TY - JOUR

T1 - The insulinotropic effect of exogenous GLP-1 is not affected by acute vagotomy in anaesthetized pigs

AU - Veedfald, Simon

AU - Hansen, Marie

AU - Christensen, Louise Wulff

AU - Larsen, Sara Agnete Hjort

AU - Hjøllund, Karina Rahr

AU - Plamboeck, Astrid

AU - Hartmann, Bolette

AU - Deacon, Carolyn F

AU - Holst, Jens Juul

N1 - This article is protected by copyright. All rights reserved.

PY - 2016/3/30

Y1 - 2016/3/30

N2 - 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(-1) or 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. This article is protected by copyright. All rights reserved.

AB - 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(-1) or 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. This article is protected by copyright. All rights reserved.

U2 - 10.1113/EP085692

DO - 10.1113/EP085692

M3 - Journal article

C2 - 27027735

VL - 101

SP - 895

EP - 912

JO - Experimental Physiology

JF - Experimental Physiology

SN - 0958-0670

IS - 7

ER -