POMC神经元在回肠转位术缓解2型糖尿病中的作用和机制
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摘要
第一部分回肠转位术对非肥胖2型糖尿病的缓解作用
背景
2型糖尿病(Type2diabetes mellitus, T2DM)是在世界范围内广泛流行的危害人类健康的重要疾病,目前全球患者人数估计在2.8亿人左右,并且发病率逐年上升,预计到2030年时患者人数将超过3.6亿人。到目前为止还没有根治2型糖尿病的方法,当前的治疗方法包括饮食,运动,口服降糖药,注射胰岛素等措施目的在于控制血糖,预防并发症的发生。尽管通过严格地控制血糖,能明显降低糖尿病并发症的发生率,但是由于患者依从性的差异,糖尿病仍造成较高的致残率和致死率。越来越多的动物及临床研究表明各种减肥手术,特别是回肠转位术对2型糖尿病有较好的缓解作用。但是其机制目前还不明确,主要的解释有：减肥效果带来的抗糖尿病作用和不依赖减肥效果的抗糖尿病作用。后者是指胃肠道结构改变引起的胃肠道激素的变化所造成的血糖的改善,还可分为前肠假说和后肠假说。每种解释都相互独立,各有倾向。目前越来越多的2型糖尿病是非肥胖或者是不伴有病态肥胖的患者,对于非肥胖2型糖尿病患者,回肠转位术是否仍然存在确切的改善作用呢?没有了明显的减肥效果,其血糖的改善到底是哪种机制主导的呢?其之间有没有相互作用?
为了探讨回肠转位术是否对非肥胖2型糖尿病有缓解作用,并讨论其缓解机制,本研究构建了非肥胖2型糖尿病回肠转位术动物模型。通过手术组与假手术组动物模型的比较,观察糖尿病的改善状况。并通过对代表各个机制假说重要激素等指标变化的对比与分析,讨论术后糖尿病改善的机制。
方法
本研究采用非肥胖2型糖尿病GK大鼠作为动物模型,随机分为3组：回肠转位术组(IT组)、回肠转位假手术组(S-IT组)、及空白对照组。回肠转位术是将距离回盲部5cm的一段10cm的回肠上提到距离Treiz韧带10cm处吻合；假手术组给予同样的横断位置,但是原位吻合。然后比较术前及术后各个实验组之间大鼠的摄食量及体重的变化、血糖状况、β细胞功能、瘦素水平、GLP-1水平及GIP水平等检测指标的变化。
结果
1.术后IT组和S-IT组大鼠的进食量和体重都明显下降(P<0.05),但是S-IT组大鼠的摄食量和体重在术后迅速回升,到术后第8周时与空白对照组无统计学差异(P>0.05)。而IT组大鼠的摄食量及体重一直维持在较低水平,始终低于S-IT组及空白对照组(P<0.05)。
2.术后2周内IT组和S-IT组的血糖及口服葡萄糖耐量实验的AUCOGTT(?)低于术前(P<0.05),但是S-IT组的血糖后期与空白对照组无统计学差异(P>0.05),而IT组大鼠的血糖及AUCOGTT都显著低于S-IT组及空白对照组(P<0.05)。
3.对胰岛素耐量实验各个时间点血糖的比较,术后IT组非肥胖2型糖尿病大鼠的胰岛素抵抗得到显著的改善(P<0.05)；S-IT组大鼠的胰岛素抵抗无明显改善,并进行性恶化,与空白对照组无统计学差异(P>0.05)。
4.通过空腹C-肽、空腹胰岛素的酶联免疫吸附试验(ELISA)检测及葡萄糖-胰岛素释放实验发现：IT组非肥胖2型糖尿病大鼠p细胞分泌胰岛素的量增加(P<0.05),而S-IT组和空白对照组在术前术后无统计学差异(P>0.05)。
5.IT组非肥胖2型糖尿病大鼠术后的空腹GLP-1水平增高,糖负荷后GLP-1分泌量增多(P<0.05)。而S-IT组和空白对照组在术前术后无统计学差异(P>0.05)。
6.3组大鼠的空腹GIP及糖负荷后GIP分泌量术前及术后均无统计学差异(P>0.05)。
7.IT组非肥胖2型糖尿病大鼠术前及术后的空腹瘦素均无统计学差异(P>0.05),但是糖负荷后AUCLeptin升高明显(P<0.05)。空白对照组术后36周的空腹瘦素比术前高(P<0.05)。
结论
本部分实验证实：
1.回肠转位术对非肥胖2型糖尿病大鼠有明显、持久的抑制摄食的作用,使其体重增加得缓慢。
2.回肠转位术对非肥胖2型糖尿病大鼠的血糖有迅速、明显、持久的改善作用。
3.探究回肠转位术对非肥胖2型糖尿病大鼠血糖改善的作用机制发现：回肠转位术对非肥胖2型糖尿病大鼠的胰岛素抵抗有显著和持久的改善作用,并且对非肥胖2型糖尿病大鼠的β细胞有改善作用,使胰岛素分泌量增加。
4.对相关激素检测发现：回肠转位术后非肥胖2型糖尿病大鼠的血GLP-1水平增高,GIP分泌量术前及术后相比无统计学差异,瘦素分泌量的变化不大,但是瘦素分泌的敏感性改善了。统计学分析,GLP-1水平的升高对血糖的影响较大,呈线性相关。GIP及瘦素的改变对IT手术改善血糖的影响无统计学意义。
上述发现表明,回肠转位术能显著改善非肥胖2型糖尿病患者的血糖,改善胰岛素抵抗,增加p细胞的胰岛素分泌量。对有关参与回肠转位术改善血糖机制可能激素的统计学分析显示,手术引起的GLP-1分泌增加发挥着主要作用。有关GLP-1的作用机制及下一步作用位点,尚待更深入的研究。
第二部分下丘脑POMC神经元在回肠转位术缓解非肥胖2型糖尿病中的作用
背景
代谢综合征是多种代谢成分异常聚集的病理状态,葡萄糖代谢异常是其中一种表现。生理状态下哺乳动物的个体都处于精确的能量自动平衡中。下丘脑是调节机体能量活动的重要部位,有着许多的神经核团,参与着复杂的神经生理活动。POMC神经元作为存在于下丘脑的一类重要的神经元,可以抑制肥胖,产生较强的厌食感,被认为是食欲相关肽神经元,调控着摄食和机体能量平衡。该神经元分泌的POMC及其衍生肽等被认为是抑制摄食和增加能量消耗的肽类物质。POMC缺陷的大鼠常常伴有肥胖及糖尿病的症状。生理状态下POMC神经元可以被升高的GLP-1所激活,也能被降低的血糖水平所抑制。回肠转位术使得非肥胖2型糖尿病大鼠术后GLP-1的水平升高,但是血糖水平降低。其POMC (?)中经元是被激活还是抑制?回肠转位术对2型糖尿病的改善作用是不是通过POMC (?)中经元发挥作用的?到目前为止还没有相关的报道。
因此本研究通过构建好的2型糖尿病回肠转位术模型,观察下丘脑中激活的POMC神经元数量及POMC翻译和表达的量。通过对回肠转位手术组与其他组动物模型的比较,探讨POMC神经元在2型糖尿病血糖改善中的作用,为揭示2型糖尿病发病机制及回肠转位术缓解2型糖尿病机制提供线索。
方法
将本实验第一部分存活的3组GK大鼠,在术后36周时处死,采集下丘脑组织和脑脊液等标本。免疫组织化学染色观察POMC神经元,对比组间大鼠下丘脑POMC神经元的个数；测量下丘脑POMC的mRNA转录量和POMC多肽的表达量；测量脑脊液中GLP-1、胰岛素和瘦素的含量,比较组间是否有统计学差异。
结果
1.接受回肠转位术的非肥胖2型糖尿病大鼠,术后36周下丘脑组织POMC mRNA的量比S-IT组和空白对照组都高(P<0.05),而S-IT组与空白对照组相比没有显著的差异(P>0.05)。
2.IT组大鼠下丘脑POMC多肽含量比S-IT组高1.5倍(P<0.05),比空白对照组高1.6倍(P<0.05),S-IT组与空白对照组相比没有显著的差异(P>0.05)。
3.IT组大鼠丘脑的POMC神经元个数多于假手术组和空白对照组(P<0.05)。
4.经过ELISA检测,IT组大鼠脑脊液中GLP-1的浓度显著高于S-IT组大鼠及空白对照组大鼠(P<0.05)。
5.IT组、S-IT组和空白对照组大鼠脑脊液中胰岛素的浓度无统计学差异(P>0.05)。
6.IT组、S-IT组和空白对照组大鼠脑脊液中瘦素水平无统计学差异(P>0.05)。
结论
本部分实验证实：
1.回肠转位术后非肥胖2型糖尿病大鼠下丘脑组织POMC mRNA的转录增多,POMC多肽表达增多。
2.接受回肠转位术的非肥胖2型糖尿病大鼠下丘脑组织POMC神经元的数量增多。根据POMC神经元及POMC的作用,它可能参与回肠转位术改善血糖的机制。
3.进一步探讨POMC被激活的原因,回肠转位术引起的GLP-1分泌增加可能发挥着主要作用。
该实验首次将神经元作用与回肠转位术改善糖尿病联系在一起,发现其改变及可能的机制,为研究2型糖尿病及手术改善糖尿病提供新的思路。
第三部分下丘脑POMC神经元在回肠转位术缓解非肥胖2型糖尿病中的机制
背景
POMC神经元被认为是食欲相关肽神经元,调控着摄食和机体能量平衡。它能够接受来自外周的信号,如：迷走神经传导的来自口咽、胃肠牵张感觉及肝脏代谢活动等所形成的刺激作用；循环中胃肠道分泌的脑肠肽及各种营养物质本身等。通过对这些信号的感知、整合反馈成脑内神经因子的形式。这些神经因子与其他的神经元相互联系,形成网络调控,对机体实时精确的应答反应。前部分实验发现IT手术后的大鼠血及脑脊液中GLP-1的水平明显增高。鉴于GLP-1可以通过自由扩散穿过血脑屏障,并且POMC神经元上有GLP-1的受体,因此可以推断POMC神经元可能被升高的GLP-1所激活。但是非肥胖2型糖尿病被回肠转位术所缓解的机制是否有激活的POMC (?)神经元参与呢?
为了更好地探讨下丘脑POMC神经元在回肠转位术缓解非肥胖2型糖尿病中的机制,我们在接受侧脑室置管的非肥胖2型糖尿病大鼠中重新构建了回肠转位术模型。比较术前及术后脑脊液中多个时间点GLP-1水平的变化及血糖的变化,并且在大鼠侧脑室中给予GLP-1受体的拮抗齐(?) Exendin(9-39),观察拮抗后大鼠2型糖尿病的症状及POMC (?)神经元的变化。
方法
采用非肥胖2型糖尿病GK大鼠作为动物模型,给予大鼠侧脑室置管术,将存活的GK大鼠随机分为如下2组：IT组和S-IT组。术前及术后各个时间点监测体重、摄食、血糖及GLP-1等多个指标。
在回肠转位术后4周时,对两组大鼠同时进行侧脑室GLP-1拮抗剂Exendin(9-39)的注射,然后比较两组大鼠的血糖及摄食等指标,观察GLP-1受体被拮抗后回肠转位术改善血糖的效果有无改变。术后6周处死所有大鼠,处死之前对IT组大鼠给同样剂量的Exendin(9-39),收集大鼠下丘脑等组织,组间观察比较GLP-1受体被拮抗后POMC神经元的状态。
结果
1.接受侧脑室置管的非肥胖2型糖尿病大鼠给予回肠转位术和假回肠转位术,术后4周IT组大鼠7只大鼠S-IT组5只大鼠一直存活到实验结束,但是IT手术组仅有6只大鼠的统计数据。
2.两组大鼠术前的体重及摄食量无统计学差异(P>0.05)。回肠转位术后IT组大鼠的进食量显著低于S-IT组大鼠,体重也明显低于S-IT大鼠(P<0.05)。
3.两组大鼠的血糖及AUCOGTT术前无显著性差异(P>0.05),回肠转位术后都出现了不同程度的血糖下降。IT组大鼠的血糖下降后始终处于较为平稳的状态,低于术前血糖水平(P<0.05)；S-IT组大鼠的血糖下降后呈现缓慢回升的趋势,与术前比较无统计学差异(P>0.05)。AUCOGTT曲线变化同血糖变化一致。IT组大鼠的AUCOGTT在下降后始终处于较低的状态,而S-IT组大鼠的AUCOGTT降低的不明显(P>0.05)。验证了回肠转位术对非肥胖2型糖尿病的缓解作用。
4.回肠转位术后IT组大鼠脑脊液GLP-1水平不断升高,显著高于术前水平(P<0.05)。但是S-IT组GLP-1的水平波动不大,术后与术前水平相比无统计学意义(P>0.05)。
5.回肠转位术后4周注射Exendin(9-39)前,IT组大鼠的摄食量比S-IT组大鼠少(P<0.05)。注射后IT组大鼠的摄食量明显增加(P<0.05),与S-IT组大鼠的摄食量相比无统计学差异(P>0.05)。S-IT组大鼠的摄食量与注射前相比无统计学差异(P>0.05)。注射前后两组大鼠的体重均无统计学变化(P>0.05)。
6.注射Exendin(9-39)前,IT组大鼠的血糖低于S-IT组大鼠的血糖(P<0.05)。注射Exendin(9-39)后,IT组大鼠的血糖升高(P<0.05),与S-IT组无统计学差异(P>0.05)。S-IT组大鼠的血糖注射前后相比无统计学差异(P>0.05)。OGTT实验也发现注射Exendin(9-39)后,IT组大鼠的血糖峰值与S-IT组大鼠无统计学差异(P>0.05)。
7.回肠转位术后6周注射Exendin(9-39)后IT组大鼠的下丘脑组织POMC mRNA的量比S-IT组低(P<0.05)。
8.术后6周注射Exendin(9-39)后IT组大鼠的下丘脑组织POMC多肽含量比S-IT组低(P<0.05)。
9.术后6周注射Exendin(9-39)后IT组大鼠丘脑的POMC神经元个数少于S-IT组(P<0.05)。
10.术后6周注射Exendin(9-39)后IT组大鼠脑脊液中GLP-1的浓度高于S-IT组大鼠(P<0.05)。胰岛素的浓度无统计学差异(P>0.05)。
结论
本部分的实验结果表明：
1.通过建立侧脑室置管的非肥胖2型糖尿病大鼠回肠转位术和假回肠转位术模型,再一次证实了回肠转位术对非肥胖2型糖尿病的治疗作用。摄食量减少,血糖及AUCOGTT得到明显的改善。
2.回肠转位术后非肥胖2型糖尿病大鼠脑脊液GLP-1随术后时间不断升高,显著高于术前水平。
3.术后注射GLP-1受体拮抗剂Exendin(9-39)能使非肥胖2型糖尿病大鼠已经改善的糖尿病症状恶化,血糖升高,摄食量增加。
4.术后注射Exendin(9-39)可以明显抑制非肥胖2型糖尿病大鼠下丘脑组织POMC神经元。使其mRNA的表达减少,POMC多肽含量降低。但大鼠脑脊液中GLP-1的浓度仍高于S-IT组大鼠。
因此非肥胖2型糖尿病大鼠下丘脑POMC神经元在回肠转位术后是被GLP-1所激活的,并且激活的POMC神经元在回肠转位术缓解非肥胖2型糖尿病中发挥重要作用。这为回肠转位术应用于临床以及进一步研究2型糖尿病提供一定的实验基础。
Part1:the remission of type2diabetes mellitus of non-obese rats after ileal transposition
Background
Type2diabetes mellitus (T2DM) presently afflicts more than280million people worldwide, and the morbidity is increasing year by year. It was expected that there would be more than360million persons by2030. However, there is no radical treatment on type2diabetes so far. Current therapies, including diet, exercise, and medication, could control plasma glucose and reduce the incidence of the complications, but the morbidity and mortality are increasing gradually because of poor compliance of patients. Interestingly, Bariatric surgeries, especially ileal transposition (IT), are shown to be an effective means of improving T2DM, but the mechanism is still unclear. The main explanations indicate that the remarkable anti-diabetic effects result from weight loss and a yet uncharacterized weight-independent mechanism. The latter is believed to be related to the hormonal changes caused by obvious physiological alterations of distal ileum after surgery. Previous studies about excluding foregut and interposing hindgut lead to the "foregut hypothesis" and "hindgut hypothesis". These explanations are all supported by mounting evidences and not mutually exclusive. However, more and more T2DM patients are not obese and have no excessive weight to loss. Could ileal transposition improve non-obese T2DM? Which mechanism is dominant without the effect of weight loss? And is there synergistic effect of these hypotheses?
To confirm the effect of ileal transposition on non-obese T2DM and investigate the mechanism of remission, the non-obese T2DM rats received ileal transposition and sham procedures. Then the changes in glucose homeostasis, insulin sensitivity,(3-cell function and many hormonal levels in plasma were compared between groups.
Methods
Non-obese diabetic Goto-Kakizaki (GK) rats were assigned to three groups randomly:IT, sham IT (S-IT) and control group. IT was performed as described:a10cm ileal segment5cm proximal to the ileocecal valve was transected, transposed and anastomosed isoperistaltically with the jejunal10cm distal to the ligament of Treitz. Sham surgeries involved the same abdominal incisions, transections and re-anastomosis of the gastrointestinal tract at multiple sites corresponding to IT, except no ileum transposition. Subsequently, the weight, food intake, beta-cell function, the level of glucose, leptin, glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide (GIP) were measured and compared between groups.
Results
1. The food intake and weight of IT group and S-IT group significantly decreased after operation (P<0.05), but those of S-IT group restored in2weeks. There were no statistic differences in food intake and weight between S-IT group and control group at postoperative week-8(P>0.05). While the food intake and weight of IT group kept low and stable level, were less than those of the other two groups (P<0.05).
2. The glucose and AUCOGTT of IT group and S-IT group significantly decreased after operation (P<0.05), but those of S-IT group restored in2weeks. After that the glucose and AUCOGTT of IT group were significantly less than those of S-IT group and control group (P<0.05).
3. The insulin sensitivity was improved after operation in IT group but S-IT group (P<0.05). There were no statistic differences in insulin sensitivity between S-IT group and control group (P>0.05).
4. The secreted insulin was more after ileal transposition in IT group but S-IT group (P<0.05), while there were no statistic differences in secreted insulin before and after operation in S-IT and control groups (P>0.05).
5. The fasting GLP-1level in IT group rats was higher after operation (P<0.05), while there were no statistic differences before and after operation in S-IT group and control group (P>0.05).
6. There were no statistic differences in GIP level between3groups before and after operation (P>0.05).
7. The fasting leptin level in control group at postoperative week-36was higher than that before operation (P<0.05). There were no statistic differences in IT group before and after operation (P>0.05).
Conclusions
This study provides experimental evidences that ileal transposition could restrain food intake, control the weight and improve the glucose of non-obese T2DM rats. After ileal transposition, the insulin resistance and status of beta-cells are improved. These improvements might result from higher GLP-1level in plasma, and there were no statistic changes in GIP and leptin level in plasma before and after operation.
Part2:the changes of POMC neurons in non-obese type2diabetes mellitus rats received ileal transposition
Background
The metabolic syndrome is a pathological state of accumulation of a variety of metabolic components, and always leads to type2diabetes mellitus. Actually every mammalian individual could keep a precise automatic energy balance in physiological state. The pro-opiomelanocortin (POMC) neurons, a specific population of arcuate nucleus neurons in the hypothalamus, are typical neurons involved in fuel balance. Along with other central neurons, they regulate energy homeostasis, balance energy intake, expenditure and storage. POMC neurons secrete POMC, which are considered as signal peptides which could decrease food intake and increase expenditure of energy by receiving and integrating afferent neural and metabolic signals conveying information about the energy status of the body. POMC-null mutation exists with obesity and type2diabetes mellitus. Studies showed that rising glucose level and GLP-1could increase POMC neurons firing, and further affect liver glucose homeostasis and insulin action. However, the glucose level of plasma decrease and GLP-1increase after ileal transposition in T2DM rats. What would be the subsequent changes of POMC neurons? Do the POMC neurons play a role in the remission of non-obese T2DM after ileal transposition? So far, the related studies are rare.
Given the role of POMC neurons in energy balance, we sought to investigate the changes of POMC neurons and its potential roles after ileal transposition. It might give clues to reveal the mechanism of T2DM and the remission after IT.
Methods
The rat models of part1were sacrificed at post-operative week-36. The cerebrospinal fluid (CSF) and hypothalamus were collected. Subsequently the quantity of POMC mRNA and POMC in hypothalamus and the number of POMC neurons were compared between IT group, S-IT group and control group. The level of GLP-1, insulin and leptin in CSF were also measured and compared.
Results
1. The expression of POMC mRNA in hypothalamus of rats of IT group was more than that of S-IT group and control group (P<0.05). And there was no statistic difference in expression of POMC mRNA between S-IT group and control group (P>0.05).
2. The POMC peptides in hypothalamus of rats of IT group was1.5times more than that of S-IT group and1.6times more than that of control group (P<0.05). And there was no statistic difference in POMC peptides between S-IT group and control group (P>0.05).
3. The number of POMC neurons in hypothalamus of rats of IT group was more than that of S-IT group and control group (P<0.05).
4. The concentration of GLP-1in CSF of rats of IT group was higher than that of S-IT group and control group by ELISA analysis (P<0.05).
5. There was no statistic difference in insulin level in CSF between three groups (P>0.05).
6. There was no statistic difference in leptin level in CSF between three groups (P<0.05), though the leptin level in CSF of control group was more than that of the other two groups.
Conclusion
The study of part2finds that POMC neurons of hypothalamus are activated after ileal transposition, and the transcription of POMC mRNA and expression of POMC are enhanced. These might result from the higher GLP-1level caused by ileal transposition. Given the role of POMC neurons in energy balance, the activated POMC neurons might play an important role in the treatment of ileal transposition on non-obese T2DM rats.
Part3:the role of POMC neurons in the remission of type2diabetes mellitus after ileal transposition
Background
The POMC neurons, located in arcuate nucleus of hypothalamus, are considered as orexia related neurons and involved in energy balance. They accurately regulate energy homeostasis, balance energy intake, expenditure and storage by receiving and integrating afferent neural and metabolic signals. These signals convey the information about the energy status of the body, and include the stretch of oropharyngeal and gastrointestinal, metabolic activity of liver, brain-gut peptides secreted by gastrointestine and various nutrients itself. In the study of part2, the POMC neurons of non-obese T2DM rats were activated after ileal transposition. And this might result from the significantly increased GLP-1level in CSF. However, it is still not known that whether the activated POMC neurons are involved in the remission of T2DM after ileal transposition, and what would happen when the GLP-1receptors are blocked.
In order to further investigate the role of POMC neurons in the remission of T2DM after ileal transposition, we made the models of non-obese T2DM received the lateral ventricle catheter before ileal transposition. The level of GLP-1was measured and compared between groups. Subsequently, Exendin (9-39), the antagonist of GLP-1receptor, was injected into the lateral ventricle of model rats. The changes of glucose tolerance, food intake, body weight and POMC neurons were compared between groups.
Methods
The model rats of non-obese T2DM received the lateral ventricle catheter before operation and then were assigned to two groups randomly:IT and sham IT (S-IT) group. Ileal transposition or sham operation was performed. Exendin (9-39), the antagonist of GLP-1receptor, was injected into the lateral ventricle of model rats at postoperative week-4. The weight, food intake, glucose and GLP-1at baseline, different time points before and after injection were recorded. And the rats were sacrificed at postoperative week-6after Exendin injection. POMC mRNA, POMC, the number of POMC neurons, the level of GLP-1, insulin and leptin in CSF were also measured and compared between groups.
Results
1. There were7rats survived in IT group and5rats survived in S-IT group at postoperative week-4.
2. There were no statistic differences in food intake and weight between IT group and S-IT group before surgery (P>0.05). However, the food intake and weight of IT group significantly decreased after ileal transposition, and were less than those of S-IT groups (P<0.05).
3. The glucose and AUCOGTT of IT group and S-IT group significantly decreased after ileal transposition (P<0.05), but those of S-IT group restored in2weeks. The glucose and AUCOGTT of IT group were significantly less than those of S-IT group (P<0.05).
4. The GLP-1level in IT group rats was higher after ileal transposition and increasing over time (P<0.05). There were no statistic differences in S-IT group before and after operation (P>0.05).
5. The food intake of IT group rats increased significantly after injection of Exendin (P<0.05), while there were no statistic differences in S-IT group before and after surgery (P>0.05). The weight of two groups rats did not change significantly after injection (P>0.05).
6. The fasting glucose of IT group rats increased significantly after injection of Exendin (P<0.05), while there were no statistic differences in S-IT group before and after surgery (P>0.05). Furthermore, there were no statistic differences in peak glucose value of OGTT between groups (P>0.05).
7. The expression of POMC mRNA in hypothalamus of IT group rats was less than that of S-IT group after injection of Exendin at postoperative week-6(P<0.05).
8. The quantity of POMC peptides in hypothalamus of rats of IT group was less than that of S-IT group after injection of Exendin at postoperative week-6(P<0.05).
9. The number of POMC neurons in hypothalamus of rats of IT group was less than that of S-IT group after injection of Exendin (P<0.05).
10. The concentration of GLP-1in CSF of rats of IT group was still higher than that of S-IT group after injection of Exendin at postoperative week-6(P<0.05).
Conclusion
The models received lateral ventricle catheter and ileal transposition confirm that ileal transposition could restrain food intake, control the weight and improve the glucose of non-obese T2DM rats. The GLP-1level in plasma and CSF is higher after ileal transposition and increases over time. When Exendin, the antagonist of GLP-1receptor, is injected into the lateral ventricle, the improvement of glucose and the control of food intake will lose. The POMC neurons of hypothalamus are inhibited, and the transcription of POMC mRNA and the expression of POMC decrease significantly, although the level of GLP-1in CSF is still high. Therefore, the higher GLP-1level activates the POMC neurons, which lead to the remission of T2DM after ileal transposition.
背景
2型糖尿病(Type2diabetes mellitus, T2DM)是在世界范围内广泛流行的危害人类健康的重要疾病,目前全球患者人数估计在2.8亿人左右,并且发病率逐年上升,预计到2030年时患者人数将超过3.6亿人。到目前为止还没有根治2型糖尿病的方法,当前的治疗方法包括饮食,运动,口服降糖药,注射胰岛素等措施目的在于控制血糖,预防并发症的发生。尽管通过严格地控制血糖,能明显降低糖尿病并发症的发生率,但是由于患者依从性的差异,糖尿病仍造成较高的致残率和致死率。越来越多的动物及临床研究表明各种减肥手术,特别是回肠转位术对2型糖尿病有较好的缓解作用。但是其机制目前还不明确,主要的解释有：减肥效果带来的抗糖尿病作用和不依赖减肥效果的抗糖尿病作用。后者是指胃肠道结构改变引起的胃肠道激素的变化所造成的血糖的改善,还可分为前肠假说和后肠假说。每种解释都相互独立,各有倾向。目前越来越多的2型糖尿病是非肥胖或者是不伴有病态肥胖的患者,对于非肥胖2型糖尿病患者,回肠转位术是否仍然存在确切的改善作用呢?没有了明显的减肥效果,其血糖的改善到底是哪种机制主导的呢?其之间有没有相互作用?
为了探讨回肠转位术是否对非肥胖2型糖尿病有缓解作用,并讨论其缓解机制,本研究构建了非肥胖2型糖尿病回肠转位术动物模型。通过手术组与假手术组动物模型的比较,观察糖尿病的改善状况。并通过对代表各个机制假说重要激素等指标变化的对比与分析,讨论术后糖尿病改善的机制。
方法
本研究采用非肥胖2型糖尿病GK大鼠作为动物模型,随机分为3组：回肠转位术组(IT组)、回肠转位假手术组(S-IT组)、及空白对照组。回肠转位术是将距离回盲部5cm的一段10cm的回肠上提到距离Treiz韧带10cm处吻合；假手术组给予同样的横断位置,但是原位吻合。然后比较术前及术后各个实验组之间大鼠的摄食量及体重的变化、血糖状况、β细胞功能、瘦素水平、GLP-1水平及GIP水平等检测指标的变化。
结果
1.术后IT组和S-IT组大鼠的进食量和体重都明显下降(P<0.05),但是S-IT组大鼠的摄食量和体重在术后迅速回升,到术后第8周时与空白对照组无统计学差异(P>0.05)。而IT组大鼠的摄食量及体重一直维持在较低水平,始终低于S-IT组及空白对照组(P<0.05)。
2.术后2周内IT组和S-IT组的血糖及口服葡萄糖耐量实验的AUCOGTT(?)低于术前(P<0.05),但是S-IT组的血糖后期与空白对照组无统计学差异(P>0.05),而IT组大鼠的血糖及AUCOGTT都显著低于S-IT组及空白对照组(P<0.05)。
3.对胰岛素耐量实验各个时间点血糖的比较,术后IT组非肥胖2型糖尿病大鼠的胰岛素抵抗得到显著的改善(P<0.05)；S-IT组大鼠的胰岛素抵抗无明显改善,并进行性恶化,与空白对照组无统计学差异(P>0.05)。
4.通过空腹C-肽、空腹胰岛素的酶联免疫吸附试验(ELISA)检测及葡萄糖-胰岛素释放实验发现：IT组非肥胖2型糖尿病大鼠p细胞分泌胰岛素的量增加(P<0.05),而S-IT组和空白对照组在术前术后无统计学差异(P>0.05)。
5.IT组非肥胖2型糖尿病大鼠术后的空腹GLP-1水平增高,糖负荷后GLP-1分泌量增多(P<0.05)。而S-IT组和空白对照组在术前术后无统计学差异(P>0.05)。
6.3组大鼠的空腹GIP及糖负荷后GIP分泌量术前及术后均无统计学差异(P>0.05)。
7.IT组非肥胖2型糖尿病大鼠术前及术后的空腹瘦素均无统计学差异(P>0.05),但是糖负荷后AUCLeptin升高明显(P<0.05)。空白对照组术后36周的空腹瘦素比术前高(P<0.05)。
结论
本部分实验证实：
1.回肠转位术对非肥胖2型糖尿病大鼠有明显、持久的抑制摄食的作用,使其体重增加得缓慢。
2.回肠转位术对非肥胖2型糖尿病大鼠的血糖有迅速、明显、持久的改善作用。
3.探究回肠转位术对非肥胖2型糖尿病大鼠血糖改善的作用机制发现：回肠转位术对非肥胖2型糖尿病大鼠的胰岛素抵抗有显著和持久的改善作用,并且对非肥胖2型糖尿病大鼠的β细胞有改善作用,使胰岛素分泌量增加。
4.对相关激素检测发现：回肠转位术后非肥胖2型糖尿病大鼠的血GLP-1水平增高,GIP分泌量术前及术后相比无统计学差异,瘦素分泌量的变化不大,但是瘦素分泌的敏感性改善了。统计学分析,GLP-1水平的升高对血糖的影响较大,呈线性相关。GIP及瘦素的改变对IT手术改善血糖的影响无统计学意义。
上述发现表明,回肠转位术能显著改善非肥胖2型糖尿病患者的血糖,改善胰岛素抵抗,增加p细胞的胰岛素分泌量。对有关参与回肠转位术改善血糖机制可能激素的统计学分析显示,手术引起的GLP-1分泌增加发挥着主要作用。有关GLP-1的作用机制及下一步作用位点,尚待更深入的研究。
第二部分下丘脑POMC神经元在回肠转位术缓解非肥胖2型糖尿病中的作用
背景
代谢综合征是多种代谢成分异常聚集的病理状态,葡萄糖代谢异常是其中一种表现。生理状态下哺乳动物的个体都处于精确的能量自动平衡中。下丘脑是调节机体能量活动的重要部位,有着许多的神经核团,参与着复杂的神经生理活动。POMC神经元作为存在于下丘脑的一类重要的神经元,可以抑制肥胖,产生较强的厌食感,被认为是食欲相关肽神经元,调控着摄食和机体能量平衡。该神经元分泌的POMC及其衍生肽等被认为是抑制摄食和增加能量消耗的肽类物质。POMC缺陷的大鼠常常伴有肥胖及糖尿病的症状。生理状态下POMC神经元可以被升高的GLP-1所激活,也能被降低的血糖水平所抑制。回肠转位术使得非肥胖2型糖尿病大鼠术后GLP-1的水平升高,但是血糖水平降低。其POMC (?)中经元是被激活还是抑制?回肠转位术对2型糖尿病的改善作用是不是通过POMC (?)中经元发挥作用的?到目前为止还没有相关的报道。
因此本研究通过构建好的2型糖尿病回肠转位术模型,观察下丘脑中激活的POMC神经元数量及POMC翻译和表达的量。通过对回肠转位手术组与其他组动物模型的比较,探讨POMC神经元在2型糖尿病血糖改善中的作用,为揭示2型糖尿病发病机制及回肠转位术缓解2型糖尿病机制提供线索。
方法
将本实验第一部分存活的3组GK大鼠,在术后36周时处死,采集下丘脑组织和脑脊液等标本。免疫组织化学染色观察POMC神经元,对比组间大鼠下丘脑POMC神经元的个数；测量下丘脑POMC的mRNA转录量和POMC多肽的表达量；测量脑脊液中GLP-1、胰岛素和瘦素的含量,比较组间是否有统计学差异。
结果
1.接受回肠转位术的非肥胖2型糖尿病大鼠,术后36周下丘脑组织POMC mRNA的量比S-IT组和空白对照组都高(P<0.05),而S-IT组与空白对照组相比没有显著的差异(P>0.05)。
2.IT组大鼠下丘脑POMC多肽含量比S-IT组高1.5倍(P<0.05),比空白对照组高1.6倍(P<0.05),S-IT组与空白对照组相比没有显著的差异(P>0.05)。
3.IT组大鼠丘脑的POMC神经元个数多于假手术组和空白对照组(P<0.05)。
4.经过ELISA检测,IT组大鼠脑脊液中GLP-1的浓度显著高于S-IT组大鼠及空白对照组大鼠(P<0.05)。
5.IT组、S-IT组和空白对照组大鼠脑脊液中胰岛素的浓度无统计学差异(P>0.05)。
6.IT组、S-IT组和空白对照组大鼠脑脊液中瘦素水平无统计学差异(P>0.05)。
结论
本部分实验证实：
1.回肠转位术后非肥胖2型糖尿病大鼠下丘脑组织POMC mRNA的转录增多,POMC多肽表达增多。
2.接受回肠转位术的非肥胖2型糖尿病大鼠下丘脑组织POMC神经元的数量增多。根据POMC神经元及POMC的作用,它可能参与回肠转位术改善血糖的机制。
3.进一步探讨POMC被激活的原因,回肠转位术引起的GLP-1分泌增加可能发挥着主要作用。
该实验首次将神经元作用与回肠转位术改善糖尿病联系在一起,发现其改变及可能的机制,为研究2型糖尿病及手术改善糖尿病提供新的思路。
第三部分下丘脑POMC神经元在回肠转位术缓解非肥胖2型糖尿病中的机制
背景
POMC神经元被认为是食欲相关肽神经元,调控着摄食和机体能量平衡。它能够接受来自外周的信号,如：迷走神经传导的来自口咽、胃肠牵张感觉及肝脏代谢活动等所形成的刺激作用；循环中胃肠道分泌的脑肠肽及各种营养物质本身等。通过对这些信号的感知、整合反馈成脑内神经因子的形式。这些神经因子与其他的神经元相互联系,形成网络调控,对机体实时精确的应答反应。前部分实验发现IT手术后的大鼠血及脑脊液中GLP-1的水平明显增高。鉴于GLP-1可以通过自由扩散穿过血脑屏障,并且POMC神经元上有GLP-1的受体,因此可以推断POMC神经元可能被升高的GLP-1所激活。但是非肥胖2型糖尿病被回肠转位术所缓解的机制是否有激活的POMC (?)神经元参与呢?
为了更好地探讨下丘脑POMC神经元在回肠转位术缓解非肥胖2型糖尿病中的机制,我们在接受侧脑室置管的非肥胖2型糖尿病大鼠中重新构建了回肠转位术模型。比较术前及术后脑脊液中多个时间点GLP-1水平的变化及血糖的变化,并且在大鼠侧脑室中给予GLP-1受体的拮抗齐(?) Exendin(9-39),观察拮抗后大鼠2型糖尿病的症状及POMC (?)神经元的变化。
方法
采用非肥胖2型糖尿病GK大鼠作为动物模型,给予大鼠侧脑室置管术,将存活的GK大鼠随机分为如下2组：IT组和S-IT组。术前及术后各个时间点监测体重、摄食、血糖及GLP-1等多个指标。
在回肠转位术后4周时,对两组大鼠同时进行侧脑室GLP-1拮抗剂Exendin(9-39)的注射,然后比较两组大鼠的血糖及摄食等指标,观察GLP-1受体被拮抗后回肠转位术改善血糖的效果有无改变。术后6周处死所有大鼠,处死之前对IT组大鼠给同样剂量的Exendin(9-39),收集大鼠下丘脑等组织,组间观察比较GLP-1受体被拮抗后POMC神经元的状态。
结果
1.接受侧脑室置管的非肥胖2型糖尿病大鼠给予回肠转位术和假回肠转位术,术后4周IT组大鼠7只大鼠S-IT组5只大鼠一直存活到实验结束,但是IT手术组仅有6只大鼠的统计数据。
2.两组大鼠术前的体重及摄食量无统计学差异(P>0.05)。回肠转位术后IT组大鼠的进食量显著低于S-IT组大鼠,体重也明显低于S-IT大鼠(P<0.05)。
3.两组大鼠的血糖及AUCOGTT术前无显著性差异(P>0.05),回肠转位术后都出现了不同程度的血糖下降。IT组大鼠的血糖下降后始终处于较为平稳的状态,低于术前血糖水平(P<0.05)；S-IT组大鼠的血糖下降后呈现缓慢回升的趋势,与术前比较无统计学差异(P>0.05)。AUCOGTT曲线变化同血糖变化一致。IT组大鼠的AUCOGTT在下降后始终处于较低的状态,而S-IT组大鼠的AUCOGTT降低的不明显(P>0.05)。验证了回肠转位术对非肥胖2型糖尿病的缓解作用。
4.回肠转位术后IT组大鼠脑脊液GLP-1水平不断升高,显著高于术前水平(P<0.05)。但是S-IT组GLP-1的水平波动不大,术后与术前水平相比无统计学意义(P>0.05)。
5.回肠转位术后4周注射Exendin(9-39)前,IT组大鼠的摄食量比S-IT组大鼠少(P<0.05)。注射后IT组大鼠的摄食量明显增加(P<0.05),与S-IT组大鼠的摄食量相比无统计学差异(P>0.05)。S-IT组大鼠的摄食量与注射前相比无统计学差异(P>0.05)。注射前后两组大鼠的体重均无统计学变化(P>0.05)。
6.注射Exendin(9-39)前,IT组大鼠的血糖低于S-IT组大鼠的血糖(P<0.05)。注射Exendin(9-39)后,IT组大鼠的血糖升高(P<0.05),与S-IT组无统计学差异(P>0.05)。S-IT组大鼠的血糖注射前后相比无统计学差异(P>0.05)。OGTT实验也发现注射Exendin(9-39)后,IT组大鼠的血糖峰值与S-IT组大鼠无统计学差异(P>0.05)。
7.回肠转位术后6周注射Exendin(9-39)后IT组大鼠的下丘脑组织POMC mRNA的量比S-IT组低(P<0.05)。
8.术后6周注射Exendin(9-39)后IT组大鼠的下丘脑组织POMC多肽含量比S-IT组低(P<0.05)。
9.术后6周注射Exendin(9-39)后IT组大鼠丘脑的POMC神经元个数少于S-IT组(P<0.05)。
10.术后6周注射Exendin(9-39)后IT组大鼠脑脊液中GLP-1的浓度高于S-IT组大鼠(P<0.05)。胰岛素的浓度无统计学差异(P>0.05)。
结论
本部分的实验结果表明：
1.通过建立侧脑室置管的非肥胖2型糖尿病大鼠回肠转位术和假回肠转位术模型,再一次证实了回肠转位术对非肥胖2型糖尿病的治疗作用。摄食量减少,血糖及AUCOGTT得到明显的改善。
2.回肠转位术后非肥胖2型糖尿病大鼠脑脊液GLP-1随术后时间不断升高,显著高于术前水平。
3.术后注射GLP-1受体拮抗剂Exendin(9-39)能使非肥胖2型糖尿病大鼠已经改善的糖尿病症状恶化,血糖升高,摄食量增加。
4.术后注射Exendin(9-39)可以明显抑制非肥胖2型糖尿病大鼠下丘脑组织POMC神经元。使其mRNA的表达减少,POMC多肽含量降低。但大鼠脑脊液中GLP-1的浓度仍高于S-IT组大鼠。
因此非肥胖2型糖尿病大鼠下丘脑POMC神经元在回肠转位术后是被GLP-1所激活的,并且激活的POMC神经元在回肠转位术缓解非肥胖2型糖尿病中发挥重要作用。这为回肠转位术应用于临床以及进一步研究2型糖尿病提供一定的实验基础。
Part1:the remission of type2diabetes mellitus of non-obese rats after ileal transposition
Background
Type2diabetes mellitus (T2DM) presently afflicts more than280million people worldwide, and the morbidity is increasing year by year. It was expected that there would be more than360million persons by2030. However, there is no radical treatment on type2diabetes so far. Current therapies, including diet, exercise, and medication, could control plasma glucose and reduce the incidence of the complications, but the morbidity and mortality are increasing gradually because of poor compliance of patients. Interestingly, Bariatric surgeries, especially ileal transposition (IT), are shown to be an effective means of improving T2DM, but the mechanism is still unclear. The main explanations indicate that the remarkable anti-diabetic effects result from weight loss and a yet uncharacterized weight-independent mechanism. The latter is believed to be related to the hormonal changes caused by obvious physiological alterations of distal ileum after surgery. Previous studies about excluding foregut and interposing hindgut lead to the "foregut hypothesis" and "hindgut hypothesis". These explanations are all supported by mounting evidences and not mutually exclusive. However, more and more T2DM patients are not obese and have no excessive weight to loss. Could ileal transposition improve non-obese T2DM? Which mechanism is dominant without the effect of weight loss? And is there synergistic effect of these hypotheses?
To confirm the effect of ileal transposition on non-obese T2DM and investigate the mechanism of remission, the non-obese T2DM rats received ileal transposition and sham procedures. Then the changes in glucose homeostasis, insulin sensitivity,(3-cell function and many hormonal levels in plasma were compared between groups.
Methods
Non-obese diabetic Goto-Kakizaki (GK) rats were assigned to three groups randomly:IT, sham IT (S-IT) and control group. IT was performed as described:a10cm ileal segment5cm proximal to the ileocecal valve was transected, transposed and anastomosed isoperistaltically with the jejunal10cm distal to the ligament of Treitz. Sham surgeries involved the same abdominal incisions, transections and re-anastomosis of the gastrointestinal tract at multiple sites corresponding to IT, except no ileum transposition. Subsequently, the weight, food intake, beta-cell function, the level of glucose, leptin, glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide (GIP) were measured and compared between groups.
Results
1. The food intake and weight of IT group and S-IT group significantly decreased after operation (P<0.05), but those of S-IT group restored in2weeks. There were no statistic differences in food intake and weight between S-IT group and control group at postoperative week-8(P>0.05). While the food intake and weight of IT group kept low and stable level, were less than those of the other two groups (P<0.05).
2. The glucose and AUCOGTT of IT group and S-IT group significantly decreased after operation (P<0.05), but those of S-IT group restored in2weeks. After that the glucose and AUCOGTT of IT group were significantly less than those of S-IT group and control group (P<0.05).
3. The insulin sensitivity was improved after operation in IT group but S-IT group (P<0.05). There were no statistic differences in insulin sensitivity between S-IT group and control group (P>0.05).
4. The secreted insulin was more after ileal transposition in IT group but S-IT group (P<0.05), while there were no statistic differences in secreted insulin before and after operation in S-IT and control groups (P>0.05).
5. The fasting GLP-1level in IT group rats was higher after operation (P<0.05), while there were no statistic differences before and after operation in S-IT group and control group (P>0.05).
6. There were no statistic differences in GIP level between3groups before and after operation (P>0.05).
7. The fasting leptin level in control group at postoperative week-36was higher than that before operation (P<0.05). There were no statistic differences in IT group before and after operation (P>0.05).
Conclusions
This study provides experimental evidences that ileal transposition could restrain food intake, control the weight and improve the glucose of non-obese T2DM rats. After ileal transposition, the insulin resistance and status of beta-cells are improved. These improvements might result from higher GLP-1level in plasma, and there were no statistic changes in GIP and leptin level in plasma before and after operation.
Part2:the changes of POMC neurons in non-obese type2diabetes mellitus rats received ileal transposition
Background
The metabolic syndrome is a pathological state of accumulation of a variety of metabolic components, and always leads to type2diabetes mellitus. Actually every mammalian individual could keep a precise automatic energy balance in physiological state. The pro-opiomelanocortin (POMC) neurons, a specific population of arcuate nucleus neurons in the hypothalamus, are typical neurons involved in fuel balance. Along with other central neurons, they regulate energy homeostasis, balance energy intake, expenditure and storage. POMC neurons secrete POMC, which are considered as signal peptides which could decrease food intake and increase expenditure of energy by receiving and integrating afferent neural and metabolic signals conveying information about the energy status of the body. POMC-null mutation exists with obesity and type2diabetes mellitus. Studies showed that rising glucose level and GLP-1could increase POMC neurons firing, and further affect liver glucose homeostasis and insulin action. However, the glucose level of plasma decrease and GLP-1increase after ileal transposition in T2DM rats. What would be the subsequent changes of POMC neurons? Do the POMC neurons play a role in the remission of non-obese T2DM after ileal transposition? So far, the related studies are rare.
Given the role of POMC neurons in energy balance, we sought to investigate the changes of POMC neurons and its potential roles after ileal transposition. It might give clues to reveal the mechanism of T2DM and the remission after IT.
Methods
The rat models of part1were sacrificed at post-operative week-36. The cerebrospinal fluid (CSF) and hypothalamus were collected. Subsequently the quantity of POMC mRNA and POMC in hypothalamus and the number of POMC neurons were compared between IT group, S-IT group and control group. The level of GLP-1, insulin and leptin in CSF were also measured and compared.
Results
1. The expression of POMC mRNA in hypothalamus of rats of IT group was more than that of S-IT group and control group (P<0.05). And there was no statistic difference in expression of POMC mRNA between S-IT group and control group (P>0.05).
2. The POMC peptides in hypothalamus of rats of IT group was1.5times more than that of S-IT group and1.6times more than that of control group (P<0.05). And there was no statistic difference in POMC peptides between S-IT group and control group (P>0.05).
3. The number of POMC neurons in hypothalamus of rats of IT group was more than that of S-IT group and control group (P<0.05).
4. The concentration of GLP-1in CSF of rats of IT group was higher than that of S-IT group and control group by ELISA analysis (P<0.05).
5. There was no statistic difference in insulin level in CSF between three groups (P>0.05).
6. There was no statistic difference in leptin level in CSF between three groups (P<0.05), though the leptin level in CSF of control group was more than that of the other two groups.
Conclusion
The study of part2finds that POMC neurons of hypothalamus are activated after ileal transposition, and the transcription of POMC mRNA and expression of POMC are enhanced. These might result from the higher GLP-1level caused by ileal transposition. Given the role of POMC neurons in energy balance, the activated POMC neurons might play an important role in the treatment of ileal transposition on non-obese T2DM rats.
Part3:the role of POMC neurons in the remission of type2diabetes mellitus after ileal transposition
Background
The POMC neurons, located in arcuate nucleus of hypothalamus, are considered as orexia related neurons and involved in energy balance. They accurately regulate energy homeostasis, balance energy intake, expenditure and storage by receiving and integrating afferent neural and metabolic signals. These signals convey the information about the energy status of the body, and include the stretch of oropharyngeal and gastrointestinal, metabolic activity of liver, brain-gut peptides secreted by gastrointestine and various nutrients itself. In the study of part2, the POMC neurons of non-obese T2DM rats were activated after ileal transposition. And this might result from the significantly increased GLP-1level in CSF. However, it is still not known that whether the activated POMC neurons are involved in the remission of T2DM after ileal transposition, and what would happen when the GLP-1receptors are blocked.
In order to further investigate the role of POMC neurons in the remission of T2DM after ileal transposition, we made the models of non-obese T2DM received the lateral ventricle catheter before ileal transposition. The level of GLP-1was measured and compared between groups. Subsequently, Exendin (9-39), the antagonist of GLP-1receptor, was injected into the lateral ventricle of model rats. The changes of glucose tolerance, food intake, body weight and POMC neurons were compared between groups.
Methods
The model rats of non-obese T2DM received the lateral ventricle catheter before operation and then were assigned to two groups randomly:IT and sham IT (S-IT) group. Ileal transposition or sham operation was performed. Exendin (9-39), the antagonist of GLP-1receptor, was injected into the lateral ventricle of model rats at postoperative week-4. The weight, food intake, glucose and GLP-1at baseline, different time points before and after injection were recorded. And the rats were sacrificed at postoperative week-6after Exendin injection. POMC mRNA, POMC, the number of POMC neurons, the level of GLP-1, insulin and leptin in CSF were also measured and compared between groups.
Results
1. There were7rats survived in IT group and5rats survived in S-IT group at postoperative week-4.
2. There were no statistic differences in food intake and weight between IT group and S-IT group before surgery (P>0.05). However, the food intake and weight of IT group significantly decreased after ileal transposition, and were less than those of S-IT groups (P<0.05).
3. The glucose and AUCOGTT of IT group and S-IT group significantly decreased after ileal transposition (P<0.05), but those of S-IT group restored in2weeks. The glucose and AUCOGTT of IT group were significantly less than those of S-IT group (P<0.05).
4. The GLP-1level in IT group rats was higher after ileal transposition and increasing over time (P<0.05). There were no statistic differences in S-IT group before and after operation (P>0.05).
5. The food intake of IT group rats increased significantly after injection of Exendin (P<0.05), while there were no statistic differences in S-IT group before and after surgery (P>0.05). The weight of two groups rats did not change significantly after injection (P>0.05).
6. The fasting glucose of IT group rats increased significantly after injection of Exendin (P<0.05), while there were no statistic differences in S-IT group before and after surgery (P>0.05). Furthermore, there were no statistic differences in peak glucose value of OGTT between groups (P>0.05).
7. The expression of POMC mRNA in hypothalamus of IT group rats was less than that of S-IT group after injection of Exendin at postoperative week-6(P<0.05).
8. The quantity of POMC peptides in hypothalamus of rats of IT group was less than that of S-IT group after injection of Exendin at postoperative week-6(P<0.05).
9. The number of POMC neurons in hypothalamus of rats of IT group was less than that of S-IT group after injection of Exendin (P<0.05).
10. The concentration of GLP-1in CSF of rats of IT group was still higher than that of S-IT group after injection of Exendin at postoperative week-6(P<0.05).
Conclusion
The models received lateral ventricle catheter and ileal transposition confirm that ileal transposition could restrain food intake, control the weight and improve the glucose of non-obese T2DM rats. The GLP-1level in plasma and CSF is higher after ileal transposition and increases over time. When Exendin, the antagonist of GLP-1receptor, is injected into the lateral ventricle, the improvement of glucose and the control of food intake will lose. The POMC neurons of hypothalamus are inhibited, and the transcription of POMC mRNA and the expression of POMC decrease significantly, although the level of GLP-1in CSF is still high. Therefore, the higher GLP-1level activates the POMC neurons, which lead to the remission of T2DM after ileal transposition.
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37. Grill HJ, Ginsberg AB, Seeley RJ, Kaplan JM. Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. J Neurosci.1998 Dec 1;18(23):10128-35.
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66. Sturm RA. Skin colour and skin cancer-MC1R, the genetic link. Melanoma Res. 2002 Oct;12(5):405-16.
67. Chagnon YC, Chen WJ, Perusse L, Chagnon M, Nadeau A, Wilkison WO, Bouchard C. Linkage and association studies between the melanocortin receptors 4 and 5 genes and obesity-related phenotypes in the Quebec Family Study. Mol Med. 1997 Oct;3(10):663-73.
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40. Bariohay B, Roux J, Tardivel C, Trouslard J, Jean A, Lebrun B. Brain-derived neurotrophic factor/tropomyosin-related kinase receptor type B signaling is a downstream effector of the brainstem melanocortin system in food intake control. Endocrinology.2009 Jun;150(6):2646-53.
41. Ste Marie L, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12339-44.
42. Butler AA, Marks DL. Fan W, Kuhn CM, Bartolome M, Cone RD. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci.2001 Jun;4(6):605-11.
43. Farooqi IS. Keogh JM, Yeo GS, Lank EJ. Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003 Mar 20;348(12):1085-95.
44. Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C, Baier LJ. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes.2008 Dec;57(12):3267-72.
45. Williams DL, Bowers RR, Bartness TJ, Kaplan JM, Grill HJ. Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat. Endocrinology.2003 Nov;144(11):4692-7.
46. Elmquist JK. Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Physiol Behav.2001 Nov-Dec;74(4-5):703-8.
47. Nicholson JR, Peter JC, Lecourt AC, Barde YA, Hofbauer KG. Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function. J Neuroendocrinol.2007 Dec;19(12):974-82.
48. Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol.2003 Mar 10;457(3):213-35.
49. Skibicka KP, Grill HJ. Energetic responses are triggered by caudal brainstem melanocortin receptor stimulation and mediated by local sympathetic effector circuits. Endocrinology.2008 Jul;149(7):3605-16.
50. Zhang ZH, Felder RB. Melanocortin receptors mediate the excitatory effects of blood-borne murine leptin on hypothalamic paraventricular neurons in rat. Am J Physiol Regul Integr Comp Physiol.2004 Feb;286(2):R303-10.
51. Voss-Andreae A, Murphy JG, Ellacott KL, Stuart RC, Nillni EA, Cone RD, Fan W. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology.2007 Apr; 148(4):1550-60.
52. Song CK, Vaughan CH, Keen-Rhinehart E, Harris RB, Richard D, Bartness TJ. Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue:neuroanatomical and functional evidence. Am J Physiol Regul Integr Comp Physiol.2008 Aug;295(2):R417-28.
53. Bartolomucci A, Possenti R, Levi A, Pavone F, Moles A. The role of the vgf gene and VGF-derived peptides in nutrition and metabolism. Genes Nutr.2007 Nov;2(2):169-80.
54. Legradi G, Lechan RM. Agouti-related protein containing nerve terminals innervate thyrotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology.1999 Aug;140(8):3643-52.
55. Sawchenko PE, Swanson LW. Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. J Comp Neurol.1982 Mar 1;205(3):260-72.
56. Hahm S, Fekete C, Mizuno TM, Windsor J, Yan H, Boozer CN, Lee C, Elmquist JK, Lechan RM, Mobbs CV, Salton SR. VGF is required for obesity induced by diet, gold thioglucose treatment, and agouti and is differentially regulated in pro-opiomelanocortin-and neuropeptide Y-containing arcuate neurons in response to fasting. J Neurosci.2002 Aug 15;22(16):6929-38.
57. Coll AP. Effects of pro-opiomelanocortin (POMC) on food intake and body weight:mechanisms and therapeutic potential? Clin Sci (Lond).2007 Aug; 113(4):171-82.
58. Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, Culler MD, Yang H, Dixit VD, Butler AA. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R-and MC4R-deficient C57BL/6J mice. Peptides.2009 Oct;30(10):1892-900.
59. Sutton GM, Trevaskis JL, Hulver MW, McMillan RP, Markward NJ, Babin MJ, Meyer EA, Butler AA. Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or-4 receptors. Endocrinology.2006 May; 147(5):2183-96.
60. Garruti G, Cotecchia S, Giampetruzzi F. Giorgino F. Giorgino R. Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome. J Gastrointestin Liver Dis.2008 Jun; 17(2):193-8.
61. Leoni G, Patel HB, Sampaio AL, Gavins FN, Murray JF, Grieco P, Getting SJ, Perretti M. Inflamed phenotype of the mesenteric microcirculation of melanocortin type 3 receptor-null mice after ischemia-reperfusion. FASEB J.2008 Dec;22(12):4228-38.
62. Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, Mountjoy KG, Cone RD. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell.1993 Mar 26;72(6):827-34.
63. Chida D, Nakagawa S, Nagai S, Sagara H, Katsumata H, Imaki T, Suzuki H, Mitani F, Ogishima T, Shimizu C, Kotaki H, Kakuta S, Sudo K, Koike T, Kubo M, Iwakura Y. Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc Natl Acad Sci U S A.2007 Nov 13;104(46):18205-10.
64. Chen W, Kelly MA, Opitz-Araya X, Thomas RE, Low MJ, Cone RD. Exocrine gland dysfunction in MC5-R-deficient mice:evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell.1997 Dec 12;91(6):789-98.
65. Chida D, Sato T, Sato Y, Kubo M, Yoda T, Suzuki H, Iwakura Y. Characterization of mice deficient in melanocortin 2 receptor on a B6/Balbc mix background. Mol Cell Endocrinol.2009 Mar 5;300(1-2):32-6.
66. Clark AJ, Metherell LA. Mechanisms of disease:the adrenocorticotropin receptor and disease. Nat Clin Pract Endocrinol Metab.2006 May;2(5):282-90.
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