Obesity
Original Article OBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY
Retrograde Gastric Electrical Stimulation Suppresses Calorie Intake in Obese Subjects Yanli Zhang1, Shiyu Du1, Long Fang1, Shukun Yao1 and Jiande D. Z. Chen2
Objective: The effect of acute retrograde gastric electrical stimulation (RGES) on food intake, gastric accommodation, and gastric emptying in obese patients was investigated. Methods: Simple obesity patients underwent RGES or sham stimulation. The maximum food intake volume was determined and the total calorie of consumed food was calculated. Gastric emptying was determined by 99m-diethylenetriaminepentaacetic acid scintigraphy. Results: Sixteen obese patients were studied, with a median BMI of 32.1 (IQR, 31.2, 33.8) kg/m2. The median gastric emptying time was 106.1 (IQR, 81.8, 122.4) min with sham stimulation and 113.0 (IQR, 83.7, 124.8) min with RGES (P 5 0.352). The mean maximum satiety food intake was 580 (IQR, 510, 725) mL with sham stimulation and 490 (IQR, 385, 590) mL with RGES (P 5 0.003). No statistically significant difference was noted between sham stimulation and RGES in the 1 and 2-h food retention rate. The total calories of maximum satiety food intake with sham stimulation were 985.2 (IQR, 842.5, 1063.1) kcal and 759.9 (IQR, 547.9, 784.9) kcal with RGES (P 5 0.007). Conclusions: Acute RGES reduces calorie intake by decreasing gastric accommodation in obese subjects. Obesity (2014) 22, 1447–1451. doi:10.1002/oby.20664
Introduction Obesity carries significant risk for cardiovascular diseases and diabetes (1). With rapid economic development and improved living conditions for the past few decades, overweight and obesity has become an important public health issue in China (2). Though conventional approaches of caloric restriction, exercise, behavioral therapies, pharmacotherapies and surgery each induces substantial weight loss, the loss is not sustained in the majority of patients (3). Two drugs approved by the US FDA, phentermine and topiramate extendedrelease and lorcaserin, only have modest effect on body weight. Recently, implantable gastric stimulation (IGS) has been used as a novel approach for the management of obesity (4). In IGS, electrodes are implanted laparoscopically in the muscular layer of the stomach and generate electric signals to induce expansion of the fundus. It is speculated that electrical stimulation causes the gastrointestinal system to release satiety signals equivalent to those conveyed after a meal by the vagus nerve, thus suppressing appetite and reducing body weight (5). IGS has been evaluated as a weight loss therapy for obese subjects (6).
Retrograde gastric electrical stimulation (RGES) is a novel modality for gastric electrical stimulation (GES) based on IGS through temporary retrograde pacing with two electrode pairs positioned proximal to the pylorus. RGES has been shown to markedly reduce water and food intake in healthy subjects and delay emptying of solid food from the stomach without apparent side effects (7,8). However, there has been no report on the effect of RGES on food intake and gastric accommodation in obese patients. In the current study, we investigated the response of obese subjects to RGES by measuring gastric accommodation, food retention rate and gastric emptying.
Methods Patients Subjects with simple obesity whose age ranged between 8 and 60 years and had a BMI 30 kg/m2 were recruited for the present study. A subject was excluded if he or she had (1) secondary obesity; (2) severe diseases that prevented participation in the study; (3) reflux esophagitis, erosive gastritis, atrophic gastritis, and peptic ulcer; (4) swallowing difficulty or sensitivity to nasal intubation;
1 Department of gastroenterology, China-Japan Friendship Hospital, Beijing, China. Correspondence: Shiyu Du ([email protected]) or Shukun Yao ([email protected]) 2 Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas, USA
Funding agencies: This work is supported by National Natural Science Fund project- effects of inhibitory gastric electric stimulation on gastric motility and brain-gut peptides, and funded by national appropriations. Disclosure: The authors declared no conflict of interest. Grant No. 81070299 Period: From January 2011 to December 2013. Received: 21 May 2013; Accepted: 12 November 2013; Published online 25 November 2013. doi:10.1002/oby.20664
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Obesity | VOLUME 22 | NUMBER 6 | JUNE 2014
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RGES Reduces Calorie Intake by Obese Subjects Zhang et al.
TABLE 1 Patient demographic data and mucosal gastric electrode parameters (N 5 16)
Age (y) BMI (kg/m2) Mucosal gastric electrodes Width (ms) Stimulation energy (smA2) Symptom scores
Total (n 5 16)
Male (n 5 8)
Female (n 5 8)
P-value
39 (30, 42) 32.1 (31.2, 33.8)
39 (35, 45) 31.7 (31.4, 32.5)
35 (27, 42) 33.3 (30.9, 35.0
0.291 0.371
5.5 (2.5, 8) 528 (240, 768) 2.5 (2.0, 3.25)
3.5 (1.5, 7.5) 336 (144, 720) 2.0 (2.0, 2.5)
6.5 (3.5, 9.0) 624 (336, 864) 3.25 (2.5, 4.0)
0.171 0.171 0.055
Data were displayed as median (IQR). P-values are from Mann-Whitney U test.
