Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

Dipeptidyl peptidase (DPP)-4 inhibition is a glucose-lowering treatment for type 2 diabetes. The classical mechanism for DPP-4 inhibitors is that they inhibit DPP-4 activity in peripheral plasma, which prevents the inactivation of the incretin hormone glucagon-like peptide (GLP)-1 in the peripheral circulation. This in turn increases circulating intact GLP-1, which results in stimulated insulin secretion and inhibited glucagon secretion, in turn increasing glucose utilization and diminishing hepatic glucose production, which, through reduction in postprandial and fasting glucose, reduces HbA1c. However, recent experimental studies in mainly rodents but also to a limited degree in humans have found additional mechanisms for DPP-4 inhibitors that may contribute to their glucose-lowering action. These nonclassical mechanisms include 1) inhibition of gut DPP-4 activity, which prevents inactivation of newly released GLP-1, which in turn augments GLP-1-induced activations of autonomic nerves and results in high portal GLP-1 levels, resulting in inhibited glucose production through portal GLP-1 receptors; 2) inhibition of islet DPP-4 activity, which prevents inactivation of locally produced intact GLP-1 in the islets, thereby augmenting insulin secretion and inhibiting glucagon secretion and possibly preventing islet inflammation; and 3) prevention of the inactivation of other bioactive peptides apart from GLP-1, such as glucose-dependent insulinotropic polypeptide, stromal-derived factor-1α, and pituitary adenylate cyclase-activating polypeptide, which may improve islet function. These pleiotropic effects may contribute to the effects of DPP-4 inhibition. This Perspectives in Diabetes outlines and discusses these nonclassical mechanisms of DPP-4 inhibition.