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    • The effect of GCK NES mutations on enzyme kinetics and

    2021-10-08

    The effect of GCK-NES mutations on enzyme kinetics and protein stability might account for the hyperglycaemia that characterizes MODY2 patients, since reduced GCK activity would increase the threshold for glucose stimulated insulin release in beta-cells [31,37,49]. However, a more in depth functional characterization of Nexturastat A these MODY2 mutations has allowed uncovering defects at other levels of GCK regulation, such as its subcellular localization. Translocation of GCK between cytoplasm and nucleus in hepatocytes depends on its interaction with GKRP, which is modulated by nutrients (mainly glucose and fructose). During periods of hypoglycaemia, GKRP inhibits and sequesters GCK in the nucleus and this glucokinase pool can be rapidly mobilized in response to increased cellular glucose [8,19]. Our results indicate that some of the MODY2 mutations in the GCK-NES likely impair the nucleo-cytoplasmic shuttling of GCK in the liver. Taking into account the important role of the liver in the homeostasis of blood glucose, this additional defect might contribute to the hyperglycaemia in these patients. Hepatoselective glucokinase activators have been identified in the last years with the aim of developing new treatments for type II diabetes [50]. Some of these compounds act as GCK-GKRP disruptors that promote GCK translocation from the nucleus to the Nexturastat A [51,52]. In this context, our findings contribute to a better knowledge of the molecular mechanisms involved in the nucleocytoplasmic shuttling of glucokinase.
    Transparency document
    Introduction Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of autosomal dominantly inherited β-cell disorders. It is characterized by nonketotic diabetes mellitus with early onset, usually before the age of 25 years (Fajans et al., 2001; Owen and Hattersley, 2001). Patients with MODY typically display the following features: a strong family history of diabetes, onset of diabetes in the second to fifth decade, insulin independence three to five years after diabetes diagnosis, absence of features of insulin resistance, and absence of β cell autoimmunity (Thanabalasingham and Owen, 2011). So far, we distinguish fourteen subtype of MODY linked to heterozygous mutations in fourteen different genes; HNF4A-MODY1, GCK-MODY2, HNF1A-MODY3, PDX1-MODY4, HNF1B-MODY5, NEUROD1-MODY6, KLF11-MODY7,CEL-MODY8, PAX4-MODY9, INS-MODY10, BLK-MODY11, ABCC8-MODY12, KCNJ11-MODY13 (Bonnefond et al., 2012) and recently APPL1-MODY14 (Prudente et al., 2015). The glucokinase gene (GCK, MIM # 138079) is located on chromosome 7 (7p15.3-p15.1), it comprises 12 exons that span 45,169 bp and encode an enzyme of 465 amino acid, called glucokinase (GCK), hexokinase IV or D (Gloyn, 2003; Osbak et al., 2009). Glucokinase is expressed predominantly in the pancreas and liver where it catalyzes the first rate-limiting reaction in glycolysis, conversion of glucose to glucose-6-phosphate. Thereby, GCK is considered as the key regulator of fasting plasma glucose concentrations. The important role of GCK in glucose homeostasis is due to its crucial implication in the regulation of insulin release which has been demonstrated by the fact that rare GCK mutations cause both hyper or hypoglycemia (Matschinsky, 2002; Gloyn, 2003). A number of 829 mutants of this gene have been registered in the Human Gene Mutation Database (HGMD) since the identification of the first mutation in the GCK gene (Vionnet et al., 1992). Heterozygous mutations in the GCK could be activating, thus leading to hyperinsulinimic hypoglycemia ‟ HH or HI; MIM # 602485” (Christesen et al., 2002; Gloyn, 2003), or inactivating, and thus leading to a discrete subtype of MODY ‟ MODY2 or GCK-MODY; MIM # 125851” (Vionnet et al., 1992). Homozygous or compound heterozygous inactivating GCK mutations result in a complete deficiency of the GCK and lead to a more severe phenotype called permanent neonatal diabetes mellitus ‟ PNDM; MIM # 606176 “(Gloyn, 2003; Njolstad et al., 2003). GCK-MODY is characterized by a stable and mild fasting hyperglycemia, which is present from birth but often detected later in life incidentally or during screening (Hattersley et al., 2006; Osbak et al., 2009). This non-progressive mild hyperglycemia explains the fact that GCK-MODY patients rarely require medication or develop microvascular complications (Owen and Hattersley, 2001; Steele et al., 2014).