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Division of Endocrinology (F.L., G.I., M.C.R., A.Z., C.T., C.V.I., U.D.M.), Departments of Clinical Sciences, Surgery P. Stefanini (G.S., N.P., M.S.B., N.B.), and Dietology (V.B.), University "La Sapienza," Rome, Italy 00161
Address all correspondence and requests for reprints to: Frida Leonetti, M.D., Ph.D., Clinica Medica 2, Dipartimento di Scienze Cliniche, Policlinico Umberto I, Viale del Policlinico 155, 00161 Roma, Italy. E-mail: frida.leonetti{at}tin.it.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study we selected 43 subjects. We studied 21 obese subjects who underwent laparoscopic bariatric surgery: 10 subjects with LASGB and 11 subjects who underwent LRYGBP. Both procedures were performed from 9 to 15 months before the study. Ten obese subjects matched for body mass index (BMI) to subjects who underwent bariatric surgery, eight patients who had undergone total gastrectomy for gastric cancer, and eight normoweight subjects formed the control groups. All the subjects had stable body weight, as defined by a change of no more than 5% in body weight during the preceding 3 months. No postgastrectomy subjects presented with cancer or cachexia at the time of sampling for ghrelin.
Obesity was defined as BMI more than 30 kg/m2. None had any evidence of psychiatric, hepatic, renal, and metabolic diseases, such as diabetes and hypothyroidism, by routine history, physical examination, and laboratory screening tests (fasting glucose, plasmatic creatinine, lipids, aspartate aminotransferase, alanine aminotransferase and glutamyl transferase, red and white cell count).
Experimental protocol
This was a cross-sectional study. All subjects were admitted to our Day Hospital after fasting overnight. An iv catheter was placed in the arm, and repeated blood samples for plasma ghrelin, insulin, and glucose measurements were performed. After all subjects had a light breakfast (250 g milk and 25 g bread) at 0900 h and lunch at 1300 h (50 g pasta; 70 g bread; 100 g steak; vegetables; and fruit, a macronutrient composition approximating that of the average lunch in Italy). Plasma ghrelin, glucose, and insulin profiles were determined with venous sampling before and after breakfast and lunch at 0900 h, 1000 h, 1100 h, 1300 h, 1400 h, and 1500 h. Samples were stored at 4 C during the collection period, after which plasma was stored at -80 C.
This study was conducted in accordance with the guidelines proposed in the Declaration of Helsinki and has been approved by review committee of " La Sapienza" University. All subjects gave their informed consent before the study began.
Brief description of surgical procedures
LASGB. Laparoscopic gastric banding was firstly reported by Belachew et al. in 1993 (23). First, a retrogastric tunnel is created, beginning on the lesser curvature at the of equator of a calibrator tube. The balloon of the calibrator tube is inflated with 25 cc of air and then pulled until the balloon is swinging against the gastroesophageal junction. The retrogastric tunnel is created above the peritoneal reflection of the bursa omentalis. The lap band (INAMED Health BioEnterics Corporation, Santa Barbara, CA) is then passed through this tunnel. The attached silicon tubing is then passed through the buckle of the band until it locks. The anterior wall of the stomach below the band is then secured to the wall above the band with interrupted suture to avoid slippage. The silicone band placed around the upper stomach creates a small pouch with a narrowed outlet. The inner surface of the silicone ring is inflatable and connected by kink-resistant. tubing to the access post, which permits postoperatory percutaneous stoma size adjustment. The pouch fills quickly with solid food and empties slowly to relieve hunger and produce a feeling of fullness.
LRYGBP. LRYGBP was first described by Wittgrove and Clark (24). We adopted the technique reported by Gagner. A 15-cc gastric pouch is created and isolated from the distal stomach by several applications of an endo-GIA II linear stapler (Tyco Healthcare, Mansfield, MA). After division of the jejunum 50 cm distal to the ligament of Treitz, the distal limb is anastomized to the isolated gastric pouch (antecolic-antegastric). The gastrojejunostomy is created with a 25 circular stapler. The laterolateral jejunojejunostomy is constructed with standard laparoscopic techniques 100 cm distal to the gastrojejunostomy using endo-GIA II linear stapler (Tyco Healthcare).
Gastrectomy. Total gastrectomy with D2 lymphadenectomy plus splenectomy was carried out for gastric cancer (stage II) at least 1 yr before the present study. The reconstruction of the alimentary tract after total gastrectomy was performed using a Roux-en-Y limb (40 cm).
Anthropometric measurements
Weight (to the nearest 0.1 kg) and height (to the nearest 0.5 cm) were measured while the subjects were fasting and wearing only their undergarments. BMI was calculated as body weight divided by height squared and was used as a marker of obesity. Waist and hip circumferences (centimeters) were measured, by the same physician, as the widest diameter between the xiphoid process of the sternum and the iliac crest and as the widest diameter over the greater trochanters, respectively.
Measurement of body fat distribution
Body composition was evaluated by electrical bioimpedance. Fat-free mass was calculated as the difference between body weight and fat mass.
