Duodenal Activation of cAMP-Dependent Protein Kinase Induces Vagal Afferent Firing and Lowers Glucose Production in Rats
Duodenal Activation of cAMP-Dependent Protein Kinase Induces Vagal Afferent Firing and Lowers Glucose Production in Rats
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DOI：
10.1053/j.gastro.2011.12.053
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发表时间：
2012-04-01
期刊：
影响因子：
29.4
通讯作者：
Lam, Tony K. T.
中科院分区：
文献类型：
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作者：
Rasmussen, Brittany A.;Breen, Danna M.;Lam, Tony K. T.
背景与目的：十二指肠感知营养物质以维持能量和葡萄糖的稳态，但对其中的信号传导和神经元机制知之甚少。我们测试了十二指肠腺苷3′，5′-环单磷酸腺苷（cAMP）依赖性蛋白激酶A （PKA）的激活对于胆囊收缩素（CCK）信号触发迷走神经传入放电和调节葡萄糖产生是否足够和必要。方法：在大鼠中，我们选择性地激活十二指肠PKA，并评估胰腺（基础胰岛素）胰夹和迷走神经传入放电期间葡萄糖动力学的变化。通过十二指肠内输注PKA激动剂（Sp-cAMPS）或CCK1受体激动剂（CCK-8）抑制十二指肠PKA激活来评估十二指肠PKA信号在葡萄糖调节中的需求。我们还评估了神经网络的参与和十二指肠PKA激活对高脂肪饮食大鼠的代谢影响。结果：在对照大鼠中，十二指肠内输注sp - camp激活了十二指肠PKA，降低了葡萄糖的产生，并与迷走神经传入放电增加有关。p- camp与PKA抑制剂H89或rp - camp共输注后，十二指肠sp - camp对代谢和神经元的影响均为阴性。联合输注丁卡因、迷走背复合体内含有n -甲基- d -天冬氨酸（NMDA）受体的nr1的分子和药理学抑制或肝迷走神经切断术均可抑制其代谢作用。在对照组大鼠中，抑制十二指肠PKA阻断了十二指肠CCK-8减少葡萄糖产生的能力，而在高脂肪饮食的大鼠中，十二指肠sp - camp绕过十二指肠CCK抵抗，激活十二指肠PKA并降低葡萄糖产生。结论：我们确定了十二指肠PKA信号的神经糖调节功能。
BACKGROUND & AIMS: 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.