Individualized Parameters Selection Of Gastric Electrical Stimulation And Its Effects On Beagle Dogs’ Food Intake, Body Weight,Gastrointestinal Hormones And Gastric Emptying

Background and ObjectiveObesity 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.MethodsEight 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.ResultsThe 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.Conclusions1. 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.