POMC神经元在回肠转位术改善非肥胖2型糖尿病中的作用机制研究

The incidence of type 2 diabetes mellitus (T2DM) increased year by year, and caused a high morbidity and mortality. Ileal transposition (IT) could effectively improve type 2 diabetes mellitus with the high level of glucagon-like peptide 1 (GLP-1) and the activity of pro-opiomelanocortin (POMC) neurons. The POMC neurons are a specific population of arcuate nucleus neurons in the hypothalamus expressing receptors of GLP-1, involved in fuel balance and improvement of glucose. However, whether the POMC neurons are activated by GLP-1 and involved in the remission of T2DM after ileal transposition is still unclear. Therefore, the T2DM rat models underwent lateral ventricle catheter are built, and randomly divided into three groups: IT group, sham IT (S-IT) group and control group. GLP-1 level in plasma, CSF and section of POMC are measured at indicated time intervals before and after surgery. Afterwards each rat receives intracerebroventricular injection of GLP-1 antagonist, the fasting blood glucose, secretion of insulin and the activity of POMC neurons are also measured before and after injection. The data from a few successful models showed that POMC neurons were activated by increasing GLP-1 and glucose was improved after ileal transposition. Moreover, when receptors of GLP-1 were blocked, POMC neurons were inhibited and the remission of T2DM was withdrawn. Thus, POMC neurons might play an important role in the remission of type 2 diabetes after ileal transposition.

2型糖尿病的发病率逐年攀升引起较高的致残率和致死率。回肠转位术可持久地缓解2型糖尿病，并且术后血GLP-1水平显著升高，饱食中枢促黑素细胞皮质素原（POMC）神经元被激活。POMC神经元表达有GLP-1受体并且能调节能量平衡及血糖，然而POMC神经元是否由升高的GLP-1激活并参与回肠转位术改善糖尿病，目前还不得而知。因此本课题设计了接受侧脑室置管的2型糖尿病大鼠模型，分为回肠转位、假手术及空白对照组，在手术前后多个时间点动态监测及比较各组大鼠血、脑脊液GLP-1、POMC分泌量；然后侧脑室注射GLP-1拮抗剂，比较手术前后及拮抗前后各组大鼠血糖、胰岛素水平及POMC神经元的激活程度。预实验发现回肠转位术后糖尿病大鼠POMC神经元随GLP-1升高而激活，血糖被改善；GLP-1受体被拮抗后POMC神经元被抑制，改善的血糖也恶化。因此POMC神经元可能在回肠转位改善2型糖尿病中发挥重要作用。

2型糖尿病发病率日益增加，给患者带来痛苦，给社会带来经济负担。回肠转位术能有效改善2型糖尿病，但是其作用机制不清楚。本研究建立了一种复杂的动物模型：先后接受侧脑室置管和回肠转位术的2型糖尿病GK大鼠。通过对大鼠模型血糖、体重、摄食量、血及脑脊液中激素及各项指标的监测，然后对脑GLP-1受体拮抗复测血糖、摄食量、血及脑脊液中激素及各项指标来验证回肠转位术后GLP-1激素、POMC神经元调控血糖的作用。结果发现回肠转位术后2型糖尿病大鼠的血糖及外周胰岛素敏感性得到明显改善；血及脑脊液中GLP-1激素水平明显升高，并且脑脊液中GLP-1水平随血液中GLP-1水平变化而变化；下丘脑POMC神经元被激活；当脑GLP-1受体被拮抗时，血及脑脊液中GLP-1水平无明显变化，但POMC神经元激活数目减少，得到改善的糖尿病大鼠的血糖也重新恶化。该研究的结果证实了回肠转位术改善2型糖尿病的治疗效果，验证并支持我们关于“POMC 神经元在回肠转位术改善2 型糖尿病中发挥作用”的新假说，一方面有利于进一步研究中枢神经系统或者其他神经核在回肠转位术改善2 型糖尿病中的作用，揭示2型糖尿病的生理及病理机制。另一方面也有利于更深一层次研究针对中枢神经系统改善2型糖尿病机制的治疗方法，改善患者生存质量，较少患者及国家的经济负担。