Do we know the true mechanism of action of the DPP-4 inhibitors?

Diabetes Obes Metab. 2018 Jan;20(1):34-41. doi: 10.1111/dom.13018. Epub 2017 Jul 13.


The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti-diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recent addition to the anti-diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side-effect profile and their low hypoglycaemia risk. The actions of DPP-4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are known substrates, but other incretin-independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP-4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.

Keywords: dipeptidyl peptidase-4 inhibitors; incretin therapy; type 2 diabetes.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Gastric Inhibitory Polypeptide / agonists
  • Gastric Inhibitory Polypeptide / metabolism
  • Gastrointestinal Motility / drug effects
  • Glucagon-Like Peptide 1 / agonists
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Incretins / adverse effects
  • Incretins / pharmacology
  • Incretins / therapeutic use*
  • Insulin / agonists
  • Insulin / metabolism
  • Insulin Secretion
  • Models, Biological*
  • Pancreas / drug effects
  • Pancreas / innervation
  • Pancreas / metabolism
  • Proteolysis / drug effects
  • Signal Transduction / drug effects
  • Synaptic Transmission / drug effects


  • Dipeptidyl-Peptidase IV Inhibitors
  • Incretins
  • Insulin
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1