(5) pregnant or lactating women; and (6) severe mental illnesses. All participants provided written informed consent. The study protocol was approved by the Ethics Committee of China-Japan Friendship Hospital, Beijing, China, and the study was carried out in accordance with the Declaration of Helsinki.
interest (ROIs) drawn around the stomach. The percentage retention in the stomach was calculated as a function of time using the decaycorrected, geometric mean of 99mTc counts. Gastric emptying time (min) and solid food retention rate (%) at 1 and 2 hours were recorded.
Retrograde gastric electrical stimulation
Food intake test
The subjects were fasted for at least 8 hours before implantation of the electrodes, which were provided as gifts by Medtronic (Switzerland). A temporary transvenous cardiac pacing lead system (Model 6416, Medtronic) was used for RGES. The lead was inserted into the stomach by nasal intubation before the endoscope was advanced via the mouth. After the antrum was adequately exposed, the distal electrode was screwed into the mucosa along the greater curvature of 5 cm above the pylorus and fixed with one or two titanium clamps. The proximal electrode was affixed to the surface of the gastric mucosa with one or two titanium clamps. The guide catheter was then pulled out of the stomach. Daily roentgenography was performed to ensure that the electrodes were properly positioned. GES was performed via the bipolar electrodes attached to the mucosa/ submucosa of the distal antrum using a universal pulse generator (Acupulser model A310, World Precision Instrument, Sarasota, FL). The pulsed train was on for a period of 2 s and off for 3 s, with an output current of 10 mA at a frequency of 40 Hz. The pulse width was increased every 2 min at an increment of 1 ms with the maximum width less than 20 ms (9). RGES or sham stimulation was performed.
Liquid nutrient load test For determination of gastric accommodation, a liquid meal (0.75 Kcal/mL) was prepared from 100 g whole milk power (Nestle, China) and 50 g solid nutrient drink (Gaolegao, Tianjin, China). The meal contained 48% carbohydrate, 13% protein, and 39% fat. After an 8-h fast, a subject was asked to drink the liquid within 5 min to satiety. The maximum intake volume (mL) was recorded. RGES was performed 30 min prior to, and 30 min following the liquid meal.
Gastric emptying Gastric emptying of a standard solid food meal labeled with 1 mCi 99m -diethylenetriaminepentaacetic acid (99mTc-DTPA) was calculated by measuring total gastric counts obtained from manual regions of
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After a 6-h fast, the subjects were provided with instant noodles, bread, and sausages and asked to eat to satiety within 20 min. The volume of food intake and the total calorie of consumed food were calculated.
Statistical analysis The volume of food intake, the maximum tolerated volume of liquid diet, gastric emptying time, and food retention rate at 1 and 2 hours were recorded. Continuous data were presented as median and interquartile range (IQR) and analyzed using SPSS15.0 statistical software (SPSS, Chicago, IL). Because of the small sample size, differences between RGES and sham periods were assessed by using Wilcoxon signed-rank test. Moreover, the Mann-Whitney U test was applied to determine the difference between genders. All statistical assessments were two-tailed and considered significant at the 0.05 level.
Results Patient demographic data and mucosal gastric electrode parameters Sixteen obese patients were enrolled in the study, and included eight males and eight females with a median age of 39 (IQR, 30, 42) years. The median age was 35 (IQR, 35, 45) years for male subjects and 35 (IQR, 27, 42) years for female subjects (P 5 0.291). They had a median BMI of 32.1 (IQR, 31.2, 33.8) kg/m2. Male and female subjects had comparable BMI (P 5 0.371). Patient demographic data and mucosal gastric electrode parameters are shown in Table 1.
Acute RGES reduces calorie intake by decreasing gastric accommodation in obese subjects We were interested in whether acute RGES exerted any effect on gastric accommodation. The liquid nutrient load test revealed that sham-
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Original Article
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OBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY
Figure 1 The maximum intake volume of obese subjects (n 5 18) with sham stimulation and acute retrograde gastric electrical stimulation (RGES). *Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signedrank test, P < 0.05.
stimulated obese patients had a mean volume of the maximum satiety food intake of 580 (IQR, 510, 725) mL. RGES noticeably reduced the maximum liquid load intake to 490 (IQR, 385, 590) mL, which was 16% lower than that of sham-stimulated subjects (P 5 0.003) (Figure 1). Furthermore, the total calories of maximum satiety food intake of obese subjects with sham stimulation was 985.2 (IQR, 842.5, 1063.1) kcal. Acute RGES reduced the total calories by 23% to 759.9 (IQR, 547.9, 784.9) kcal (P 5 0.007) (Figure 2).