Analytical procedures
Plasma ghrelin was determined in duplicate by RIA kits (ghrelin human RIA kit catalog no. RK-031-30, Phoenix Pharmaceuticals, Belmont, CA). Phoenix’s ghrelin human RIA kit detects full-length, des-octanoyl human ghrelin, including Ser3-octanoyl and Ser3-des-octanoyl ghrelins.
Plasma glucose was determined by the glucose oxidase method [autoanalyzer, Beckman Coulter, Inc., Fullerton, CA; coefficient of variation (CV) 1.9 ± 0.2%]. Plasma total cholesterol (CV 3.4 ± 0.2%), high-density lipoprotein cholesterol (CV 3.7 ± 0.4%), and triglyceride (CV 3.1 ± 0.5%) concentrations were measured using enzymatic kits (Ortho-Clinical Diagnostic, Milan, Italy). Blood samples for plasma insulin measurements were collected in heparinized tubes. After centrifugation, plasma insulin concentrations were determined with a commercial RIA kit (CV 3.0 ± 0.3%) (Linco Research, St. Charles, MO). Serum TSH was measured by ultrasensitive assay (immunoradiometric assay, Serono MAIA-clone method, Serono Inc., Rockland, MA). Serum glutamic-oxaloacetic transaminase, serum glutamate pyruvate transaminase, and 
-glutamyl transpeptidase were measured by standard enzymatic assay analysis using commercially available kits.
Statistical analysis
Data are presented as mean ± SD. Comparisons of clinical parameters before and after bariatric surgery procedures were performed with Mann-Whitney U test with 95% confidence interval (CI). ANOVA followed by multiple comparisons were used to evaluate the differences among the groups with the calculation of 95% CI. Simple linear regression analysis was carried out using standard techniques. Two-tailed P < 0.05 indicated statistical significance. We used InStat software (GraphPad, San Diego, CA) for statistical analysis.
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Results |
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. No significant difference in age among obese subjects, normoweight subjects, and the groups of patients who underwent surgical procedure was observed. Only patients with total gastric resection were older than other subjects (P = 0.05). No significant difference in BMI among subjects who underwent LRYGBP and LASGB was found. Patients with total gastrectomy showed a BMI lower than obese subjects and patients who underwent bariatric surgical procedures (P < 0.01).
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Subjects who underwent LRYGBP improved their metabolic pattern after the operation. BMI (P < 0.001), waist and hip circumferences (P = 0.004 and P < 0.001, respectively) decreased. Insulin sensitivity detected by homeostasis model assessment insulin resistance (HOMA-IR) index was significantly improved (P < 0.001; Table 2) Also, fasting plasma insulin and -glutamyl transpeptidase were lower (P = 0.002 and P = 0.05, respectively). Blood pressure, fasting glucose, total cholesterol, and triglycerides showed a trend of lowering after the operation.
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). Diastolic blood pressure, fasting glucose, and plasma insulin were lower than before the operation (P = 0.05, P = 0.02, and P = 0.05, respectively) and systolic blood pressure showed a trend of lowering.
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Postbariatric surgery plasma ghrelin (Fig. 1)
Obese subjects showed ghrelin plasma levels significantly lower than normoweight subjects (407.3 ± 21.6 vs. 813 ± 72.4 pg/ml, P < 0.01, -452.6 to -357.5 95% CI). Patients with LRYGBP showed ghrelin levels lower than LASGB (213.5 ± 73.9 vs. 314.2 ± 84.3 pg/ml, P = 0.04, -170.1 to -31.9 95% CI). Patients with LRYGBP had ghrelin lower than normoweight and obese subjects (P < 0.01, -710.5 to -607.9 95% CI and P < 0.05, 263.0 to 124.9 95% CI, respectively). Also patients who underwent LASGB showed plasma ghrelin levels lower than both normoweight and obese subjects (P < 0.01, -551.4 to -446.4 95% CI; P < 0.05, -153.0 to -32.1 95% CI, respectively). Patients with total gastrectomy showed plasmatic ghrelin levels extremely lower than those in all other groups (32.6 ± 18.7 pg/ml, P < 0.001 for all).
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)In the group of normoweight subjects, plasmatic ghrelin levels rose significantly before breakfast and lunch (P < 0.05 and P < 0.005, respectively) and fell significantly after breakfast and lunch (P < 0.05 and P < 0.005, respectively). In the group of obese subjects, plasmatic ghrelin levels rose significantly before lunch (P < 0.05) and fell significantly after lunch (P < 0.05). No significant difference in plasma ghrelin levels before and after breakfast was observed in the obese group.
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Insulin profile
Both groups of subjects who underwent LRYGBP and LASGB procedures preserved physiological profile of insulin. Nevertheless, in both groups we observed a weak response of plasma insulin in the first phase after meal (Fig. 3).
