bimatoprost GCK MODY is the most common form of MODY
GCK-MODY is the most common form of MODY diabetes in many populations (Chevre et al., 1998; Massa et al., 2001; Barrio et al., 2002; Estalella et al., 2007; Pruhova et al., 2010; Capuano et al., 2012; Giuffrida et al., 2017). However, data about GCK-MODY among North African populations are very rare. Actually, we only found one study that linked hyperglycemia to the c.-457C>T GCK mutation in two Tunisian subjects (Ben Khelifa et al., 2018). In fact, confirmation of a clinically suspected GCK-MODY at molecular level reassured parents about the outcome of their children's diabetes, it allowed avoiding unnecessary therapy and daily follow-up and thereby improving patient's life quality. Moreover, it allows an early management of gestational diabetes in women carrying GCK mutations (Spyer et al., 2001; Hattersley, 2005; Stride et al., 2014).
Subjects and methods
Discussion Maturity-onset diabetes of the young (MODY) is a heterogeneous group of autosomal dominantly inherited disorders. Heterozygous inactivating mutations in the GCK gene are linked to GCK-MODY which is a phenotype that manifests since birth as a mild fasting hyperglycemia, therefore it is often diagnosed incidentally or during screening (Hattersley, 2005; Spyer et al., 2009); this early manifestation could explain the high prevalence of this type of MODY among pediatric population (Massa et al., 2001; Barrio et al., 2002; Schober et al., 2009; Pruhova et al., 2010; Haliloglu et al., 2016). In the present study, we screened sixteen subjects (a proband and fifteen relatives) for mutations in the GCK gene; we targeted this gene based on their family history of diabetes over four generations with suggestive bimatoprost inheritance and their clinical and laboratory data. In fact, many young diabetic members of the probands' relatives suffered from non-progressive mild familial hyperglycemia despite not being under treatment and thus, for over many years; which is consistent with GCK-MODY phenotype (Stride et al., 2002; Schober et al., 2009; Stride et al., 2014). Our study indicates that the c.253A>T/ p.R85W mutation within the GCK gene co-segregates with either IFG or diabetes among screened subjects, whereas it is absent among healthy relatives. The c.253A>T (p.R85W) GCK mutation has been linked to GCK-MODY in 2011 (dbSNP entry rs193922290) and has been described in the ClinVar as ‘likely pathogenic’. Among the sixteen subjects included in this study, eleven carried the p.R85W GCK mutation and nine out of the eleven mutation carriers display metabolic and clinical features of GCK-MODY subjects comparable to what have been reported by other studies (Steele et al., 2013; Haliloglu et al., 2016). Interestingly, these same patients were not undertaking any medical treatment and diet alone was sufficient to achieve a good glycemic control. Furthermore, it seems that subject IV-1 is a GCK-MODY patient carrying β-cell autoantibodies. It is worth noting that positivity for at least one β-cell antibody has been described in MODY and T2D patients (Schober et al., 2009) and even among healthy children (Kondrashova et al., 2007). As for the two other mutation carriers (II-1 and III-1) despite that are being under treatment, they manifested deterioration of metabolic control (HbA1c ≥7.8%); dyslipidemia, overweight for patient II-1 and obesity for patient III-1 which suggests the co-occurrence of T2D in these patients based on what have been reported by Steele et al. (Steele et al., 2013). Martin et al. (Martin et al., 2008) have reported that putative unfavorable alleles could affect phenotype of GCK-MODY patients with time, they lead to insulin resistance and therefor to the deterioration of the disorder, based on that they advise patients with GCK-MODY to avoid gain excessive weight. Moreover, several studies have reported that other monogenic diabetes or T2D could coexist with GCK-MODY (Fendler et al., 2014, Ortega-Rodriguez et al., 2001; Calcaterra et al., 2012; Maltoni et al., 2012; Stanik et al., 2012). In case of its co-incidence with another form of diabetes, GCK-MODY phenotype will be hidden by the co-occurring diabetes due to the mild nature of hyperglycemia linked to GCK mutations.