Division of Diabetology and Endocrinology, Kanazawa Medical University, Ishikawa Japan.
Am J Physiol Endocrinol Metab. 2013 Aug 1;305(3):E376-87. doi: 10.1152/ajpendo.00565.2012. Epub 2013 May 28.
We previously reported that glucagon-like peptide-1 (GLP-1) appearance in the portal vein facilitates hepatic vagal afferent activity, and this further augments reflexively the pancreatic vagal efferents in anesthetized rats, suggesting a neuroincretin effect of GLP-1. To determine whether the GLP-1-induced vagal pathways lead to a neuronal-mediated component (NMC) of insulin secretion, we infused GLP-1 at a physiological or pharmacological dose (1 or 3 pmol·kg(-1)·min(-1), respectively) into the portal vein in conscious rats with selective hepatic vagotomy (Vagox) or sham operation (Sham). The experiments consisted of two sequential 10-min intraportal infusions (P1 and P2): glucose at a physiological rate (56 μmol·kg(-1)·min(-1)) in P1 and the glucose plus GLP-1 or vehicle in P2. Under arterial isoglycemia across the groups, the physiological GLP-1 infusion in Sham augmented promptly and markedly arterial insulin levels, approximately twofold the levels in glucose alone infusion (P < 0.005), and insulin levels in Vagox diminished apparently (P < 0.05). Almost 60% of the GLP-1-induced insulin secretion (AUC) in Sham met the NMC, i.e., difference between insulin secretion in Sham and Vagox, (AUC 976 ± 65 vs. 393 ± 94 pmol·min/l, respectively, P < 0.005). Intraportal pharmacological GLP-1 infusion further augmented insulin secretion in both groups, but the NMC remained in 46% (NS; Sham vs. Vagox). In contrast, "isoglycemic" intravenous GLP-1 infusion (3 pmol·kg(-1)·min(-1)) evoked an equal insulin secretion in both groups. Thus, the present results indicate that GLP-1 appearing in the portal vein evokes a powerful neuronal-mediated insulinotropic effect, suggesting the neuroincretin effect.
我们之前曾报道过，胰高血糖素样肽-1（GLP-1）在门静脉中的出现有助于肝迷走传入活动，这进一步反射性地增强了麻醉大鼠的胰腺迷走传出活动，提示 GLP-1 具有神经内分泌素的作用。为了确定 GLP-1 诱导的迷走神经通路是否导致胰岛素分泌的神经元介导成分（NMC），我们在选择性肝迷走神经切断术（Vagox）或假手术（Sham）的清醒大鼠中以生理或药理剂量（分别为 1 或 3 pmol·kg(-1)·min(-1))门静脉内输注 GLP-1。实验包括两个连续的 10 分钟门静脉内输注（P1 和 P2）：P1 中以生理速率（56 μmol·kg(-1)·min(-1))输注葡萄糖，P2 中输注葡萄糖加 GLP-1 或载体。在各组动脉血糖恒定时，Sham 中的生理 GLP-1 输注迅速且明显地增加了动脉胰岛素水平，约为单独输注葡萄糖时的两倍（P < 0.005），而 Vagox 中的胰岛素水平明显下降（P < 0.05）。Sham 中约 60%的 GLP-1 诱导的胰岛素分泌（AUC）符合 NMC，即 Sham 和 Vagox 之间胰岛素分泌的差异，（AUC 分别为 976 ± 65 和 393 ± 94 pmol·min/l，P < 0.005）。门静脉内药理学 GLP-1 输注进一步增加了两组的胰岛素分泌，但 NMC 仍占 46%（NS；Sham 与 Vagox 相比）。相比之下，“等血糖”静脉内 GLP-1 输注（3 pmol·kg(-1)·min(-1))在两组中引起了相等的胰岛素分泌。因此，本研究结果表明，门静脉中出现的 GLP-1 引发了强大的神经元介导的胰岛素促分泌作用，提示了神经内分泌素的作用。
