Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword?. Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Brouwers, Martijn C.G.J.; Jacobs, Chantal; Bast, Aalt; Stehouwer, Coen D.A.; Schaper, Nicolaas C.
• Is Part Of: Trends in molecular medicine. Volume 21:Issue 10(2015)
• Page Start: 583
• Page End: 594
• Publication Date: 2015-10
• Subjects: Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; Physiology, Pathological -- Periodicals; 572.8
• DOI: 10.1016/j.molmed.2015.08.004
• Languages: English
• ISSNs: 1471-4914

Abstract

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. Trends: Disruption of the GKRP–glucokinase complex is a promising new antidiabetic target, since it results in lower plasma glucose levels without inducing hypoglycemia. Missense variants in the gene encoding GKRP ( GCKR ) allow us to gain an impression of the safety and efficacy of GKRP–glucokinase disruptors, as the biological effects of these variants are similar to those of exogenous disruptors. The GCKR minor allele is associated not only with protection against T2DM but also with predisposition to dyslipidemia, gout, and NAFLD. The relationship between GCKR and cardiovascular disease has been inconclusive.