Toronto General Research Institute, University Health Network, Toronto, Canada.
Gastroenterology. 2011 Nov;141(5):1720-7. doi: 10.1053/j.gastro.2011.06.042. Epub 2011 Jun 23.
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-δ in the duodenum is sufficient and necessary for duodenal nutrient sensing and regulates hepatic glucose production through a neuronal network in rats.
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.
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.
In the duodenal mucosa, PKC-δ regulates glucose homeostasis.
蛋白激酶 C（PKC）在肝脏和大脑中的激活会改变肝脏的葡萄糖代谢，但对于其在胃肠道葡萄糖调节中的作用知之甚少。我们研究了十二指肠中 PKC-δ的激活是否足以且必需用于十二指肠营养感应，并通过大鼠中的神经网络调节肝葡萄糖生成。
在大鼠中，我们抑制十二指肠 PKC，并评估再喂养激活的营养感应机制是否在葡萄糖调节中出现中断。然后，我们进行了药理学和分子实验以靶向十二指肠 PKC-δ，以获得和丧失功能；我们评估了在维持基础胰岛素水平的情况下，胰腺夹闭期间对葡萄糖生成调节的影响。
PKC-δ在十二指肠黏膜层中被检测到；十二指肠内输注 PKC 抑制剂在再喂养期间破坏了葡萄糖稳态，表明十二指肠 PKC-δ的激活足以且必需调节葡萄糖稳态。1-油酰基-2-乙酰基-sn-甘油（OAG）的十二指肠内输注特异性激活十二指肠黏膜 PKC-δ和肠-脑-肝神经元途径，以减少葡萄糖生成。十二指肠黏膜 PKC-δ 的分子和药理学抑制消除了十二指肠 OAG 和脂质降低葡萄糖生成的能力。
在十二指肠黏膜中，PKC-δ调节葡萄糖稳态。