RGES prolongs gastric emptying in male obese subjects The median gastric emptying time was 106.1 (IQR, 81.8, 122.4) min with sham stimulation (Table 2). Acute RGES caused a statistically insignificant prolongation of gastric emptying time (median, 113.0 and IQR, 83.7, 124.8 min) (P 5 0.352). Furthermore, no statistically significant difference was noted with sham stimulation or RGES in the 1- and 2-hour food retention rate. We further analyzed whether RGES had different effects on food intake and gastric emptying stratified by sex. In male obese subjects, the median gastric emptying time was 81.8 (IQR, 70.4, 106.1) min with sham stimulation (Table 2). Acute RGES significantly prolonged gastric emptying time (median, 102.5; IQR, 83.7, 115.3) min) (P < 0.05). By contrast, RGES caused no apparent prolongation of gastric emptying time in female subjects compared with sham stimulation (sham: median, 122.4; IQR, 102.6, 129.6 vs. RGES: median, 120.6; IQR, 100.0, 128.2; P 5 0.327). Furthermore, the 1- and 2-h food retention rate with RGES was significantly higher compared with sham stimulation in male subjects (both, P < 0.05), whereas no marked difference was noted in female obese subjects with sham stimulation and RGES (both, P > 0.05).
Rapid vs. slow gastric emptying The median gastric emptying time (106 min) with sham stimulation was chosen as the cutoff for arbitrary categorization of the subjects into rapid and slow gastric emptying subjects. Eight patients fell
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Figure 2 The total calories of consumed food with sham stimulation and acute retrograde gastric electrical stimulation (RGES). *Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signed-rank test, P < 0.05.
into the rapid gastric emptying group and 8 into the slow emptying group. The median gastric emptying time was 88.7 (IQR, 78.5, 101.2) min for the rapid gastric emptying group and 123.6 (IQR, 116.0, 130.4) min for the slow gastric emptying group (P 5 0.001) (Table 3). Three-fourths (75%, 6/8) of patients in the rapid gastric emptying group had markedly prolonged gastric emptying time, whereas 37.5% (3/8) of the patients in the slow gastric emptying group had prolonged gastric emptying time (P < 0.05). The 1- and 2-hour food retention rates with RGES were significantly higher in the slow gastric emptying group than in the rapid gastric emptying group (P < 0.05).
Discussion Implantable gastric stimulators (IGS) have been used as a treatment for obesity, and this approach often employs short pulse trains (2 s on, 3 s off, pulse frequency 40 Hz, pulse width 0.3 ms, and pulse amplitude 5–10 mA). Literature has shown that GES using pulse trains or long pulses at a width >1 ms can affect gastric motility by causing changes in the gastric slow wave, antral contraction, and gastric emptying (7,9,10). Such stimulation is called inhibitory GES (iGES). In this study, the RGES we used was a type of iGES. IGS with a width < 1 ms has no or little effect on gastric motility. IGS and iGES both activate satiety neurons located in the hypothalamus through vagal and spinal afferent pathways, and alter central nervous system and gastrointestinal hormone levels. Study has shown that RGES has stronger effects on mechanical, neuronal, and hormonal pathways as compared to IGS (11-13). Animal studies revealed that compared to IGS, RGES markedly inhibits slow wave propagation in the stomach and causes greater expansion of gastric fundus, thus delaying gastric emptying (14). Yao et al. demonstrated that RGES markedly reduced food and water intake and delayed gastric emptying without causing noticeable side effects (7,8). In the current study, we investigated the effects of RGES on gastric functions of obese patients and found
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RGES Reduces Calorie Intake by Obese Subjects Zhang et al.
TABLE 2 Gastric emptying time and food retention rate in obese patient
Parameters
Acute RGES
Gastric half-emptying 113.0 time (N 5 16), min Male (n 5 8) 102.5 Female (n 5 8) 120.6 Solid food retention rate (%) 1 hour 65.0 Male 60.9 Female 68.0 2 hour 47.5 Male 42.9 Female 51.0
(83.7, 124.8)
TABLE 3 Gastric emptying time and food retention rate in obese patients with rapid or slow gastric emptying
Sham stimulation
P
106.1 (81.8, 122.4)
0.352
(83.7, 115.3) 81.8 (70.4, 106.1) 0.050a (100.0, 128.2) 122.4 (102.6, 129.6) 0.327 (57.9, (53.4, (61.9, (31.4, (27.7, (39.7,
70.5) 68.9) 73.1) 53.2) 49.6) 54.1)
64.3 54.1 67.2 44.5 28.7 49.6
(54.1, (48.8, (60.8, (28.7, (17.9, (39.7,
67.2) 60.3) 75.7) 49.6) 44.6) 54.3)
0.326 0.036a 0.208 0.121 0.036a 0.779
Data presented as median (interquartile range). a Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signed-rank test, P < 0.05.
that RGES significantly reduced calorie intake and gastric accommodation as reflected by markedly reduced maximum tolerated intake volume of a liquid diet. Furthermore, compared to sham stimulation RGES markedly delayed gastric emptying time in male obese subjects. The mechanisms whereby RGES reduces gastric accommodation in obese patients include disruption of gastric activities and gastric motility disorder and gastric expansion, enhancement and delay of satiety. In dogs, RGES has been shown to cause expansion of an empty stomach (15). RGES may affect signal transduction of visceral afferent nerves and lower tolerance. However, the exact mechanisms underlying reduction in gastric accommodation by RGES require further investigation. The United States IGS trial (5) was not as successful as the European trail (16), and this may have been the result of some potential confounding factors. Imprecise inclusion/exclusion criteria might have allowed the inclusion of patients with dysphagia. Some patients might have had poor compliance, as they might have increased ingestion in an attempt to confirm the device’s effectiveness. The 6mA output current was lower than the 10-mA current used in the European trial. Higher output current is more effective for weight loss. There might also have been technical problems such as dislocation of implanted wires in some patients.
