The insulinotropic effect of exogenous glucagon‐like peptide‐1 is not affected by acute vagotomy in anaesthetized pigs

Abstract

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

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

“…However, while rodent data support the notion that vagal signalling may be involved in the anti‐hyperglycaemic actions of endogenous GLP‐1 and DPP‐4 inhibitors, the situation in non‐rodent species is less clear. The insulinotropic and glucagonostatic effects of exogenously administered GLP‐1 (infused via the mesenteric artery) were unaltered by truncal vagotomy in anaesthetised pigs, although it was argued that an endocrine effect due to a spillover into the systemic circulation may have overshadowed any neural signalling component . In humans, the incretin effect is still maintained after pancreas transplantation, suggesting that innervation of the pancreas may not be prerequisite.…”

“…The insulinotropic and glucagonostatic effects of exogenously administered GLP-1 (infused via the mesenteric artery) were unaltered by truncal vagotomy in anaesthetised pigs, although it was argued that an endocrine effect due to a spillover into the systemic circulation may have overshadowed any neural signalling component. 35 In humans, the incretin effect is still maintained after pancreas transplantation, 36 suggesting that innervation of the pancreas may not be prerequisite. Subjects with a truncal vagotomy (associated with previous surgery for duodenal ulcer or oesophageal cancer) also have an intact incretin effect, but there was some impairment in GImediated glucose disposal and in the ability of DPP-4 inhibition to enhance insulin secretion, 37 while the effects of exogenous GLP-1 on food intake were lost.…”

Endogenous glucagon‐like peptide (GLP)‐1 as alternative for GLP‐1 receptor agonists: Could this work and how?

“…huge doses) on food intake, 131,132 glucose tolerance, 134 insulin secretion 136 and fat mass 132 do not seem to require the vagus nerve.…”

“…In one study, the inhibiting effect of intravenous GLP‐1 on gastric acid secretion was diminished in vagotomised humans 123 . However, in animal (in particular rodent) studies, the effect of intravenous or subcutaneous administered GLP‐1(RA) (usually in huge doses) on food intake, 131,132 glucose tolerance, 134 insulin secretion 136 and fat mass 132 do not seem to require the vagus nerve.…”