Intraportal administration of DPP-IV inhibitor regulates insulin secretion and food intake mediated by the hepatic vagal afferent nerve in rats.
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.
Department of Internal Medicine 1, Faculty of Medicine, Oita University, Yufu, Oita, Japan.
Kansuke
K
Fujiwara
Koro
K
Gotoh
Seiichi
S
Chiba
Takayuki
T
Masaki
Isao
I
Katsuragi
Tetsuya
T
Kakuma
Hironobu
H
Yoshimatsu
D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D007262:Infusions, Intravenous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008099:Liver / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D011169:Portal Vein / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014628:Vagotomy / Q000379:methods; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin