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

• Published in: Cell death & disease Vol. 8; no. 2; p. e2609
• Main Authors: Yang, Mengliu, Wang, Jinzhi, Wu, Shaobo, Yuan, Lei, Zhao, Xiaodong, Liu, Chaohong, Xie, Jing, Jia, Yanjun, Lai, Yerui, Zhao, Allan Zijian, Boden, Guenther, Li, Ling, Yang, Gangyi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.02.2017
• Subjects: Animals; Duodenum - metabolism; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose - metabolism; Homeostasis - physiology; Insulin - metabolism; Liver - metabolism; Original; Protein Kinase C-delta - metabolism; Rats; Receptors, N-Methyl-D-Aspartate - metabolism; Signal Transduction - physiology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.28

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.