Intraportal Administration of DPP-IV Inhibitor Regulates Insulin Secretion and Food Intake Mediated by the Hepatic Vagal Afferent Nerve in Rats

J Neurochem. 2012 Apr;121(1):66-76. doi: 10.1111/j.1471-4159.2011.07563.x. Epub 2012 Feb 15.

Abstract

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and suppresses food intake. Recent studies indicate that the hepatic vagal afferent nerve is involved in this response. Dipeptidyl peptidase-IV (DPP-IV) inhibitor extends the half-life of endogenous GLP-1 by preventing its degradation. This study aimed to determine whether DPP-IV inhibitor-induced elevation of portal GLP-1 levels affect insulin secretion and feeding behavior via the vagal afferent nerve and hypothalamus. The effect of DPP-IV inhibitor infusion into the portal vein or peritoneum on portal and peripheral GLP-1 levels, food intake, and plasma insulin and glucose was examined in sham-operated and vagotomized male Sprague-Dawley rats. Analyses of neuronal histamine turnover and immunohistochemistry were used to identify the CNS pathway that mediated the response. Intraportal administration of the DPP-IV inhibitor significantly increased portal (but not peripheral) GLP-1 levels, increased insulin levels, and decreased glucose levels. The DPP-IV inhibitor suppressed 1- and 12- but not 24-h cumulative food intake. Intraportal infusion of the DPP-IV inhibitor increased hypothalamic neuronal histamine turnover and increased c-fos expression in several areas of the brain. These responses were blocked by vagotomy. Our results indicate that DPP-IV inhibitor-induced changes in portal but not systemic GLP-1 levels affect insulin secretion and food intake. Furthermore, our findings suggest that a neuronal pathway that includes the hepatic vagal afferent nerve and hypothalamic neuronal histamine plays an important role in the pharmacological actions of DPP-IV inhibitor.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage*
  • Eating / drug effects
  • Eating / physiology*
  • Infusions, Intravenous
  • Insulin / metabolism*
  • Insulin Secretion
  • Liver / drug effects
  • Liver / innervation
  • Liver / metabolism
  • Male
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism*
  • Portal Vein / drug effects
  • Portal Vein / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Vagotomy / methods
  • Vagus Nerve / drug effects
  • Vagus Nerve / metabolism*

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Insulin