title: Duodenal PKC-δ and cholecystokinin signaling axis regulates glucose production.
abstract: OBJECTIVE
  Metabolism of long-chain fatty acids within the duodenum leads to the activation of duodenal mucosal protein kinase C (PKC)-δ and the cholecystokinin (CCK)-A receptor to lower glucose production through a neuronal network. However, the interfunctional relationship between duodenal PKC-δ and CCK remains elusive. Although long-chain fatty acids activate PKC to stimulate the release of CCK in CCK-secreting cells, CCK has also been found to activate PKC-δ in pancreatic acinar cells. We here evaluate whether activation of duodenal mucosal PKC-δ lies upstream (and/or downstream) of CCK signaling to lower glucose production.
  
  
  METHODS
  We first determined with immunofluorescence whether PKC-δ and CCK were colocalized within the duodenal mucosa. We then performed gain- and loss-of-function experiments targeting duodenal PKC-δ and the CCK-A receptor and evaluated the impact on changes in glucose kinetics during pancreatic (basal insulin) clamps in rats in vivo.
  
  
  RESULTS
  Immunostaining of PKC-δ was found to colocalize with CCK in the duodenal mucosa. Intraduodenal coinfusion of either the CCK-A receptor antagonist MK-329 or CR-1409 with the PKC activator negated the ability of duodenal mucosal PKC-δ activation to lower glucose production during the pancreatic clamps in normal rats. Conversely, molecular and pharmacological inhibition of duodenal PKC-δ did not negate the ability of the duodenal CCK-A receptor agonist CCK-8 to lower glucose production, indicating that activation of duodenal PKC-δ lies upstream (and not downstream) of CCK signaling. Finally, intraduodenal PKC activator infusion failed to lower glucose production in rats with high-fat diet-induced duodenal CCK resistance.
  
  
  CONCLUSIONS
  In summary, activation of duodenal PKC-δ leads to the stimulation of CCK release and activation of the CCK-A receptor signaling axis to lower glucose production in normal rats, but fails to bypass duodenal CCK-resistance in high fat-fed rats.
authors: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors: Danna M
authors: DM
authors: Breen
authors: Jessica T Y
authors: JT
authors: Yue
authors: Brittany A
authors: BA
authors: Rasmussen
authors: Andrea
authors: A
authors: Kokorovic
authors: Grace W C
authors: GW
authors: Cheung
authors: Tony K T
authors: TK
authors: Lam
mesh_terms: D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism*; D004386:Duodenum / Q000201:enzymology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D043886:Receptor, Cholecystokinin A; D002766:Cholecystokinin; D051745:Protein Kinase C-delta; D005947:Glucose