Duodenal PKC-δ and cholecystokinin signaling axis regulates glucose production.

OBJECTIVE:Metabolism of long-chain fatty acids within the duodenum leads to the activation of duodenal mucosal protein kinase C and the cholecystokinin (CCK)-A receptor to lower glucose production through a neuronal network. However, the interfunctional relationship between duodenal and CCK remains elusive. Although long-chain fatty acids activate to stimulate the release of CCK in CCK-secreting cells, CCK has also been found to activate duanyu1531-δ in pancreatic acinar cells. We here evaluate whether activation of duodenal mucosal duanyu1531-δ lies upstream (and/or downstream) of CCK signaling to lower glucose production. RESEARCH DESIGN AND METHODS:We first determined with immunofluorescence whether duanyu1531-δ and CCK were colocalized within the duodenal mucosa. We then performed gain- and loss-of-function experiments targeting duodenal duanyu1531-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 duanyu1531-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 duanyu1531 activator negated the ability of duodenal mucosal duanyu1531-δ activation to lower glucose production during the pancreatic clamps in normal rats. Conversely, molecular and pharmacological inhibition of duodenal duanyu1531-δ did not negate the ability of the duodenal CCK-A receptor agonist CCK-8 to lower glucose production, indicating that activation of duodenal duanyu1531-δ lies upstream (and not downstream) of CCK signaling. Finally, intraduodenal duanyu1531 activator infusion failed to lower glucose production in rats with high-fat diet-induced duodenal CCK resistance. CONCLUSIONS:In summary, activation of duodenal duanyu1531-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.

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