The insulinotropic effect of exogenous GLP-1 is not affected by acute vagotomy in anaesthetized pigs

New Findings

What is the central question of this study?

We investigated whether intestinal vagal afferents are necessary for the insulinotropic effect of GLP-1 infused GLP-1 into a mesenteric artery or a peripheral vein before and after acute truncal vagotomy.

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 levels of GLP-1 after intravenous infusion may have overshadowed any neural signalling component. We propose that further investigations in to the possible vagal afferent signalling of GLP-1 would best be pursued using enteral stimuli to provide high subepithelial levels of endogenous GLP-1.

Glucagon-like peptide 1(GLP-1) is secreted from the gut in response to luminal stimuli and stimulates insulin secretion glucose dependently. Due to rapid enzymatic degradation of GLP-1 by dipeptidyl peptidase-4 (DPP-4), a signalling pathway involving activation of intestinal vagal afferents has been proposed. We conducted two series of experiments in α-chloralose-anaesthetized pigs. Protocol I: pigs (n = 14) were allocated for either intravenous(iv) or intra-arterial(mesenteric) GLP-1 infusions (1 and 2 pmol kg⁻¹ min⁻¹, 30 min) while maintaining permissive glucose levels at 6 mmol l⁻¹ by iv glucose infusion. GLP-1 infusions were repeated after acute truncal vagotomy. Protocol II: pigs (n = 27) were allocated into 6 groups. GLP-1 was infused intravenously or intra-arterially(mesenteric) for 1 h at 3 pmol kg⁻¹ min⁻¹or 30 pmol kg⁻¹ min⁻¹. During steady state (21 min into the GLP-1 infusion), glucose (0.2 g/kg, iv) was administered over 9 min to stimulate beta cell secretion. 30 min after the glucose infusion GLP-1 infusions were discontinued. Following a washout period the vagal trunks were severed in 4/6 groups (vagal trunks were left intact in 2/6 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 levels were similar but intact GLP-1 levels were much lower when infused via the mesenteric artery due to extensive degradation of GLP-1 in the splanchnic bed. This demonstrates the effectiveness with which intestinal capillary DPP-4 protects the systemic circulation from intact GLP-1, consistent with a local role for GLP-1 involving activation of vagal pathways.

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