PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target

Int J Mol Sci. 2021 Mar 20;22(6):3170. doi: 10.3390/ijms22063170.


Hypofibrinolysis is a key abnormality in diabetes and contributes to the adverse vascular outcome in this population. Plasminogen activator inhibitor (PAI)-1 is an important regulator of the fibrinolytic process and levels of this antifibrinolytic protein are elevated in diabetes and insulin resistant states. This review describes both the physiological and pathological role of PAI-1 in health and disease, focusing on the mechanism of action as well as protein abnormalities in vascular disease with special focus on diabetes. Attempts at inhibiting protein function, using different techniques, are also discussed including direct and indirect interference with production as well as inhibition of protein function. Developing PAI-1 inhibitors represents an alternative approach to managing hypofibrinolysis by targeting the pathological abnormality rather than current practice that relies on profound inhibition of the cellular and/or acellular arms of coagulation, and which can be associated with increased bleeding events. The review offers up-to-date knowledge on the mechanisms of action of PAI-1 together with the role of altering protein function to improve hypofirbinolysis. Developing PAI-1 inhibitors may form for the basis of future new class of antithrombotic agents that reduce vascular complications in diabetes.

Keywords: PAI-1 inhibitors; cardiovascular disease; diabetes; hypofibrinolysis; plasminogen activator inhibitor 1 (PAI-1); therapeutics.

Publication types

  • Review

MeSH terms

  • Animals
  • Antifibrinolytic Agents / pharmacology
  • Antifibrinolytic Agents / therapeutic use
  • Biomarkers
  • Diabetes Complications / blood
  • Diabetes Mellitus / etiology*
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / therapy
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / therapy
  • Disease Management
  • Disease Susceptibility
  • Enzyme Activation / drug effects
  • Fibrinolysis
  • Humans
  • Molecular Targeted Therapy
  • Plasminogen Activator Inhibitor 1 / chemistry
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Structure-Activity Relationship


  • Antifibrinolytic Agents
  • Biomarkers
  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human