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. We therefore measured the concentrations of GLP-1 in different vascular compartments before and after DPP-4 inhibition with vildagliptin (1 mg/kg) in anaesthetised (αchloralose) pigs (n= 6) given intravenous neuromedin C (NC, 120 nmol), a known stimulus for GLP-1. Blood samples were obtained simultaneously from a carotid artery and the femoral, hepatic and portal veins and analysed for total GLP-1 using the ‘side-viewing’antiserum 2135, reacting with a mid-sequence of GLP-1, and intact GLP-1 concentrations by sandwich ELISA. DPP-4 activity was assayed by a fluorescence assay (see electronic supplementary material [ESM] Methods). NC augmented concentrations of total GLP-1 six-to eightfold, both before and after vildagliptin administration (see Fig. 1). Both total and intact GLP-1 concentrations were highest in the portal vein and decreased progressively as the distance from the site of release increased, with lowest concentrations being found in the peripheral venous plasma. Before vildagliptin administration, GLP-1 was extensively degraded by DPP-4 at all sites (incremental AUC for intact arterial GLP-1 before being 79.2±14.8 pmol/l× min, while intact portal GLP-1 after was 460.0±65.5 pmol/l× min), indicating that the peripheral (and therefore pancreatic islet) exposure to intact GLP-1 amounts to only 20% of the splanchnic/portal exposure (see