Rapid hepatic metabolism blunts the endocrine action of portally infused GLP-1 in male rats.

Journal Article (Journal Article)

Glucagon-like peptide-1 (GLP-1) is an enteral peptide that contributes to the incretin effect. GLP-1 action is typically described as endocrine, but this mechanism has been questioned because rapid inactivation in the circulation by dipeptidylpeptidase 4 (DPP4) results in a short half-life, limiting the amount of the hormone that can reach the pancreatic islet. An alternative mechanism for GLP-1 to regulate insulin secretion through neuroendocrine signaling originating from sensors in the portal vein has been proposed. We hypothesized that portal infusion of GLP-1 would cause greater glucose-stimulated insulin secretion than equimolar administration into the jugular vein. To test this, hyperglycemic clamps with superimposed graded infusions of GLP-1 into the jugular or portal veins of male rats were performed. These experiments were repeated with pharmacologic DPP4 inhibition to determine the effect of GLP-1 metabolism in the jugular and portal venous beds. Contrary to our hypothesis, we found a higher insulinotropic effect with jugular compared with portal GLP-1, which was associated with higher plasma concentrations of intact GLP-1. The greater insulinotropic effect of jugular venous GLP-1 persisted even with pharmacological DPP4 inhibition. These findings do not support an important role of portal vein GLP-1 signaling for the incretin effect but highlight the hepatoportal bed as a major site of GLP-1 degradation that persists even with pharmacological inhibition. Together, these results support rapid inactivation of enterally released GLP-1 in the liver as limiting endocrine actions on the β-cell and raise questions about the conventional endocrine model of pharmacologic effects of DPP4 inhibitors.

Full Text

Duke Authors

Cited Authors

  • Aulinger, BA; Perabo, M; Seeley, RJ; Parhofer, KG; D'Alessio, DA

Published Date

  • February 1, 2020

Published In

Volume / Issue

  • 318 / 2

Start / End Page

  • E189 - E197

PubMed ID

  • 31743041

Pubmed Central ID

  • PMC7052580

Electronic International Standard Serial Number (EISSN)

  • 1522-1555

Digital Object Identifier (DOI)

  • 10.1152/ajpendo.00298.2019

Language

  • eng

Conference Location

  • United States