Duodenal PKC-δ and Cholecystokinin Signaling Axis Regulates Glucose Production

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 12; pp. 3148 - 3153
• Main Authors: BREEN, Danna M, YUE, Jessica T. Y, RASMUSSEN, Brittany A, KOKOROVIC, Andrea, CHEUNG, Grace W. C, LAM, Tony K. T
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2011
• Subjects: Animals; Biological and medical sciences; Cholecystokinin - metabolism; Diabetes. Impaired glucose tolerance; Duodenum - enzymology; Duodenum - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fluorescent Antibody Technique; Glucose - metabolism; Male; Medical sciences; Metabolism; Protein Kinase C-delta - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A - metabolism; Signal Transduction - physiology; Endocrinopathy; Signal transduction; Cholecystokinin; Glucose; Neuropeptide; Diabetes mellitus
• DOI: 10.2337/db11-0852
• ISSN: 0012-1797

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. 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. 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. 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.