Parameters Gastric half-emptying time, min Solid food retention rate (%) 1 hour 2 hour
Rapid gastric Slow gastric emptying (n 5 8) emptying (n 5 8) 88.7 (78.5, 101.2)
57.6 (48.3, 58.3) 26.6 (9.4, 32.7)
P
123.6 (116.0, 130.4) 0.001a
66.6 (60.3, 73.7) 48.9 (46.2, 54.1)
0.005a 0.006a
Data presented as median (interquartile range). a Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signed-rank test, P < 0.05.
and through temporary retrograde pacing causes the spread of retrograde electric waves from the gastric antrum to the proximal stomach, antagonizing the propagation of the normal gastric slow wave. These waves disrupt the normal electrical waves that propagate distally and cause gastric hypomotility. In the present study, we found that RGES did not significantly inhibit gastric emptying in obese patients overall. We found that among the subjects, 50% showed significantly delayed gastric emptying time (>106 min). Additionally, we found that RGES markedly delayed gastric emptying time in male obese subjects while exerting no apparent effect in female obese subjects. The mechanism for this sex-dependent discrepancy needs further investigation. RGES is not appropriate as a treatment for obesity as the electrodes are only implanted temporarily; however, RGES can be used to screen the response of obese patients for long-term implanted GES. The GES parameters can then be individualized according to each patient’s internal sensitivity to RGES. Directions for future RGES research may include animal studies that elucidate the long-term effects of RGES on feeding and body weight, as well as their neuroendocrine mechanisms, cooperation with other research institutions to research and develop implantable RGES and to demonstrate their safety and effectiveness through animal studies. In conclusion, acute RGES markedly reduces calorie intake of obese patients and lowers gastric accommodation. It may be of promise for the treatment of simple obesity. O
C 2013 The Obesity Society V
The liquid nutrient diet load test measures the maximum intake volume of a liquid diet by assessing sensation of the proximal stomach and gastric accommodation. It is a simple and noninvasive method compared to the “gold standard” electronic barostat (17). Reduction in maximum intake of a liquid diet indicates impairment of gastric accommodation. We found that acute RGES caused a 16% reduction in the mean volume of the maximum satiety food intake from 580 (IQR, 510, 725) mL (sham stimulation) to 490 (IQR, 385, 590) mL. The finding indicates that RGES markedly inhibits accommodation of the proximal stomach. It has been shown that gastric emptying plays an important role in regulating food intake and increased gastric emptying may be implicated in obesity (18). RGES stimulates the distal stomach at a frequency that induces gastric hypermotility,
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References 1. Lu M, Lu Q, Zhang Y, Tian G. ApoB/apoA1 is an effective predictor of coronary heart disease risk in overweight and obesity. J Biomed Res 2011;25:266-273. 2. Day K, Alfonzo M, Chen Y, Guo Z, Lee KK. Overweight, obesity, and inactivity and urban design in rapidly growing Chinese cities. Health Place 2013;21C:29-38. 3. Huang CK, Tsai JC, Lo CH, et al. Preliminary surgical results of single-incision transumbilical laparoscopic bariatric surgery. Obes Surg 2011;21:391-394. 4. Favretti F, De Luca M, Segato G, et al. Treatment of morbid obesity with the transcend implantable gastric stimulator (IGS): A prospective survey. Obes Surg 2004;14:666-670. 5. Shikora SA, Bergenstal R, Bessler M, et al. Implantable gastric stimulation for the treatment of clinically severe obesity: Results of the SHAPE trial. Surg Obes Relat Dis 2009;5:31-37. 6. Bohdjalian A, Prager G, Aviv R, et al. One-year experience with Tantalus: A new surgical approach to treat morbid obesity. Obes Surg 2006;16:627-634.
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OBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY 7. Yao SK, Ke MY, Wang ZF, Xu DB, Zhang YL, JD Chen. Visceral sensitivity to gastric stimulation and its correlation with alterations in gastric emptying and accommodation in humans. Obes Surg 2005;15:247-253. 8. Yao SK, Ke MY, Wang ZF, Xu DB, Zhang YL, JD Chen. Retrograde gastric pacing reduces food intake and delays gastric emptying in humans: A potential therapy for obesity? Dig Dis Sci 2005;50:1569-1575. 9. Xing JH, Chen JD. Effects and mechanisms of long-pulse gastric electrical stimulation on canine gastric tone and accommodation. Neurogastroenterol Motil 2006;18:136-143. 10. Zhang J, Xu X, Chen JD. Chronic tachygastrial electrical stimulation reduces food intake in dogs. Obesity (Silver Spring) 2007;15:330-339. 11. Sun Y, Chen JD. Gastric electrical stimulation inhibits postprandial antral tone partially via nitrergic pathway in conscious dogs. Am J Physiol Regul Integr Comp Physiol 2006;290:R904-R908. 12. Sun X, Tang M, Zhang J, Chen JD. Excitatory effects of gastric electrical stimulation on gastric distension responsive neurons in ventromedial hypothalamus (VMH) in rats. Neurosci Res 2006;55:451-457.
