title: A report of 2 new cases of MODY2 and review of the literature: implications in the search for type 2 diabetes drugs.
abstract: Glucokinase (GCK) acts as a glucose sensor and stimulates the release of insulin from pancreatic β-cells and any GCK gene mutations can lead to different forms of diabetes, such as GCK-monogenic diabetes of the young type 2 (MODY2), permanent neonatal diabetes and congenital hyperinsulinism. Many MODY2 causing mutations display a variation in the degree of severity, ranging from mild dietary-restricted forms to more detrimental presentation requiring insulin replacement. The present study reviews known and two novel GCK mutations in terms of molecular perturbation of the GCK atomic structure but also emphasizes the inactivating and activating properties of the GCK as treatment for T2DM. In silico analysis demonstrated that the newly discovered mutation p.Arg447Pro causes structural conformational changes that lead to the destabilization of the functional properties of the protein resulting in the reduction of glucose and MgATP2- affinity. The novel p.Glu440Stop nonsense mutation on the other hand inactivates the cytoplasmic enzymatic activity of the protein as it is responsible for the loss of the C-terminal end of the polypeptide that includes vital glucose-releasing residues. Based on the in silico models of existing structural data we identified several classes of GCK mutations and discuss their relation to disease outcome. GCK has a central role in controlling body glucose homeostasis and therefore is considered an outstanding drug target for developing new antidiabetic therapies using small molecular activators (GKAs). This study emphasizes the importance in understanding how inactivating and activating GCK mutations affect the mechanistic properties of this glucose sensor. Such information can become the basis for drug discovery of therapeutic compounds and the treatment of T2DM by targeting the GCK allosteric activator site.
authors.affiliation: Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus.
authors.forename: Christos
authors.initials: C
authors.lastname: Shammas
authors.forename: Vassos
authors.initials: V
authors.lastname: Neocleous
authors.forename: Marie M
authors.initials: MM
authors.lastname: Phelan
authors.forename: Lu-Yun
authors.initials: LY
authors.lastname: Lian
authors.forename: Nicos
authors.initials: N
authors.lastname: Skordis
authors.forename: Leonidas A
authors.initials: LA
authors.lastname: Phylactou
mesh_terms: D001120:Arginine; D002648:Child; D018389:Codon, Nonsense; D044903:Congenital Hyperinsulinism / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D005941:Glucokinase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D005951:Glucose Tolerance Test; D018698:Glutamic Acid; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007231:Infant, Newborn; D009154:Mutation; D011392:Proline
chemical_list: D018389:Codon, Nonsense; D007004:Hypoglycemic Agents; D018698:Glutamic Acid; D001120:Arginine; D011392:Proline; D005941:Glucokinase
keywords: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase; ATP; Congenital hyperinsulinism; DPP-4; G6P; GCK; GKAs; GKRP; GLP-1; GLUT2; GSIR; Glucokinase; Glucokinase activators; MODY2; Maturity-onset diabetes of the young; Monogenic diabetes of young type 2; Neonatal diabetes; OGTT; Oral Glucose Tolerance test; PFKFBI; SUR1; T2DM; Type 2 diabetes; adenosine triphosphate; dipeptidyl peptidase enzyme; glucagon-like peptide-1; glucokinase regulatory protein; glucose 6-phosphate; glucose transporter-2; glucose-stimulated insulin release; sulfonylurea receptor 1