett A, De Franco E, et al. Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. Hum Mol Genet. 2014;23:6432-40.

15. Chakera AJ, Steele AM, Gloyn AL, Shepherd MH, Shields B, Ellard S, et al. Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care. 2015;38:1383-92.

16. Spyer G, Macleod KM, Shepherd M, Ellard S, Hattersley AT. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med. 2009;26:14-8.