Duodenal GLP-1 signaling regulates hepatic glucose production through a PKC-δ-dependent neurocircuitry.
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.
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Mengliu
M
Yang
Chongqing Key Lab of Child Infection and Immunity Children's Hospital of Chongqing Medical University, Chongqing, China.
Jinzhi
J
Wang
The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Shaobo
S
Wu
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Lei
L
Yuan
Chongqing Key Lab of Child Infection and Immunity Children's Hospital of Chongqing Medical University, Chongqing, China.
Xiaodong
X
Zhao
Chongqing Key Lab of Child Infection and Immunity Children's Hospital of Chongqing Medical University, Chongqing, China.
Chaohong
C
Liu
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Jing
J
Xie
Chongqing Key Lab of Child Infection and Immunity Children's Hospital of Chongqing Medical University, Chongqing, China.
Yanjun
Y
Jia
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Yerui
Y
Lai
Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong, China.
Allan Zijian
AZ
Zhao
The Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA, USA.
Guenther
G
Boden
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Ling
L
Li
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Gangyi
G
Yang
D000818:Animals; D004386:Duodenum / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D016194:Receptors, N-Methyl-D-Aspartate; D052216:Glucagon-Like Peptide 1; D051745:Protein Kinase C-delta; D005947:Glucose