Duodenal Mucosal Protein Kinase C-δ Regulates Glucose Production in Rats

BACKGROUND & AIMS: 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-delta 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-delta; we evaluated the impact on glucose production regulation during the pancreatic clamping, while basal levels of insulin were maintained. RESULTS: PKC-delta 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-delta 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-delta and a gutbrain-liver neuronal pathway to reduce glucose production. Molecular and pharmacologic inhibition of duodenal mucosal PKC-delta negated the ability of duodenal OAG and lipids to reduce glucose production. CONCLUSIONS: In the duodenal mucosa, PKC-delta regulates glucose homeostasis.