title: Glucokinase (GCK) and other susceptibility genes for beta-cell dysfunction: the candidate approach.
abstract: There are well-documented examples in the literature of where determining the genetic aetiology of a disorder has provided insights into important regulatory pathways and protein interactions, and, more recently, has led to improved treatment options for patients. The studies of monogenic forms of beta-cell dysfunction are no exception. Naturally occurring mutations in the gene for the beta-cell enzyme glucokinase (GCK) result in both hyper- and hypo-glycaemia. Over 200 mutations have been described, and careful study of the mutational mechanisms for a number of these has provided important insights into glucokinase regulation. Increased understanding of post-translational regulatory mechanisms holds the promise of novel pharmacotherapeutic options for the treatment of T2DM (Type 2 diabetes mellitus). It is well established that common genetic variation in genes involved in monogenic forms of beta-cell dysfunction contributes to susceptibility to T2DM. Recent genome-wide scans for association have identified a number of novel T2DM susceptibility genes which probably influence beta-cell mass and/or function. Their identification allows the investigation of the role of rare mutations in monogenic beta-cell dysfunction. Current results indicate the importance of these genes in pancreatic development and suggest that mutations which result in a severe functional defect could be lethal.
authors.affiliation: Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK. anna.gloyn@drl.ox.ac.uk
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Tribble
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Paul R V
authors.initials: PR
authors.lastname: Johnson
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005941:Glucokinase / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology*; D009154:Mutation / Q000235:genetics
chemical_list: D005941:Glucokinase