title: Molecular targeting of the GK-GKRP pathway in diabetes.
abstract: BACKGROUND
  Type 2 diabetes mellitus is a major healthcare concern. Significant efforts are being devoted toward developing new, safe, and more effective treatments. One approach involves activating glucokinase (GK). Earlier GK activator (GKA) approaches have focused on direct activation of GK through allosteric activators.
  
  
  METHODS
  This review summarizes the roles of GK and its key partner glucokinase regulatory protein in glucose metabolism and describes approaches that may alleviate hypoglycemic risk observed with GKAs.
  
  
  CONCLUSIONS
  The current GKA therapeutic approaches are associated with disappointing success rates. In rodent animal models, efficacy was observed with GKA. However, in all human studies, GKAs effectively lowered blood glucose, but at the expense of an increased risk of hypoglycemia. Other liabilities like loss of efficacy with time and increase in blood pressure or triglyceride levels have been reported with different molecules. To avoid hypoglycemic risk, alternative approaches to regulate GK activity have been initiated. Data from clinical trials using these agents are either not yet available to the public or the compounds are too early in development for humans. GK is a promising target for antidiabetic therapy. Despite encouraging biology, more research is required to fully understand GK as a drug target.
authors.affiliation: Amgen, Inc., Department of Metabolic Disorders , Thousand Oaks, CA , USA.
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellacani
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004789:Enzyme Activation; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology; D010179:Pancreas / Q000201:enzymology
chemical_list: D002352:Carrier Proteins; C080906:glucokinase regulatory protein; D005941:Glucokinase
keywords: glucokinase; glucokinase regulatory protein; hepatoselective; hypoglycemia; pancreatic glucokinase; type 2 diabetes