Abbreviations DPP-4 Dipeptidyl peptidase GLP-1 Glucagon-like peptide-1 NC Neuromedin CTo 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 (α-chloralose) 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 Fig. 1). Similarly, the increase in GLP-1 concentration in peripheral venous plasma during stimulation amounted to only 8% of the increase in the portal concentration.Diabetologia (2011) 54:2206-2208 DOI 10.1007/s00125-011-2168-7 ESMIn contrast, total GLP-1 concentrations were reduced after vildagliptin administration. To...

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New Findings r What is the central question of this study?We investigated whether intestinal vagal afferents are necessary for the insulinotropic effect of glucagon-like peptide-1 (GLP-1) infused into a mesenteric artery or a peripheral vein before and after acute truncal vagotomy. r What is the main finding and its importance?We found no effect of truncal vagotomy on the insulinotropic effect of exogenous GLP-1 and speculate that high circulating concentrations of GLP-1 after i.v. and i.a. infusion might have overshadowed any neural signalling component. We propose that further investigations into the possible vagal afferent signalling of GLP-1 would best be pursued using enteral stimuli to provide high subepithelial levels of endogenous GLP-1. , i.v.) was administered over 9 min to stimulate β-cell secretion. Thirty minutes after the glucose infusion, GLP-1 infusions were discontinued. Following a washout period, the vagal trunks were severed in four of six groups (vagal trunks were left intact in two of six groups), whereupon all infusions were repeated. We found no effect of vagotomy on insulin or glucagon secretion during administration of exogenous GLP-1 in any experiment. We speculate that the effect of exogenous GLP-1 overshadowed any effect occurring via the vagus. Within dosage groups, total GLP-1 concentrations were similar, but intact GLP-1 concentrations were much lower when infused via the mesenteric artery because of extensive degradation of GLP-1 in the splanchnic bed. This demonstrates the effectiveness with which intestinal capillary dipeptidyl Glucagon