Dipeptidyl peptidase-4 inhibition increases portal concentrations of intact glucagon-like peptide-1 (GLP-1) to a greater extent than peripheral concentrations in anaesthetised pigs

Excerpt

To the Editor: The dipeptidyl peptidase (DPP-4) inhibitors widely used for diabetes treatment may be viewed as being surprisingly effective, particularly when compared with the other class of incretin-based therapy, the glucagon-like peptide-1 (GLP-1) analogues (mimetics), because the inhibitors are associated with only modest increases in peripheral intact GLP-1, whereas much higher agonist concentrations can be achieved using the analogues. It has been calculated that only 10–15% of newly secreted GLP-1 reaches the pancreas as the intact hormone via the circulation [1, 2] because of local and hepatic DPP-4-mediated degradation, leading to the suggestion that GLP-1 may act more locally by interacting with afferent neurons within the intestine or portal vein before it is degraded by DPP-4. Thus it could be speculated that local concentrations of intact GLP-1, particularly after administration of DPP-4 inhibitor, may be much higher than peripheral venous concentrations, which could, at least partially, explain the effectiveness of the inhibitors [3]. However, it is at present unknown what the actual concentrations of endogenous GLP-1 are in the various vascular beds and how much intact GLP-1 concentrations in sites such as the portal vein rise following DPP-4 inhibition. …