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13. Qin C, Chen JD, Zhang J, Foreman RD. Modulatory effects and afferent pathways of gastric electrical stimulation on rat thoracic spinal neurons receiving input from the stomach. Neurosci Res 2007;57:29-39. 14. Xing J, Brody F, Brodsky J, et al. Gastric electrical-stimulation effects on canine gastric emptying, food intake, and body weight. Obes Res 2003;11:41-47. 15. Ouyang H, Yin J, Chen JD. Therapeutic potential of gastric electrical stimulation for obesity and its possible mechanisms: A preliminary canine study. Dig Dis Sci 2003;48:698-705. 16. De Luca M, Segato G, Busetto L, et al. Progress in implantable gastric stimulation: Summary of results of the European multi-center study. Obes Surg 2004;14: S33-S39. 17. Tack J, Caenepeel P, Piessevaux H, Cuomo R, Janssens J. Assessment of meal induced gastric accommodation by a satiety drinking test in health and in severe functional dyspepsia. Gut 2003;52:1271-1277. 18. Verdich C, Madsen JL, Toubro S, Buemann B, Holst JJ, Astrup A. Effect of obesity and major weight reduction on gastric emptying. Int J Obes 2000;24: 899-905.
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Original Article OBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY
Retrograde Gastric Electrical Stimulation Suppresses Calorie Intake in Obese Subjects Yanli Zhang1, Shiyu Du1, Long Fang1, Shukun Yao1 and Jiande D. Z. Chen2
Objective: The effect of acute retrograde gastric electrical stimulation (RGES) on food intake, gastric accommodation, and gastric emptying in obese patients was investigated. Methods: Simple obesity patients underwent RGES or sham stimulation. The maximum food intake volume was determined and the total calorie of consumed food was calculated. Gastric emptying was determined by 99m-diethylenetriaminepentaacetic acid scintigraphy. Results: Sixteen obese patients were studied, with a median BMI of 32.1 (IQR, 31.2, 33.8) kg/m2. The median gastric emptying time was 106.1 (IQR, 81.8, 122.4) min with sham stimulation and 113.0 (IQR, 83.7, 124.8) min with RGES (P 5 0.352). The mean maximum satiety food intake was 580 (IQR, 510, 725) mL with sham stimulation and 490 (IQR, 385, 590) mL with RGES (P 5 0.003). No statistically significant difference was noted between sham stimulation and RGES in the 1 and 2-h food retention rate. The total calories of maximum satiety food intake with sham stimulation were 985.2 (IQR, 842.5, 1063.1) kcal and 759.9 (IQR, 547.9, 784.9) kcal with RGES (P 5 0.007). Conclusions: Acute RGES reduces calorie intake by decreasing gastric accommodation in obese subjects. Obesity (2014) 22, 1447–1451. doi:10.1002/oby.20664
Introduction Obesity carries significant risk for cardiovascular diseases and diabetes (1). With rapid economic development and improved living conditions for the past few decades, overweight and obesity has become an important public health issue in China (2). Though conventional approaches of caloric restriction, exercise, behavioral therapies, pharmacotherapies and surgery each induces substantial weight loss, the loss is not sustained in the majority of patients (3). Two drugs approved by the US FDA, phentermine and topiramate extendedrelease and lorcaserin, only have modest effect on body weight. Recently, implantable gastric stimulation (IGS) has been used as a novel approach for the management of obesity (4). In IGS, electrodes are implanted laparoscopically in the muscular layer of the stomach and generate electric signals to induce expansion of the fundus. It is speculated that electrical stimulation causes the gastrointestinal system to release satiety signals equivalent to those conveyed after a meal by the vagus nerve, thus suppressing appetite and reducing body weight (5). IGS has been evaluated as a weight loss therapy for obese subjects (6).
Retrograde gastric electrical stimulation (RGES) is a novel modality for gastric electrical stimulation (GES) based on IGS through temporary retrograde pacing with two electrode pairs positioned proximal to the pylorus. RGES has been shown to markedly reduce water and food intake in healthy subjects and delay emptying of solid food from the stomach without apparent side effects (7,8). However, there has been no report on the effect of RGES on food intake and gastric accommodation in obese patients. In the current study, we investigated the response of obese subjects to RGES by measuring gastric accommodation, food retention rate and gastric emptying.
Methods Patients Subjects with simple obesity whose age ranged between 8 and 60 years and had a BMI 30 kg/m2 were recruited for the present study. A subject was excluded if he or she had (1) secondary obesity; (2) severe diseases that prevented participation in the study; (3) reflux esophagitis, erosive gastritis, atrophic gastritis, and peptic ulcer; (4) swallowing difficulty or sensitivity to nasal intubation;
1 Department of gastroenterology, China-Japan Friendship Hospital, Beijing, China. Correspondence: Shiyu Du ([email protected]) or Shukun Yao ([email protected]) 2 Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas, USA
Funding agencies: This work is supported by National Natural Science Fund project- effects of inhibitory gastric electric stimulation on gastric motility and brain-gut peptides, and funded by national appropriations. Disclosure: The authors declared no conflict of interest. Grant No. 81070299 Period: From January 2011 to December 2013. Received: 21 May 2013; Accepted: 12 November 2013; Published online 25 November 2013. doi:10.1002/oby.20664
www.obesityjournal.org
Obesity | VOLUME 22 | NUMBER 6 | JUNE 2014
1447
Obesity
RGES Reduces Calorie Intake by Obese Subjects Zhang et al.
TABLE 1 Patient demographic data and mucosal gastric electrode parameters (N 5 16)
Age (y) BMI (kg/m2) Mucosal gastric electrodes Width (ms) Stimulation energy (smA2) Symptom scores
Total (n 5 16)
Male (n 5 8)
Female (n 5 8)
P-value
39 (30, 42) 32.1 (31.2, 33.8)
39 (35, 45) 31.7 (31.4, 32.5)
35 (27, 42) 33.3 (30.9, 35.0
0.291 0.371
5.5 (2.5, 8) 528 (240, 768) 2.5 (2.0, 3.25)
3.5 (1.5, 7.5) 336 (144, 720) 2.0 (2.0, 2.5)
6.5 (3.5, 9.0) 624 (336, 864) 3.25 (2.5, 4.0)
0.171 0.171 0.055
Data were displayed as median (IQR). P-values are from Mann-Whitney U test.
(5) pregnant or lactating women; and (6) severe mental illnesses. All participants provided written informed consent. The study protocol was approved by the Ethics Committee of China-Japan Friendship Hospital, Beijing, China, and the study was carried out in accordance with the Declaration of Helsinki.
interest (ROIs) drawn around the stomach. The percentage retention in the stomach was calculated as a function of time using the decaycorrected, geometric mean of 99mTc counts. Gastric emptying time (min) and solid food retention rate (%) at 1 and 2 hours were recorded.
Retrograde gastric electrical stimulation
Food intake test
The subjects were fasted for at least 8 hours before implantation of the electrodes, which were provided as gifts by Medtronic (Switzerland). A temporary transvenous cardiac pacing lead system (Model 6416, Medtronic) was used for RGES. The lead was inserted into the stomach by nasal intubation before the endoscope was advanced via the mouth. After the antrum was adequately exposed, the distal electrode was screwed into the mucosa along the greater curvature of 5 cm above the pylorus and fixed with one or two titanium clamps. The proximal electrode was affixed to the surface of the gastric mucosa with one or two titanium clamps. The guide catheter was then pulled out of the stomach. Daily roentgenography was performed to ensure that the electrodes were properly positioned. GES was performed via the bipolar electrodes attached to the mucosa/ submucosa of the distal antrum using a universal pulse generator (Acupulser model A310, World Precision Instrument, Sarasota, FL). The pulsed train was on for a period of 2 s and off for 3 s, with an output current of 10 mA at a frequency of 40 Hz. The pulse width was increased every 2 min at an increment of 1 ms with the maximum width less than 20 ms (9). RGES or sham stimulation was performed.
Liquid nutrient load test For determination of gastric accommodation, a liquid meal (0.75 Kcal/mL) was prepared from 100 g whole milk power (Nestle, China) and 50 g solid nutrient drink (Gaolegao, Tianjin, China). The meal contained 48% carbohydrate, 13% protein, and 39% fat. After an 8-h fast, a subject was asked to drink the liquid within 5 min to satiety. The maximum intake volume (mL) was recorded. RGES was performed 30 min prior to, and 30 min following the liquid meal.
Gastric emptying Gastric emptying of a standard solid food meal labeled with 1 mCi 99m -diethylenetriaminepentaacetic acid (99mTc-DTPA) was calculated by measuring total gastric counts obtained from manual regions of
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After a 6-h fast, the subjects were provided with instant noodles, bread, and sausages and asked to eat to satiety within 20 min. The volume of food intake and the total calorie of consumed food were calculated.
Statistical analysis The volume of food intake, the maximum tolerated volume of liquid diet, gastric emptying time, and food retention rate at 1 and 2 hours were recorded. Continuous data were presented as median and interquartile range (IQR) and analyzed using SPSS15.0 statistical software (SPSS, Chicago, IL). Because of the small sample size, differences between RGES and sham periods were assessed by using Wilcoxon signed-rank test. Moreover, the Mann-Whitney U test was applied to determine the difference between genders. All statistical assessments were two-tailed and considered significant at the 0.05 level.
Results Patient demographic data and mucosal gastric electrode parameters Sixteen obese patients were enrolled in the study, and included eight males and eight females with a median age of 39 (IQR, 30, 42) years. The median age was 35 (IQR, 35, 45) years for male subjects and 35 (IQR, 27, 42) years for female subjects (P 5 0.291). They had a median BMI of 32.1 (IQR, 31.2, 33.8) kg/m2. Male and female subjects had comparable BMI (P 5 0.371). Patient demographic data and mucosal gastric electrode parameters are shown in Table 1.
Acute RGES reduces calorie intake by decreasing gastric accommodation in obese subjects We were interested in whether acute RGES exerted any effect on gastric accommodation. The liquid nutrient load test revealed that sham-
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Original Article
Obesity
OBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY
Figure 1 The maximum intake volume of obese subjects (n 5 18) with sham stimulation and acute retrograde gastric electrical stimulation (RGES). *Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signedrank test, P < 0.05.
stimulated obese patients had a mean volume of the maximum satiety food intake of 580 (IQR, 510, 725) mL. RGES noticeably reduced the maximum liquid load intake to 490 (IQR, 385, 590) mL, which was 16% lower than that of sham-stimulated subjects (P 5 0.003) (Figure 1). Furthermore, the total calories of maximum satiety food intake of obese subjects with sham stimulation was 985.2 (IQR, 842.5, 1063.1) kcal. Acute RGES reduced the total calories by 23% to 759.9 (IQR, 547.9, 784.9) kcal (P 5 0.007) (Figure 2).
RGES prolongs gastric emptying in male obese subjects The median gastric emptying time was 106.1 (IQR, 81.8, 122.4) min with sham stimulation (Table 2). Acute RGES caused a statistically insignificant prolongation of gastric emptying time (median, 113.0 and IQR, 83.7, 124.8 min) (P 5 0.352). Furthermore, no statistically significant difference was noted with sham stimulation or RGES in the 1- and 2-hour food retention rate. We further analyzed whether RGES had different effects on food intake and gastric emptying stratified by sex. In male obese subjects, the median gastric emptying time was 81.8 (IQR, 70.4, 106.1) min with sham stimulation (Table 2). Acute RGES significantly prolonged gastric emptying time (median, 102.5; IQR, 83.7, 115.3) min) (P < 0.05). By contrast, RGES caused no apparent prolongation of gastric emptying time in female subjects compared with sham stimulation (sham: median, 122.4; IQR, 102.6, 129.6 vs. RGES: median, 120.6; IQR, 100.0, 128.2; P 5 0.327). Furthermore, the 1- and 2-h food retention rate with RGES was significantly higher compared with sham stimulation in male subjects (both, P < 0.05), whereas no marked difference was noted in female obese subjects with sham stimulation and RGES (both, P > 0.05).
Rapid vs. slow gastric emptying The median gastric emptying time (106 min) with sham stimulation was chosen as the cutoff for arbitrary categorization of the subjects into rapid and slow gastric emptying subjects. Eight patients fell
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Figure 2 The total calories of consumed food with sham stimulation and acute retrograde gastric electrical stimulation (RGES). *Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signed-rank test, P < 0.05.
into the rapid gastric emptying group and 8 into the slow emptying group. The median gastric emptying time was 88.7 (IQR, 78.5, 101.2) min for the rapid gastric emptying group and 123.6 (IQR, 116.0, 130.4) min for the slow gastric emptying group (P 5 0.001) (Table 3). Three-fourths (75%, 6/8) of patients in the rapid gastric emptying group had markedly prolonged gastric emptying time, whereas 37.5% (3/8) of the patients in the slow gastric emptying group had prolonged gastric emptying time (P < 0.05). The 1- and 2-hour food retention rates with RGES were significantly higher in the slow gastric emptying group than in the rapid gastric emptying group (P < 0.05).
Discussion Implantable gastric stimulators (IGS) have been used as a treatment for obesity, and this approach often employs short pulse trains (2 s on, 3 s off, pulse frequency 40 Hz, pulse width 0.3 ms, and pulse amplitude 5–10 mA). Literature has shown that GES using pulse trains or long pulses at a width >1 ms can affect gastric motility by causing changes in the gastric slow wave, antral contraction, and gastric emptying (7,9,10). Such stimulation is called inhibitory GES (iGES). In this study, the RGES we used was a type of iGES. IGS with a width < 1 ms has no or little effect on gastric motility. IGS and iGES both activate satiety neurons located in the hypothalamus through vagal and spinal afferent pathways, and alter central nervous system and gastrointestinal hormone levels. Study has shown that RGES has stronger effects on mechanical, neuronal, and hormonal pathways as compared to IGS (11-13). Animal studies revealed that compared to IGS, RGES markedly inhibits slow wave propagation in the stomach and causes greater expansion of gastric fundus, thus delaying gastric emptying (14). Yao et al. demonstrated that RGES markedly reduced food and water intake and delayed gastric emptying without causing noticeable side effects (7,8). In the current study, we investigated the effects of RGES on gastric functions of obese patients and found
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RGES Reduces Calorie Intake by Obese Subjects Zhang et al.
