Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword?

Trends Mol Med. 2015 Oct;21(10):583-594. doi: 10.1016/j.molmed.2015.08.004.


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.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing* / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Animals
  • Carrier Proteins / metabolism
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Diabetes Mellitus, Type 2* / therapy
  • Genetic Predisposition to Disease
  • Glucokinase / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Metabolomics
  • Mice


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GCKR protein, human
  • Gckr protein, mouse
  • Hypoglycemic Agents
  • Intracellular Signaling Peptides and Proteins
  • Glucokinase