title: Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword?
abstract: The continuous search for drugs targeting type 2 diabetes mellitus (T2DM) has led to the identification of small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP). Although mice studies are encouraging, it will take years before these disruptors can be introduced to T2DM patients. Recently, genome-wide association studies (GWASs) have shown that variants in the gene encoding GKRP protect against T2DM and kidney disease but predispose to gout, nonalcoholic fatty liver disease, and dyslipidemia. These genetic data, together with previous experience with systemic and hepatospecific glucokinase activators, provide insight into the anticipated efficacy and safety of small-molecule disruptors in humans. Interestingly, they suggest that the opposite--enhanced GKRP-glucokinase binding--could be beneficial in selected patients.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands. Electronic address: mcgj.brouwers@mumc.nl.
authors.forename: Martijn C G J
authors.initials: MCGJ
authors.lastname: Brouwers
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Jacobs
authors.affiliation: Department of Toxicology, Faculty of Health Medicine and Life Sciences, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.affiliation: General Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Coen D A
authors.initials: CDA
authors.lastname: Stehouwer
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
authors.forename: Nicolaas C
authors.initials: NC
authors.lastname: Schaper
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D020022:Genetic Predisposition to Disease; D005941:Glucokinase / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D055432:Metabolomics; D051379:Mice
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C485100:GCKR protein, human; C499483:Gckr protein, mouse; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D005941:Glucokinase