Department of Medicine, Division of Digestive Diseases and Brain Research Institute, CURE, Digestive Diseases Research Center, University of California, Los Angeles, CA, USA.
Neuroscience. 2010 Aug 25;169(2):706-19. doi: 10.1016/j.neuroscience.2010.05.008. Epub 2010 May 8.
We identified ventrolateral medullary nuclei in which thyrotropin-releasing hormone (TRH) regulates glucose metabolism by modulating autonomic activity. Immunolabeling revealed dense prepro-TRH-containing fibers innervating the rostroventrolateral medulla (RVLM) and nucleus ambiguus (Amb), which contain, respectively, pre-sympathetic motor neurons and vagal motor neurons. In anesthetized Wistar rats, microinjection of the stable TRH analog RX77368 (38-150 pmol) into the RVLM dose-dependently and site-specifically induced hyperglycemia and hyperinsulinemia. At 150 pmol, blood glucose reached a peak of 180+/-18 mg% and insulin increased 4-fold. The strongest hyperglycemic effect was induced when RX77368 was microinjected into C1 area containing adrenalin cells. Spinal cord transection at cervical-7 abolished the hyperglycemia induced by RVLM RX77368, but not the hyperinsulinemic effect. Bilateral vagotomy prevented the rise in insulin, resulting in a prolonged hyperglycemic response. The hyperglycemic and hyperinsulinemic effects of the TRH analog in the RVLM was peptide specific, since angiotensin II or a substance P analog at the same dose had weak or no effects. Microinjection of RX77368 into the Amb stimulated insulin secretion without influencing glucose levels. In conscious type 2 diabetic Goto-Kakizaki (GK) rats, intracisternal injection of RX77368 induced a remarkably amplified hyperglycemic effect with suppressed insulin response compared to Wistar rats. RX77368 microinjected into the RVLM of anesthetized GK rats induced a significantly potentiated hyperglycemic response and an impaired insulin response, compared to Wistar rats. These results indicate that the RVLM is a site at which TRH induces sympathetically-mediated hyperglycemia and vagally-mediated hyperinsulinemia, whereas the Amb is mainly a vagal activating site for TRH. Hyperinsulinemia induced by TRH in the RVLM is not secondary to the hyperglycemic response. The potentiated hyperglycemic and suppressed hyperinsulinemic responses in diabetic GK rats indicate that an unbalanced "sympathetic-over-vagal" activation by TRH in brainstem RVLM contributes to the pathophysiology of impaired glucose homeostasis in type 2 diabetes.
我们发现，促甲状腺素释放激素（TRH）通过调节自主活动来调节腹外侧延髓核中的葡萄糖代谢。免疫标记显示，密集的含有前促甲状腺素释放激素的纤维支配头腹外侧延髓（RVLM）和疑核（Amb），其中分别包含交感运动神经元和迷走运动神经元。在麻醉的 Wistar 大鼠中，将稳定的 TRH 类似物 RX77368（38-150 pmol）微注射到 RVLM 中，剂量依赖性地、特异性地诱导高血糖和高胰岛素血症。在 150 pmol 时，血糖达到 180±18mg%的峰值，胰岛素增加了 4 倍。当 RX77368 微注射到含有肾上腺素细胞的 C1 区时，会引起最强的高血糖效应。颈 7 脊髓切断术消除了 RVLM RX77368 引起的高血糖，但不消除高胰岛素血症效应。双侧迷走神经切断术阻止了胰岛素的升高，导致高血糖反应延长。RVLM 中 TRH 类似物的高血糖和高胰岛素效应是肽特异性的，因为血管紧张素 II 或同样剂量的 P 物质类似物只有微弱或没有作用。将 RX77368 微注射到 Amb 中会刺激胰岛素分泌而不影响血糖水平。在清醒的 2 型糖尿病 Goto-Kakizaki（GK）大鼠中，与 Wistar 大鼠相比，RX77368 经 cisternal 注射诱导出明显放大的高血糖效应，胰岛素反应受到抑制。与 Wistar 大鼠相比，麻醉 GK 大鼠 RVLM 中 RX77368 的微注射诱导出明显增强的高血糖反应和受损的胰岛素反应。这些结果表明，RVLM 是 TRH 诱导交感神经介导的高血糖和迷走神经介导的高胰岛素血症的部位，而 Amb 主要是 TRH 的迷走神经激活部位。RVLM 中 TRH 诱导的高胰岛素血症不是高血糖反应的继发性。糖尿病 GK 大鼠中增强的高血糖和抑制的高胰岛素血症反应表明，脑桥 RVLM 中 TRH 引起的不平衡的“交感神经过度迷走神经”激活导致 2 型糖尿病葡萄糖稳态受损的病理生理学。