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In a univariate linear regression analysis, plasma ghrelin levels were inversely related to BMI in all subjects and taking into account only obese subjects. (r = -0.48, P = 0.03 P = -0.579, and P = 0.02, respectively). A negative correlation between ghrelin and fasting insulin was found only in the group of obese subjects (r = - 0.51, P = 0.05). No correlation among ghrelin and age, HOMA-IR index, plasma glucose, waist circumference, and fat mass was observed. These correlations were substantially unchanged stratifying for sex.
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Discussion |
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Our findings seem to indicate that both laparoscopic bariatric procedures adopted for the treatment of severe obesity are characterized by low levels of plasma ghrelin and loss of its physiological oscillation in relation to food (mean follow-up of 12 months). These results could explain, at least in part, the reduction of appetite that occurred mostly in subjects who underwent gastric bypass (25, 26, 27, 28, 29, 30).
Gastric bypass seems to provide a stronger suppression of ghrelin in comparison with gastric banding procedure. These findings are consistent with the hypothesis that suppression of ghrelin is one mechanism by which gastric bypass can reduce body weight long term, more than gastric banding. Nevertheless, the mechanism by which gastric bypass leads to a reduction in ghrelin levels is still not completely clear. It was advanced by the hypothesis that a permanent absence of food in the empty stomach resulting from gastric bypass could cause a continuous stimulatory signal that ultimately suppresses ghrelin production through a process of overriding inhibition (13). A modification in vagal control of fundus and anthrum cells of the stomach because of a gastric bypass procedure could be involved in paradoxical lowering of ghrelin production. In fact, ghrelin is primarily secreted by neuroendocrine cells of fundus and anthrum of the stomach with the positive control of vagal afferences (1, 2). Nevertheless, data on vagal innervation after gastric bypass are controversial. In fact, some studies (31, 32) have indicated that vagal innervation in excluded stomach could be preserved after gastric bypass, whereas others have not. However, ghrelin seems to act differently from other hormones secreted by the stomach (33, 34), and its secretion could be modified by the altered gastrointestinal anatomy. It has been also reported that gastric bypass induces early hormonal changes, despite an unchanged BMI (35), suggesting that this procedure has an endocrine mechanism of action, perhaps independently of BMI. BMI is crucial in defining the role of ghrelin in weight loss, and a great degree of BMI could influence the results. In this sense we think that an important issue of our study was the evaluation of groups of patients with the same BMI. However, this is not a prospective study and does not indicate causality of the relationship of the procedure to ghrelin levels after surgery.
The low levels of ghrelin after gastric banding also could be explained probably by different mechanisms in comparison with the gastric bypass procedure. In fact, laparoscopic adjustable gastric banding even preserving stomach in its anatomical site induces restrictive modification of gastric volume (less the 20 ml) and alteration of peristalsis. The poor amount of food in the stomach could modify its physiological peristalsis, inducing an altered response of ghrelin production. In addition, gastric banding prevents pathologic gastroesophageal reflux but could impair the relaxation of the lower esophageal sphincter, leading to weak esophageal peristalsis (36). Ghrelin exhibited gastroprokinetic activity with structural resemblance to motilin (37), a gut neuropeptide, and its lowering after gastric banding could explain the impaired esophageal peristalsis. Moreover, ghrelin seems to act quite similarly to motilin after gastric banding. In fact, preoperatively, levels of motilin have been also reported to be significantly decreased after gastric banding procedures (38). Ghrelin, also called agent motilin-related peptide, could be part of a family of gastrointestinal hormones linking endocrine control of energy balance with the regulation of gastrointestinal motility (39).
In our data plasma ghrelin showed the higher oscillation in response to a meal mainly after lunch in obese subjects. This finding could be explained with the macronutrient composition of a typical Italian breakfast. In fact, our subjects ingested a light breakfast with absence of fat and with a low protein component. This breakfast is different from breakfast in other countries, such as the United States, and suggests our different outcomes.
In our data we found a negative correlation between fasting insulin and plasma ghrelin only in obese subjects. This finding was substantially consistent with previous studies reporting a relationship of ghrelin with fasting insulin and/or insulin resistance indices (40, 41). Subjects who underwent bariatric procedures preserved a physiological profile of insulin after the meal. Nevertheless, in both groups no correlation between fasting insulin and ghrelin was found. The weak response of insulin and the loss of physiological ghrelin oscillation at mealtime may be a possible explanation of the lack of this correlation in these subjects. A recent clamp study (42) showed that acute hyperinsulinemia reduces ghrelin levels in healthy people. Nevertheless, future studies will be needed to better address the relationship of ghrelin with insulin in obese subjects and patients who have undergone restrictive gastric procedures. In addition, a significant nadir after meals could have been missed by having 1-h time samples instead of 20- to 30-min timed samples.
In conclusion, a significant difference in plasma ghrelin levels between patients who have undergone laparoscopic gastric bypass and laparoscopic adjustable gastric banding was found, suggesting that both procedures could induce weight loss by different mechanisms in which ghrelin could be involved.
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Footnotes |
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Received January 27, 2003.
Accepted May 15, 2003.
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