TABLE 2 Gastric emptying time and food retention rate in obese patient
Parameters
Acute RGES
Gastric half-emptying 113.0 time (N 5 16), min Male (n 5 8) 102.5 Female (n 5 8) 120.6 Solid food retention rate (%) 1 hour 65.0 Male 60.9 Female 68.0 2 hour 47.5 Male 42.9 Female 51.0
(83.7, 124.8)
TABLE 3 Gastric emptying time and food retention rate in obese patients with rapid or slow gastric emptying
Sham stimulation
P
106.1 (81.8, 122.4)
0.352
(83.7, 115.3) 81.8 (70.4, 106.1) 0.050a (100.0, 128.2) 122.4 (102.6, 129.6) 0.327 (57.9, (53.4, (61.9, (31.4, (27.7, (39.7,
70.5) 68.9) 73.1) 53.2) 49.6) 54.1)
64.3 54.1 67.2 44.5 28.7 49.6
(54.1, (48.8, (60.8, (28.7, (17.9, (39.7,
67.2) 60.3) 75.7) 49.6) 44.6) 54.3)
0.326 0.036a 0.208 0.121 0.036a 0.779
Data presented as median (interquartile range). a Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signed-rank test, P < 0.05.
that RGES significantly reduced calorie intake and gastric accommodation as reflected by markedly reduced maximum tolerated intake volume of a liquid diet. Furthermore, compared to sham stimulation RGES markedly delayed gastric emptying time in male obese subjects. The mechanisms whereby RGES reduces gastric accommodation in obese patients include disruption of gastric activities and gastric motility disorder and gastric expansion, enhancement and delay of satiety. In dogs, RGES has been shown to cause expansion of an empty stomach (15). RGES may affect signal transduction of visceral afferent nerves and lower tolerance. However, the exact mechanisms underlying reduction in gastric accommodation by RGES require further investigation. The United States IGS trial (5) was not as successful as the European trail (16), and this may have been the result of some potential confounding factors. Imprecise inclusion/exclusion criteria might have allowed the inclusion of patients with dysphagia. Some patients might have had poor compliance, as they might have increased ingestion in an attempt to confirm the device’s effectiveness. The 6mA output current was lower than the 10-mA current used in the European trial. Higher output current is more effective for weight loss. There might also have been technical problems such as dislocation of implanted wires in some patients.
Parameters Gastric half-emptying time, min Solid food retention rate (%) 1 hour 2 hour
Rapid gastric Slow gastric emptying (n 5 8) emptying (n 5 8) 88.7 (78.5, 101.2)
57.6 (48.3, 58.3) 26.6 (9.4, 32.7)
P
123.6 (116.0, 130.4) 0.001a
66.6 (60.3, 73.7) 48.9 (46.2, 54.1)
0.005a 0.006a
Data presented as median (interquartile range). a Indicates a significant difference between RGES and sham stimulation by using Wilcoxon signed-rank test, P < 0.05.
and through temporary retrograde pacing causes the spread of retrograde electric waves from the gastric antrum to the proximal stomach, antagonizing the propagation of the normal gastric slow wave. These waves disrupt the normal electrical waves that propagate distally and cause gastric hypomotility. In the present study, we found that RGES did not significantly inhibit gastric emptying in obese patients overall. We found that among the subjects, 50% showed significantly delayed gastric emptying time (>106 min). Additionally, we found that RGES markedly delayed gastric emptying time in male obese subjects while exerting no apparent effect in female obese subjects. The mechanism for this sex-dependent discrepancy needs further investigation. RGES is not appropriate as a treatment for obesity as the electrodes are only implanted temporarily; however, RGES can be used to screen the response of obese patients for long-term implanted GES. The GES parameters can then be individualized according to each patient’s internal sensitivity to RGES. Directions for future RGES research may include animal studies that elucidate the long-term effects of RGES on feeding and body weight, as well as their neuroendocrine mechanisms, cooperation with other research institutions to research and develop implantable RGES and to demonstrate their safety and effectiveness through animal studies. In conclusion, acute RGES markedly reduces calorie intake of obese patients and lowers gastric accommodation. It may be of promise for the treatment of simple obesity. O
C 2013 The Obesity Society V
The liquid nutrient diet load test measures the maximum intake volume of a liquid diet by assessing sensation of the proximal stomach and gastric accommodation. It is a simple and noninvasive method compared to the “gold standard” electronic barostat (17). Reduction in maximum intake of a liquid diet indicates impairment of gastric accommodation. We found that acute RGES caused a 16% reduction in the mean volume of the maximum satiety food intake from 580 (IQR, 510, 725) mL (sham stimulation) to 490 (IQR, 385, 590) mL. The finding indicates that RGES markedly inhibits accommodation of the proximal stomach. It has been shown that gastric emptying plays an important role in regulating food intake and increased gastric emptying may be implicated in obesity (18). RGES stimulates the distal stomach at a frequency that induces gastric hypermotility,
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