title: Duodenal activation of cAMP-dependent protein kinase induces vagal afferent firing and lowers glucose production in rats.
abstract: OBJECTIVE
  The duodenum senses nutrients to maintain energy and glucose homeostasis, but little is known about the signaling and neuronal mechanisms involved. We tested whether duodenal activation of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) is sufficient and necessary for cholecystokinin (CCK) signaling to trigger vagal afferent firing and regulate glucose production.
  
  
  METHODS
  In rats, we selectively activated duodenal PKA and evaluated changes in glucose kinetics during the pancreatic (basal insulin) pancreatic clamps and vagal afferent firing. The requirement of duodenal PKA signaling in glucose regulation was evaluated by inhibiting duodenal activation of PKA in the presence of infusion of the intraduodenal PKA agonist (Sp-cAMPS) or CCK1 receptor agonist (CCK-8). We also assessed the involvement of a neuronal network and the metabolic impact of duodenal PKA activation in rats placed on high-fat diets.
  
  
  RESULTS
  Intraduodenal infusion of Sp-cAMPS activated duodenal PKA and lowered glucose production, in association with increased vagal afferent firing in control rats. The metabolic and neuronal effects of duodenal Sp-cAMPS were negated by coinfusion with either the PKA inhibitor H89 or Rp-CAMPS. The metabolic effect was also negated by coinfusion with tetracaine, molecular and pharmacologic inhibition of NR1-containing N-methyl-d-aspartate (NMDA) receptors within the dorsal vagal complex, or hepatic vagotomy in rats. Inhibition of duodenal PKA blocked the ability of duodenal CCK-8 to reduce glucose production in control rats, whereas duodenal Sp-cAMPS bypassed duodenal CCK resistance and activated duodenal PKA and lowered glucose production in rats on high-fat diets.
  
  
  CONCLUSIONS
  We identified a neural glucoregulatory function of duodenal PKA signaling.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Rasmussen
authors.forename: Danna M
authors.initials: DM
authors.lastname: Breen
authors.forename: Ping
authors.initials: P
authors.lastname: Luo
authors.forename: Grace W C
authors.initials: GW
authors.lastname: Cheung
authors.forename: Clair S
authors.initials: CS
authors.lastname: Yang
authors.forename: Biying
authors.initials: B
authors.lastname: Sun
authors.forename: Andrea
authors.initials: A
authors.lastname: Kokorovic
authors.forename: Weifang
authors.initials: W
authors.lastname: Rong
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059305:Diet, High-Fat; D004386:Duodenum / Q000187:drug effects / Q000201:enzymology* / Q000294:innervation*; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006706:Homeostasis; D006727:Hormone Antagonists / Q000494:pharmacology; D008099:Liver / Q000294:innervation* / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
chemical_list: D020536:Enzyme Activators; D006727:Hormone Antagonists; C409466:NR1 NMDA receptor; D047428:Protein Kinase Inhibitors; D043887:Receptor, Cholecystokinin B; D016194:Receptors, N-Methyl-D-Aspartate; D002766:Cholecystokinin; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose