慢性个体化胃电刺激的参数筛选及其对犬摄食、体重、胃肠激素及胃排空的影响
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摘要
背景和目的
肥胖在全球的急剧蔓延使得减重问题刻不容缓。由于目前缺乏能够安全而且有效减轻体重的治疗方法,因此人们迫切需要寻找新的治疗手段。胃电刺激(gastric electrical stimulation, GES)是近年来开展的一种很有前景的治疗肥胖的新方法。胃电刺激系统由胃电刺激器(又称电子脉冲发生器)和一对或多对电极共同组成。通过手术将电极植入胃壁,电极的另一端通过导线连接于胃电刺激器,由胃电刺激器发放一定模式的电脉冲刺激发挥作用。相对于传统减肥手术,胃电刺激的植入不改变胃肠道正常的解剖结构,创伤较小,安全性较高。
大量动物实验及临床研究发现胃电刺激具有抑制摄食、减轻体重的作用,但是研究还发现,并不是所有患者都可以取得较好的疗效。随着对胃电刺激研究的深入,最近越来越多的实验证明,个体内脏敏感性存在差异,而目前胃电刺激器产品只能提供波宽较窄的、固定的刺激参数,以上因素可能是导致患者疗效不佳的主要原因。这就提示了需要研发新型的胃电刺激器,以便在较大范围内实现胃电刺激参数的可调节性。
我们与清华大学微电子学研究所合作,历经5年的研究,研制出了新型的可调式胃电刺激器。这种可调式胃电刺激器,从体外发送信号调节刺激参数,可以实现参数的可调节性和多样化组合。同时由于对供电方法进行了改进,其可提供的脉冲波宽范围大大增加,可以满足不同个体的需要。
本研究应用新型可调式胃电刺激器对比格犬进行为期3个月的慢性个体化胃电刺激,同时给予3个月假刺激作为自身对照。实验过程中,首先采用一系列刺激参数进行胃电刺激,观察犬的症状和摄食量,对刺激参数进行筛选,同时观察犬的耐受规律；然后采用上述刺激参数进行3个月的慢性胃电刺激,观察胃电刺激对比格犬症状、摄食量和体重的影响,验证新型胃电刺激器的有效性。以酶联免疫吸附法和放射免疫分析的方法检测血胃肠激素,以核素闪烁扫描技术检测固体胃排空,观察胃电刺激对胃肠激素和胃排空的影响,为进一步研究胃电刺激的作用及其机理提供一定的实验基础；并且通过观察胃电刺激器植入机体后的组织相容性,进一步验证胃电刺激器的安全性。
方法
成年健康雌性比格犬8只,体重8.5-13.0kg,全麻下皮下埋置胃电刺激器,腹腔镜下植入胃电刺激电极。
第一部分：建立胃电刺激的动物模型,筛选个体化胃电刺激参数。刺激模式为串脉冲：输出波宽0.13～10ms,电流O.5mA～12mA,频率40Hz,2s-on、3s-off的周期性矩形脉冲。以一系列不同的刺激参数进行刺激,观察犬的症状和摄食量,对刺激参数进行筛选,同时观察个体化的胃电刺激参数耐受规律。
第二部分：采用个体化的刺激参数,观察胃电刺激3个月及假刺激3个月期间比格犬的症状、摄食量和体重的变化。
第三部分：观察个体化胃电刺激对比格犬外周血中摄食相关胃肠激素浓度的影响。采集胃电刺激3个月末及假刺激3个月末的进食前及进食后的血浆,通过酶联免疫吸附法及放射免疫法检测胃肠激素的浓度。
第四部分：应用核素闪烁扫描技术评价个体化胃电刺激对固体胃排空的影响。选取胃电刺激3个月末及假刺激3个月末,分别进行核素胃排空检测。计算胃半排空时间及进食后1小时、2小时胃固体存留率。
第五部分：通过观察胃电刺激器及电极固定部位组织的病理学改变,了解胃电刺激器的组织相容性,验证胃电刺激器的安全性。
结果
8只比格犬均顺利地完成了实验研究,依从性良好。
第一部分：比格犬对胃电刺激的承受性有明显个体化趋势,每只动物在高强度胃电刺激时的症状表现各不相同。不同动物的最大可接受的刺激参数波动范围较大(0.75ms/8mA～3.0ms/10mA,只对脉宽和电流强度进行调节,其它参数均固定)。在胃电刺激过程中,有效刺激参数波动范围较大(初期有效刺激参数波动在0.5ms/3mA～1.0ms/10mA,后期最大有效刺激参数波动在1.0ms/10mA～7.0ms/10mA)。同时观察到动物存在耐受现象,即连续应用相同刺激参数后,个体对胃电刺激的敏感性下降,刺激效果减弱。适当加大胃电刺激参数后,仍能够减少摄食,而不引起明显的症状。耐受出现的平均时间是10.2±2.1天。提示长期应用胃电刺激时需要个体化调整刺激参数。
第二部分：应用可调式胃电刺激器对比格犬进行3个月的个体化胃电刺激,与假刺激相比,犬的平均摄食量显著减少(A组(210.9±9.0)g/dvs.(279.1±24.6)g/d,P<0.05;B组(157.2±12.9)g/d vs.(224.5±8.8)g/d,P<0.05)；胃电刺激3个月末犬的体重较假刺激显著降低(A组(10.4±1.1)kg vs.(11.5±0.9)kg,P<0.05；B组(7.8±0.3)kg vs.(9.4±0.6) kg, P<0.05)。
第三部分：个体化胃电刺激3个月后对于进食前6种胃肠激素(Ghrelin、 PYY3-36、GLP-1、SS、Insulin、Leptin)浓度的影响,较假刺激无统计学差异。个体化胃电刺激3个月后对于进食后6种胃肠激素(Ghreln、PYY3-36、GLP-1、SS、 Insulin、Leptin)浓度的影响,较假刺激无统计学差异。其中,与假刺激相比,可以观察到胃电刺激3个月后,进食前Ghrelin、PYY3-36、Leptin有升高趋势,进食后PYY3.36. Insulin有升高趋势,进食后GLP-1、SS有降低趋势。
第四部分：胃电刺激3个月后与假刺激比较,胃电刺激可以显著延长固体胃半排空时间(Median:181.0mm vs.127.7min, P=0.028)。对胃固体餐1小时存留率无显著影响((86.9±8.4)%vs.(82.3±7.2)%,P=0.195);胃电刺激可以显著增加胃固体餐2小时存留率((67.7±13.8)%vs.(53.9±14.6)%,P=0.055)。
第五部分：动物对新型胃电刺激器的承受性良好,植入后未观察到明显的不良反应。胃电刺激器及电极植入部位的组织病理反应较轻,仅观察到刺激器周围有纤维囊形成,电极周围胃壁浆肌层有少量炎细胞浸润,粘膜及粘膜下层均未见明显炎症反应。表明该刺激器的组织相容性较好。
结论
1、比格犬对胃电刺激呈显著的个体化差异。胃电刺激过程中,动物存在耐受现象。长期应用需要个体化调整刺激参数。
2、新型可调式胃电刺激器进行的慢性个体化胃电刺激能够显著减少比格犬的摄食量,降低体重。
3、慢性个体化胃电刺激对血浆中6种摄食相关胃肠激素未见显著影响。
4、慢性个体化胃电刺激导致的固体胃排空时间延长可能是其减少摄食的重要机制。
5、动物对新型胃电刺激器的承受性良好,组织相容性好。
总之,腹腔镜下植入的慢性个体化胃电刺激创伤小、安全、有效,具有较好的临床应用前景。
Background and Objective
Obesity is a major public health problem worldwide and prevention of obesity has become a pressing task. Gastric electrical stimulation (GES) has been considered as a new promising therapeutic option in treating obesity. The system of gastric electrical stimulation consists of gastric electrical stimulator (electrical pulse generator) and one or more pairs of electrodes. The electrodes are implanted into stomach by surgery. The other side of the electrodes is connected to a gastric electrical stimulator by guide wire. The effects of GES are delivered by electrical pulses to the stomach. Gastrointestinal anatomy is not affected during the procedure of GES. GES is less invasive and a safer method for treating obesity compared with bariatric surgery.
GES has been reported to reduce food intake and body weight in animals and in human studies. However, in some studies, a loss in excess body weight was not always observed. Recently, more experiments have proved that visceral sensitivity in obesity patients to stimulation parameters was important in the stimulation process. The narrow width of pulse wave and fixed parameters pattern for all patients might be the main problems for the failure of the treatments. Anew type of gastric electrical stimulator is needed to investigate which has adjustable parameters in a wide range.
In collaboration with Institute of Microelectronics of Tsinghua University for5years, we have developed a new type of adjustable gastric electrical stimulator. The stimulation parameters of the new device are adjusted by external signal. The character of adjustment and combination of diversification can be carried out. Furthermore due to the method for power supply is improved, the output width of pulse wave can be increased greatly to meet the individual need.
In this study, the new type device was applied to produce chronic individual gastric electric stimulation on Beagle dogs for3months. Sham stimulation for3months was for own control. Parameters were selected and adjusted according to demand during the study. Resistance (i.e., diminution in the response to GES after long-term use) was assessed. Food intake and body weight were measured to evaluate the effects of GES.
Then GES was conducted to observe the impacts on Beagle dogs' gastrointestinal hormones and gastric empting and discussed the possible mechanisms underlying the effects. The histocompatibility of the device was observed to verify the safety of the device.
Methods
Eight healthy female adult Beagle dogs, ranging in weight from8.5-13.0kg, were involved in the experiment. The electrodes were implanted by using laparoscopy and the stimulator was embedded subcutaneously.
Part Ⅰ:An animal model of GES was built. Individualized parameters were selected. The stimulatory pattern was pulse train:pulse width0.13ms-10ms, amplitude0.5mA-12mA, frequency40Hz,2s-on,3s-off periodic rectangular pulse. Parameters were selected and adjusted according to demand during the study. Resistance was assessed.
Part Ⅱ:In this part, by using individual parameters, symptoms, food intake and body weight were measured to evaluate the effect of GES for3months.
Part Ⅲ:GES was conducted to observe the impacts on Beagle dogs' gastrointestinal hormones concentrations. The time selected to collect blood was as follows:the time at the end of GES of3months and the time at the end of sham GES of3months. Preprandial and postprandial samples were drawn accordingly.
Part Ⅳ:By using single photon emission computed tomography, individual GES was conducted to observe the impacts on Beagle dogs' gastric empting. The time selected to examining gastric empting was as follows:the time at the end of GES of3months and the time at the end of sham GES of3months accordingly. Relevant results of the gastric half-empting time, the retention rate of solid meal at60minutes and120minutes were recorded.
Party Ⅴ:By the method of histopathology, pathological changes at the implant sites were observed. The histocompatibility was evaluated.
Results
The study was successfully complete in all eight dogs with good compliance. No complication occurred during the study.
Part Ⅰ:The response of dogs to GES varied according to individual dogs. Symptoms of every dog during higher intensity of GES were different. During chronic GES, a trend of individualized parameters was clearly observed. The initial effective stimulation parameters included the pulse widths were0.5ms-1.0ms, and amplitudes were3mA-10mA (with the pulse widths and amplitudes adjusted and the other parameters fixed). The initial maximum acceptable parameters included the pulse widths were0.75ms-3ms, and amplitudes were8mA-10mA. The effective stimulation parameters of the later part of GES included the pulse widths were1.0ms-7.0ms, and amplitudes were10mA. Resistance was induced by chronic GES. Stimulation parameters needed to be adjusted every10.2±2.1days because of resistance. After parameters adjusted according to demand, inhibitory effect on food intake was observed by increasing the intensity of stimulation. Intermittent adjustment of stimulation parameters according to demand was required for long-term application of GES.
Part Ⅱ:At the end of GES of3months, with this new adjustable device, the mean food intake of the dogs was reduced significantly compared with that of sham GES (in group A (210.9±9.0) g/d vs.(279.1±24.6) g/d,P<0.05; in group B (157.2±12.9) g/d vs.(224.5±8.8) g/d, P<0.05). And body weight was reduced significantly compared with that of sham GES (in group A (10.4±1.1) kg vs.(11.5±0.9) kg, P<0.05; in group B (7.8±0.3) kg vs.(9.4±0.6) kg, P<0.05)
Part III:The plasma concentrations of ghrelin, PYY3.36, GLP-1, SS, leptin and insulin in preprandial levels had no statistically significant differences between the periods of GES and sham GES. The plasma concentrations of ghrelin, PYY3.36, GLP-1, SS, leptin and insulin in postprandial levels had no statistically significant differences between the periods of GES and sham GES. At the end of GES of3months, the trend of increase in preprandial plasma ghrelin, PYY3.36, leptin, the trend of increase in postprandial plasma PYY3.36, insulin, and the trend of decrease in postprandial plasma GLP-1, SS were obviously existed compared with these of sham GES.
Part IV:The gastric half-empting time at the end of GES of3months was increased compared with that of sham GES (Median:181.Omin vs.127.7min, P=0.028). The retention rate of solid meal at60minutes had no statistically significant difference between GES and sham GES (86.9±8.4%vs.82.3±7.2%, P=0.195). The retention rate of solid meal at120minutes at the end of GES of3months was increased compared with that of sham GES (67.7±13.8%vs.53.9±14.6%, P=0.055)
Part V:Good compliance was observed in all8dogs and no significant adverse reaction after implantation was observed. Pathological changes about the tissues around gastric electrical stimulator and the electrodes were very light. There was an ideal histocompatibility about this new device.
Conclusions
1. The response to GES varied according to individual dogs. Resistance was induced by chronic GES. Intermittent adjustment of stimulation parameters was required for long-term application of GES.
2. Food intake and body weight of the dogs were reduced significantly with this new adjustable device which could be used for treating obesity.
3. GES had no significant impacts on6gastrointestinal hormones in plasma.
4. The increase of the gastric half-empting time of solid meal which was induced by individual GES might be the important mechanism for reducing food intake.
5. Pathological changes about the tissues around gastric electrical stimulator and the electrodes were light. There was an ideal histocompatibility about this new device.
The individual gastric electrical stimulation was found to be safe and effective and had a potential prospect for clinical application.
肥胖在全球的急剧蔓延使得减重问题刻不容缓。由于目前缺乏能够安全而且有效减轻体重的治疗方法,因此人们迫切需要寻找新的治疗手段。胃电刺激(gastric electrical stimulation, GES)是近年来开展的一种很有前景的治疗肥胖的新方法。胃电刺激系统由胃电刺激器(又称电子脉冲发生器)和一对或多对电极共同组成。通过手术将电极植入胃壁,电极的另一端通过导线连接于胃电刺激器,由胃电刺激器发放一定模式的电脉冲刺激发挥作用。相对于传统减肥手术,胃电刺激的植入不改变胃肠道正常的解剖结构,创伤较小,安全性较高。
大量动物实验及临床研究发现胃电刺激具有抑制摄食、减轻体重的作用,但是研究还发现,并不是所有患者都可以取得较好的疗效。随着对胃电刺激研究的深入,最近越来越多的实验证明,个体内脏敏感性存在差异,而目前胃电刺激器产品只能提供波宽较窄的、固定的刺激参数,以上因素可能是导致患者疗效不佳的主要原因。这就提示了需要研发新型的胃电刺激器,以便在较大范围内实现胃电刺激参数的可调节性。
我们与清华大学微电子学研究所合作,历经5年的研究,研制出了新型的可调式胃电刺激器。这种可调式胃电刺激器,从体外发送信号调节刺激参数,可以实现参数的可调节性和多样化组合。同时由于对供电方法进行了改进,其可提供的脉冲波宽范围大大增加,可以满足不同个体的需要。
本研究应用新型可调式胃电刺激器对比格犬进行为期3个月的慢性个体化胃电刺激,同时给予3个月假刺激作为自身对照。实验过程中,首先采用一系列刺激参数进行胃电刺激,观察犬的症状和摄食量,对刺激参数进行筛选,同时观察犬的耐受规律；然后采用上述刺激参数进行3个月的慢性胃电刺激,观察胃电刺激对比格犬症状、摄食量和体重的影响,验证新型胃电刺激器的有效性。以酶联免疫吸附法和放射免疫分析的方法检测血胃肠激素,以核素闪烁扫描技术检测固体胃排空,观察胃电刺激对胃肠激素和胃排空的影响,为进一步研究胃电刺激的作用及其机理提供一定的实验基础；并且通过观察胃电刺激器植入机体后的组织相容性,进一步验证胃电刺激器的安全性。
方法
成年健康雌性比格犬8只,体重8.5-13.0kg,全麻下皮下埋置胃电刺激器,腹腔镜下植入胃电刺激电极。
第一部分：建立胃电刺激的动物模型,筛选个体化胃电刺激参数。刺激模式为串脉冲：输出波宽0.13～10ms,电流O.5mA～12mA,频率40Hz,2s-on、3s-off的周期性矩形脉冲。以一系列不同的刺激参数进行刺激,观察犬的症状和摄食量,对刺激参数进行筛选,同时观察个体化的胃电刺激参数耐受规律。
第二部分：采用个体化的刺激参数,观察胃电刺激3个月及假刺激3个月期间比格犬的症状、摄食量和体重的变化。
第三部分：观察个体化胃电刺激对比格犬外周血中摄食相关胃肠激素浓度的影响。采集胃电刺激3个月末及假刺激3个月末的进食前及进食后的血浆,通过酶联免疫吸附法及放射免疫法检测胃肠激素的浓度。
第四部分：应用核素闪烁扫描技术评价个体化胃电刺激对固体胃排空的影响。选取胃电刺激3个月末及假刺激3个月末,分别进行核素胃排空检测。计算胃半排空时间及进食后1小时、2小时胃固体存留率。
第五部分：通过观察胃电刺激器及电极固定部位组织的病理学改变,了解胃电刺激器的组织相容性,验证胃电刺激器的安全性。
结果
8只比格犬均顺利地完成了实验研究,依从性良好。
第一部分：比格犬对胃电刺激的承受性有明显个体化趋势,每只动物在高强度胃电刺激时的症状表现各不相同。不同动物的最大可接受的刺激参数波动范围较大(0.75ms/8mA～3.0ms/10mA,只对脉宽和电流强度进行调节,其它参数均固定)。在胃电刺激过程中,有效刺激参数波动范围较大(初期有效刺激参数波动在0.5ms/3mA～1.0ms/10mA,后期最大有效刺激参数波动在1.0ms/10mA～7.0ms/10mA)。同时观察到动物存在耐受现象,即连续应用相同刺激参数后,个体对胃电刺激的敏感性下降,刺激效果减弱。适当加大胃电刺激参数后,仍能够减少摄食,而不引起明显的症状。耐受出现的平均时间是10.2±2.1天。提示长期应用胃电刺激时需要个体化调整刺激参数。
第二部分：应用可调式胃电刺激器对比格犬进行3个月的个体化胃电刺激,与假刺激相比,犬的平均摄食量显著减少(A组(210.9±9.0)g/dvs.(279.1±24.6)g/d,P<0.05;B组(157.2±12.9)g/d vs.(224.5±8.8)g/d,P<0.05)；胃电刺激3个月末犬的体重较假刺激显著降低(A组(10.4±1.1)kg vs.(11.5±0.9)kg,P<0.05；B组(7.8±0.3)kg vs.(9.4±0.6) kg, P<0.05)。
第三部分：个体化胃电刺激3个月后对于进食前6种胃肠激素(Ghrelin、 PYY3-36、GLP-1、SS、Insulin、Leptin)浓度的影响,较假刺激无统计学差异。个体化胃电刺激3个月后对于进食后6种胃肠激素(Ghreln、PYY3-36、GLP-1、SS、 Insulin、Leptin)浓度的影响,较假刺激无统计学差异。其中,与假刺激相比,可以观察到胃电刺激3个月后,进食前Ghrelin、PYY3-36、Leptin有升高趋势,进食后PYY3.36. Insulin有升高趋势,进食后GLP-1、SS有降低趋势。
第四部分：胃电刺激3个月后与假刺激比较,胃电刺激可以显著延长固体胃半排空时间(Median:181.0mm vs.127.7min, P=0.028)。对胃固体餐1小时存留率无显著影响((86.9±8.4)%vs.(82.3±7.2)%,P=0.195);胃电刺激可以显著增加胃固体餐2小时存留率((67.7±13.8)%vs.(53.9±14.6)%,P=0.055)。
第五部分：动物对新型胃电刺激器的承受性良好,植入后未观察到明显的不良反应。胃电刺激器及电极植入部位的组织病理反应较轻,仅观察到刺激器周围有纤维囊形成,电极周围胃壁浆肌层有少量炎细胞浸润,粘膜及粘膜下层均未见明显炎症反应。表明该刺激器的组织相容性较好。
结论
1、比格犬对胃电刺激呈显著的个体化差异。胃电刺激过程中,动物存在耐受现象。长期应用需要个体化调整刺激参数。
2、新型可调式胃电刺激器进行的慢性个体化胃电刺激能够显著减少比格犬的摄食量,降低体重。
3、慢性个体化胃电刺激对血浆中6种摄食相关胃肠激素未见显著影响。
4、慢性个体化胃电刺激导致的固体胃排空时间延长可能是其减少摄食的重要机制。
5、动物对新型胃电刺激器的承受性良好,组织相容性好。
总之,腹腔镜下植入的慢性个体化胃电刺激创伤小、安全、有效,具有较好的临床应用前景。
Background and Objective
Obesity is a major public health problem worldwide and prevention of obesity has become a pressing task. Gastric electrical stimulation (GES) has been considered as a new promising therapeutic option in treating obesity. The system of gastric electrical stimulation consists of gastric electrical stimulator (electrical pulse generator) and one or more pairs of electrodes. The electrodes are implanted into stomach by surgery. The other side of the electrodes is connected to a gastric electrical stimulator by guide wire. The effects of GES are delivered by electrical pulses to the stomach. Gastrointestinal anatomy is not affected during the procedure of GES. GES is less invasive and a safer method for treating obesity compared with bariatric surgery.
GES has been reported to reduce food intake and body weight in animals and in human studies. However, in some studies, a loss in excess body weight was not always observed. Recently, more experiments have proved that visceral sensitivity in obesity patients to stimulation parameters was important in the stimulation process. The narrow width of pulse wave and fixed parameters pattern for all patients might be the main problems for the failure of the treatments. Anew type of gastric electrical stimulator is needed to investigate which has adjustable parameters in a wide range.
In collaboration with Institute of Microelectronics of Tsinghua University for5years, we have developed a new type of adjustable gastric electrical stimulator. The stimulation parameters of the new device are adjusted by external signal. The character of adjustment and combination of diversification can be carried out. Furthermore due to the method for power supply is improved, the output width of pulse wave can be increased greatly to meet the individual need.
In this study, the new type device was applied to produce chronic individual gastric electric stimulation on Beagle dogs for3months. Sham stimulation for3months was for own control. Parameters were selected and adjusted according to demand during the study. Resistance (i.e., diminution in the response to GES after long-term use) was assessed. Food intake and body weight were measured to evaluate the effects of GES.
Then GES was conducted to observe the impacts on Beagle dogs' gastrointestinal hormones and gastric empting and discussed the possible mechanisms underlying the effects. The histocompatibility of the device was observed to verify the safety of the device.
Methods
Eight healthy female adult Beagle dogs, ranging in weight from8.5-13.0kg, were involved in the experiment. The electrodes were implanted by using laparoscopy and the stimulator was embedded subcutaneously.
Part Ⅰ:An animal model of GES was built. Individualized parameters were selected. The stimulatory pattern was pulse train:pulse width0.13ms-10ms, amplitude0.5mA-12mA, frequency40Hz,2s-on,3s-off periodic rectangular pulse. Parameters were selected and adjusted according to demand during the study. Resistance was assessed.
Part Ⅱ:In this part, by using individual parameters, symptoms, food intake and body weight were measured to evaluate the effect of GES for3months.
Part Ⅲ:GES was conducted to observe the impacts on Beagle dogs' gastrointestinal hormones concentrations. The time selected to collect blood was as follows:the time at the end of GES of3months and the time at the end of sham GES of3months. Preprandial and postprandial samples were drawn accordingly.
