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  • In conclusion we provided the first


    In conclusion, we provided the first evidence of a modification and regulation of GCK by O-GlcNAc modification that until now was not explored. This discovery provides important clues in the prevention of hyperglycemia and development of novel therapeutic drugs to treat type 2 diabetes.
    Acknowledgments We are indebted to the Research Federation FRABio (Univ. Lille, CNRS, FR 3688, FRABio, Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires) for providing the scientific and technical environment conducive to achieving this work. We would like to thank Pr. D. Vocadlo (Simon Fraser University) who provided us NButGT. SB is a recipient of a fellowship from the “gs2:Ministère de l'Enseignement Supérieur et de la Recherche”and from the “Région Nord-Pas de Calais”.
    Introduction Glucokinase (GCK, hexokinase type IV) catalyzes the phosphorylation of glucose to glucose-6-phosphate (G6P), which is a rate-limiting step in glycolysis [1], [2]. Glucokinase is characterized by a high Km for glucose and a lack of allosteric inhibition by G6P compared to hexokinases I–III. Thus, the rate of glucose phosphorylation is directly proportional to blood glucose levels. Glucokinase is expressed principally in pancreatic β-cells and hepatocytes, but is also present in certain hypothalamic neurons and enteroendocrine cyclin dependent kinase inhibitor [2]. The GCK gene consists of exons 1a, 1b, and 2–10, and two alternate promoters regulate the tissue-specific expression of exons 1a and 1b [3], [4]. Exon 1a is expressed in β-cells, enteroendocrine cells, and neuronal cells, whereas exon 1b is expressed in hepatocytes only. In β-cells, glucokinase serves as a glucose sensor and plays a crucial role in the regulation of insulin secretion [5]. Heterozygous inactivating mutations in the GCK gene cause a type of maturity-onset diabetes of the young (MODY2), which is characterized by abnormalities in insulin secretion [4], [6]. Homozygous inactivating mutations in the GCK gene result in a more severe phenotype presenting at birth as permanent neonatal diabetes [7]. In contrast, activating mutations in the GCK gene cause hyperinsulinemic hypoglycemia [8]. Liver glucokinase also plays an essential role in controlling blood glucose levels and maintaining cellular metabolic functions [2]. After glucose is taken up by the liver, it is converted to G6P by glucokinase and stored as glycogen. MODY2 patients reportedly have impaired glucose uptake by liver and decreased accumulation of hepatic glycogen [9], [10]. Hepatic glucokinase is also required for the proper activation of glycolytic and lipogenic gene expression in the liver [11]. In addition to these hepatic roles of glucokinase, previous studies have shown that this enzyme is involved in metabolic communication between the liver and different tissues. Adenovirus-mediated overexpression of glucokinase in the liver decreased adaptive thermogenesis by downregulating the expression of thermogenesis-related genes in brown adipose tissue (BAT) [12]. In addition, liver-specific glucokinase knockout mice generated by the Cre/loxP system exhibited impaired insulin secretion in response to glucose [13]. These results suggest the presence of intertissue (liver-to-BAT as well as liver-to-β-cell) metabolic pathways. To understand better the roles of hepatic glucokinase in vivo, we generated a new line of Gck knockout mice by ablating liver-specific exon 1b. The Gck (−/−) mice characterized in the present study exhibited hyperglycemia after glucose load, a defect in hepatic glycogen accumulation, and reduced glycolytic and lipogenic gene expression in the liver. However, these mice displayed neither an insulin secretion defect nor altered expression of thermogenesis-related genes (Ucp1, Pgc1a, and Dio2) in BAT when fed a normal chow diet, suggesting that intertissue regulation by glucokinase is not functional under these conditions. Further studies are necessary to clarify the roles of hepatic glucokinase in intertissue metabolic communication.