title: Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism.
abstract: OBJECTIVE
  Glucokinase regulator (GCKR) encodes glucokinase regulatory protein (GKRP), a hepatocyte-specific inhibitor of the glucose-metabolizing enzyme glucokinase (GCK). Genome-wide association studies have identified a common coding variant within GCKR associated with multiple metabolic traits. This review focuses on recent insights into the critical role of GKRP in hepatic glucose metabolism that have stemmed from the study of human genetics. This knowledge has improved our understanding of glucose and lipid physiology and informed the development of targeted molecular therapeutics for diabetes.
  
  
  RESULTS
  Rare GCKR variants have effects on GKRP expression, localization, and activity. These variants are collectively associated with hypertriglyceridaemia but are not causal. Crystal structures of GKRP and the GCK-GKRP complex have been solved, providing greater insight into the molecular interactions between these proteins. Finally, small molecules have been identified that directly bind GKRP and reduce blood glucose levels in rodent models of diabetes.
  
  
  CONCLUSIONS
  GCKR variants across the allelic spectrum have effects on glucose and lipid homeostasis. Functional analysis has highlighted numerous molecular mechanisms for GKRP dysfunction. Hepatocyte-specific GCK activation via small molecule GKRP inhibition may be a new avenue for type 2 diabetes treatment, particularly considering evidence indicating GKRP loss-of-function alone does not cause hypertriglyceridaemia.
authors.affiliation: aOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK bCenter for the Science of Therapeutics, Broad Institute cHoward Hughes Medical Institute, Broad Institute, Cambridge, Massachusetts, USA dNIHR Oxford Biomedical Research Centre, ORH Trust, OCDEM, Churchill Hospital, Oxford, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Raimondo
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rees
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D014280:Triglycerides; C080906:glucokinase regulatory protein; D005947:Glucose