Part Ⅳ:By using single photon emission computed tomography, individual GES was conducted to observe the impacts on Beagle dogs' gastric empting. The time selected to examining gastric empting was as follows:the time at the end of GES of3months and the time at the end of sham GES of3months accordingly. Relevant results of the gastric half-empting time, the retention rate of solid meal at60minutes and120minutes were recorded.
Party Ⅴ:By the method of histopathology, pathological changes at the implant sites were observed. The histocompatibility was evaluated.
Results
The study was successfully complete in all eight dogs with good compliance. No complication occurred during the study.
Part Ⅰ:The response of dogs to GES varied according to individual dogs. Symptoms of every dog during higher intensity of GES were different. During chronic GES, a trend of individualized parameters was clearly observed. The initial effective stimulation parameters included the pulse widths were0.5ms-1.0ms, and amplitudes were3mA-10mA (with the pulse widths and amplitudes adjusted and the other parameters fixed). The initial maximum acceptable parameters included the pulse widths were0.75ms-3ms, and amplitudes were8mA-10mA. The effective stimulation parameters of the later part of GES included the pulse widths were1.0ms-7.0ms, and amplitudes were10mA. Resistance was induced by chronic GES. Stimulation parameters needed to be adjusted every10.2±2.1days because of resistance. After parameters adjusted according to demand, inhibitory effect on food intake was observed by increasing the intensity of stimulation. Intermittent adjustment of stimulation parameters according to demand was required for long-term application of GES.
Part Ⅱ:At the end of GES of3months, with this new adjustable device, the mean food intake of the dogs was reduced significantly compared with that of sham GES (in group A (210.9±9.0) g/d vs.(279.1±24.6) g/d,P<0.05; in group B (157.2±12.9) g/d vs.(224.5±8.8) g/d, P<0.05). And body weight was reduced significantly compared with that of sham GES (in group A (10.4±1.1) kg vs.(11.5±0.9) kg, P<0.05; in group B (7.8±0.3) kg vs.(9.4±0.6) kg, P<0.05)
Part III:The plasma concentrations of ghrelin, PYY3.36, GLP-1, SS, leptin and insulin in preprandial levels had no statistically significant differences between the periods of GES and sham GES. The plasma concentrations of ghrelin, PYY3.36, GLP-1, SS, leptin and insulin in postprandial levels had no statistically significant differences between the periods of GES and sham GES. At the end of GES of3months, the trend of increase in preprandial plasma ghrelin, PYY3.36, leptin, the trend of increase in postprandial plasma PYY3.36, insulin, and the trend of decrease in postprandial plasma GLP-1, SS were obviously existed compared with these of sham GES.
Part IV:The gastric half-empting time at the end of GES of3months was increased compared with that of sham GES (Median:181.Omin vs.127.7min, P=0.028). The retention rate of solid meal at60minutes had no statistically significant difference between GES and sham GES (86.9±8.4%vs.82.3±7.2%, P=0.195). The retention rate of solid meal at120minutes at the end of GES of3months was increased compared with that of sham GES (67.7±13.8%vs.53.9±14.6%, P=0.055)
Part V:Good compliance was observed in all8dogs and no significant adverse reaction after implantation was observed. Pathological changes about the tissues around gastric electrical stimulator and the electrodes were very light. There was an ideal histocompatibility about this new device.
Conclusions
1. The response to GES varied according to individual dogs. Resistance was induced by chronic GES. Intermittent adjustment of stimulation parameters was required for long-term application of GES.
2. Food intake and body weight of the dogs were reduced significantly with this new adjustable device which could be used for treating obesity.
3. GES had no significant impacts on6gastrointestinal hormones in plasma.
4. The increase of the gastric half-empting time of solid meal which was induced by individual GES might be the important mechanism for reducing food intake.
5. Pathological changes about the tissues around gastric electrical stimulator and the electrodes were light. There was an ideal histocompatibility about this new device.
The individual gastric electrical stimulation was found to be safe and effective and had a potential prospect for clinical application.
引文
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