A report of 2 new cases of MODY2 and review of the literature: implications in the search for type 2 diabetes drugs.

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.

Shammas C ，Neocleous V ，Phelan MM ，Lian LY ，Skordis N ，Phylactou LA ... -  《-》

Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects.

Matschinsky FM ，Zelent B ，Doliba NM ，Kaestner KH ，Vanderkooi JM ，Grimsby J ，Berthel SJ ，Sarabu R ... -  《-》

Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.

Glucokinase is a key regulatory enzyme in the pancreatic beta-cell. It plays a crucial role in the regulation of insulin secretion and has been termed the pancreatic beta-cell sensor. Given its central role in the regulation of insulin release, it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyperglycemia and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY), characterized by mild hyperglycemia, which is present at birth, but is often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype, presenting at birth as permanent neonatal diabetes mellitus (PNDM). Several heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 195 mutations in the GCK gene have been described, in a total of 285 families. There are no common mutations and the mutations are distributed throughout the gene. Mutations that cause hypoglycemia are located in various exons in a discrete region of the protein termed the heterotropic allosteric activator site. The identification of a GCK mutation in hyper- and hypoglycemia has implications for the clinical course and clinical management of the disorder.

Gloyn AL 《-》

A novel glucokinase gene mutation and its effect on glycemic/C-peptide fluctuations in a patient with maturity-onset diabetes of the young type 2.

Loomba-Albrecht LA ，Jame M ，Bremer AA 《-》

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity.

García-Herrero CM ，Galán M ，Vincent O ，Flández B ，Gargallo M ，Delgado-Alvarez E ，Blázquez E ，Navas MA ... -  《DIABETOLOGIA》