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Cell Death Dis. 2017 Feb 9;8(2):e2609. doi: 10.1038/cddis.2017.28.

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

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Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Chongqing Key Lab of Child Infection and Immunity Children's Hospital of Chongqing Medical University, Chongqing, China.
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.
Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong, China.
The Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA, USA.


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.

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