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

• Published in: Diabetes, obesity & metabolism Vol. 20; no. 1; pp. 34 - 41
• Main Authors: Andersen, Emilie S., Deacon, Carolyn F., Holst, Jens J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2018; Wiley Subscription Services, Inc
• Subjects: Animals; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - physiopathology; dipeptidyl peptidase‐4 inhibitors; Dipeptidyl-peptidase IV; 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; GIP protein; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - agonists; Glucagon-Like Peptide 1 - metabolism; Homeostasis; Humans; Hypoglycemia; incretin therapy; Incretins - adverse effects; Incretins - pharmacology; Incretins - therapeutic use; Insulin - agonists; Insulin - metabolism; Insulin Secretion; Models, Biological; Pancreas - drug effects; Pancreas - innervation; Pancreas - metabolism; Paracrine signalling; Peptidase; Preservation; Proteolysis - drug effects; Signal Transduction - drug effects; Synaptic Transmission - drug effects; type 2 diabetes; dipeptidyl peptidase-4 inhibitors; incretin therapy; type 2 diabetes
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/dom.13018

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.