TY - JOUR
T1 - Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword?
AU - Brouwers, M.C.G.J.
AU - Jacobs, C.
AU - Bast, Aalt
AU - Stehouwer, C.D.A.
AU - Schaper, N.C.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.molmed.2015.08.004
DO - 10.1016/j.molmed.2015.08.004
M3 - Article
C2 - 26432016
SN - 1471-4914
VL - 21
SP - 583
EP - 594
JO - Trends in Molecular Medicine
JF - Trends in Molecular Medicine
IS - 10
ER -