Lessons from glucokinase activators: the problem of declining efficacy

Expert Opin Ther Pat. 2014 Nov;24(11):1155-9. doi: 10.1517/13543776.2014.965680. Epub 2014 Sep 30.


The concept of activation of glucokinase (encoded by the Gck gene) as a potential therapy for type 2 diabetes has been explored by several pharmaceutical companies. Small-molecule Gck activators (GKAs) were found to be effective at increasing glucose disposal by hepatocytes and lowering blood glucose in animal models of diabetes during acute or chronic exposure and in human type 2 diabetes during short-term exposure. However, several clinical trials of GKAs were discontinued because of declining efficacy during chronic exposure or other issues. In some cases, declining efficacy was associated with an increase in plasma triglycerides. Accordingly, increased hepatic triglyceride production or steatosis was inferred as the likely cause for declining efficacy. However, other mechanisms of tachyphylaxis need to be considered. For example, elevated glucose concentration causes induction of glucose 6-phosphatase (G6pc) and repression of Gck in hepatocytes. This is best explained as an adaptative mechanism to maintain intracellular phosphometabolite homeostasis. Enhancement of G6pc induction and Gck repression by GKAs because of perturbed phosphometabolite homeostasis could explain the decline in GKA efficacy during chronic exposure. Progress in understanding the mechanisms of intracellular phosphometabolite homeostasis is crucial for development of better drug therapies and appropriate dietary intervention for type 2 diabetes.

Keywords: glucokinase; glucokinase activators; liver metabolism; type 2 diabetes.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Enzyme Activators / pharmacology*
  • Enzyme Activators / therapeutic use
  • Glucokinase / drug effects*
  • Glucokinase / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Patents as Topic


  • Enzyme Activators
  • Hypoglycemic Agents
  • Glucokinase