Duodenal GLP-1 signaling regulates hepatic glucose production through a PKC-\u03b4-dependent neurocircuitry

Mengliu Yang,Gangyi Yang,Shaobo Wu,Yanjun Jia,Xiaodong Zhao,Lei Yuan,Chaohong Liu,Guenther Boden,Yerui Lai,Jinzhi Wang,Jing Xie,Ling Li,Allan Zijian Zhao

doi:10.1038/cddis.2017.28

Abstract

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion and acts as a neuropeptide to control glucose homeostasis, but little is known whether intestinal GLP-1 has any effect in the control of hepatic glucose production (HGP). Here we found that intraduodenal infusion of GLP-1 activated duodenal PKC-δ, lowered HGP and was accompanied by a decrease in hepatic expression of gluconeogenic enzymes and an increase in hepatic insulin signaling in rats. However, gut co-infusion of either the GLP-1 receptor antagonist Ex-9, or the PKC-δ inhibitor rottlerin with GLP-1, negated the ability of gut GLP-1 to lower HGP and to increase hepatic insulin signaling during clamps. The metabolic and molecular signal effects of duodenal GLP-1 were also negated by co-infusion with tetracaine, pharmacologic inhibition of N-methyl-d-aspartate receptors within the dorsalvagal complex, or hepatic vagotomy in rats. In summary, we identified a neural glucoregulatory function of gut GLP-1 signaling.

Highlights

glucagon-like peptide-1 (GLP-1) is a 30 amino acid peptide produced by post-translational processing of the proglucagon gene product in enteroendocrine cells (L-cells), which are most prevalent in the mucosa of the distal small intestine and colon.[4]
It is possible that once secreted in a paracrine fashion, GLP-1 activates GLP-1 receptors (GLP-1R) expressed in mucosal cells of the upper gastrointestinal tract through vagal afferent neurons to regulate glucose production.[14]
To examine whether GLP-1R is expressed in the duodenum, GLP-1Rimmunoreactivity was performed in rat duodenum tissue

Summary

Introduction

It is well established that nutrients can stimulate the release of gut-peptide hormones, such as cholecystokinin (CCK), pancreatic polypeptide, peptide YY and glucagon-like peptide-1 (GLP-1), which are involved in the regulation of food intake and gastrointestinal function.[1,2,3] GLP-1 is a 30 amino acid peptide produced by post-translational processing of the proglucagon gene product in enteroendocrine cells (L-cells), which are most prevalent in the mucosa of the distal small intestine and colon.[4]. GLP-1 can be found throughout all regions of the porcine, rat and human small intestine.[5] The actions of GLP-1 are mediated by specific GLP-1 receptors (GLP-1R), a G-proteincoupled receptor (GPR). We described a novel role of intestinal GLP-1 that triggers a gut–brain–liver neuronal network to regulate HGP by using liraglutide, a human GLP-1R agonist, and Exenatide, a natural analog of GLP-1

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