title: Duodenal mucosal protein kinase C-δ regulates glucose production in rats.
abstract: OBJECTIVE
  Activation of protein kinase C (PKC) enzymes in liver and brain alters hepatic glucose metabolism, but little is known about their role in glucose regulation in the gastrointestinal tract. We investigated whether activation of PKC-δ in the duodenum is sufficient and necessary for duodenal nutrient sensing and regulates hepatic glucose production through a neuronal network in rats.
  
  
  METHODS
  In rats, we inhibited duodenal PKC and evaluated whether nutrient-sensing mechanisms, activated by refeeding, have disruptions in glucose regulation. We then performed gain- and loss-of-function pharmacologic and molecular experiments to target duodenal PKC-δ; we evaluated the impact on glucose production regulation during the pancreatic clamping, while basal levels of insulin were maintained.
  
  
  RESULTS
  PKC-δ was detected in the mucosal layer of the duodenum; intraduodenal infusion of PKC inhibitors disrupted glucose homeostasis during refeeding, indicating that duodenal activation of PKC-δ is necessary and sufficient to regulate glucose homeostasis. Intraduodenal infusion of the PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) specifically activated duodenal mucosal PKC-δ and a gut-brain-liver neuronal pathway to reduce glucose production. Molecular and pharmacologic inhibition of duodenal mucosal PKC-δ negated the ability of duodenal OAG and lipids to reduce glucose production.
  
  
  CONCLUSIONS
  In the duodenal mucosa, PKC-δ regulates glucose homeostasis.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kokorovic
authors.forename: Grace W C
authors.initials: GW
authors.lastname: Cheung
authors.forename: Danna M
authors.initials: DM
authors.lastname: Breen
authors.forename: Madhu
authors.initials: M
authors.lastname: Chari
authors.forename: Carol K L
authors.initials: CK
authors.lastname: Lam
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D000818:Animals; D004075:Diglycerides / Q000494:pharmacology*; D004386:Duodenum / Q000294:innervation / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007413:Intestinal Mucosa / Q000294:innervation / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009474:Neurons / Q000502:physiology; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004075:Diglycerides; C038237:1-oleoyl-2-acetylglycerol; D051745:Protein Kinase C-delta; D005947:Glucose