Glucokinase Activators for Type 2 Diabetes: Challenges and Future Developments

Drugs. 2020 Apr;80(5):467-475. doi: 10.1007/s40265-020-01278-z.


Increased hepatic glucose output, the primary liver dysregulation associated with Type 2 diabetes mellitus (T2DM), is not directly or effectively targeted by the currently available classes of glucose-lowering medications except metformin. This unmet need might be addressed through activation of a specific enzyme-member of the hexokinase family, namely glucokinase (GK). GK serves as a "glucose-sensor" or "glucose receptor" in pancreatic cells, eliciting glucose-stimulated insulin secretion, and as glucose "gate-keeper" in hepatocytes, promoting hepatic glucose uptake and glycogen synthesis and storage. GK activation by small molecules present an alternative approach to restore/improve glycaemic control in patients with T2DM. GK activators (GKAs) may increase insulin secretion from the pancreas and promote glycogen synthesis in the liver, and hence reduce hepatic glucose output. Despite several setbacks in their development, interest in the GKA class has been renewed, particularly since the introduction of a novel, dual-acting full GKA, dorzagliatin, and a novel hepatoselective molecule, TTP399. In this article we provide an overview of the role, efficacy, safety and future developments of GKAs in the management of T2DM.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucokinase / metabolism*
  • Humans
  • Organic Chemicals / pharmacology
  • Pyrazoles / pharmacology


  • Organic Chemicals
  • Pyrazoles
  • TTP399
  • Glucokinase
  • Dorzagliatin