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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Background:

Bariatric surgery is the most effective treatment for achieving long-term weight loss in morbidly obese patients. This study investigated prospective changes in gut hormones and metabolic indices after Roux-en-equation image gastric bypass (RYGB).

Methods:

Six patients were seen before, and at 1, 3 and 6 months after operation. Blood was collected after a 12-h fast and at regular intervals after a mixed 420-kcal meal. Hormonal responses were determined, and comparisons between basal levels and areas under the curve were made. Visual analogue scores were used to assess satiety, hunger and nausea.

Results:

Mean body mass index decreased from 48·3 kg/m2 before surgery to 36·4 kg/m2 6 months after RYGB. This was accompanied by a decrease in fasting leptin (P < 0·001) and insulin (P = 0·021) levels. At 1, 3 and 6 months after operation, progressively increasing peptide YY (P < 0·001), enteroglucagon (P = 0·045) and glucagon-like peptide 1 (P = 0·042) responses were observed. There was no change in fasting ghrelin levels (P = 0·144). Postprandial satiety was significantly increased by 1 month after surgery and this was maintained until the end of the study (P < 0·001).

Conclusion:

RYGB resulted in substantial weight loss with enhanced postprandial satiety, a sustained weight plateau, and proportionate reduction in fasting insulin and leptin levels. Lack of the expected increase in appetite and food intake as components of a counter-regulatory response may be explained by gut adaptation and the consequent graded rise in the levels of gut hormones that promote satiety. Copyright © 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

The increasing prevalence of obesity has become a major health issue worldwide and is accompanied by a rising demand on healthcare resources to combat obesity-related co-morbidities, principally cardiovascular disease and type 2 diabetes mellitus1. The Swedish Obese Subjects Study has shown that, after follow-up for 10 years, morbidly obese patients who had bariatric surgery had long-term weight loss, better quality of life, improved glycaemic and blood pressure control, and lower triglyceride levels than those who had conventional management2.

Bariatric surgery can be divided into three categories: restrictive procedures such as vertical banded gastroplasty and adjustable gastric banding, purely malabsorptive procedures such as the now obsolete jejunoileal bypass, and ‘hybrid’ operations that combine restrictive and bypass components including Roux-en-equation image gastric bypass (RYGB). The exact mechanisms of weight loss after hybrid surgery have not been precisely determined.

Ghrelin, produced mainly in the gastric fundus, stimulates food intake in rodents and humans, acting via increased hypothalamic expression of the orexigenic neuropeptide Y3, 4. An initial cross-sectional study showed that weight loss through dietary restriction was accompanied by an increase in the circadian profile of ghrelin, whereas weight loss after RYGB was associated with a profound suppression of ghrelin levels5. Subsequent prospective studies, however, have shown inconsistent and conflicting ghrelin responses after RYGB, although the majority showed either a decrease or abrogation of the anticipated compensatory rise6.

A growing number of peptides produced by the gastrointestinal tract have been shown to have inhibitory effects on appetite and food intake7, 8. Peptide YY (PYY) is released postprandially from the distal intestinal tract and has been reported to act within the arcuate nucleus to inhibit the release of neuropeptide Y9. Intravenous infusions of PYY3–36 in humans are associated with reduced food intake and increased satiety9, 10. Morbidly obese patients are not resistant to exogenous PYY3–36, but have reduced endogenous plasma PYY concentrations10. Cross-sectional studies have shown an increased PYY response after RYGB11, 12.

The enteroglucagons are a family of peptides produced by differential splicing of the products of the preproglucagon gene by proconvertase enzymes. Members include oxyntomodulin (OXM), glucagon-like peptide (GLP) 1 and GLP-2. OXM has anorectic actions whereas GLP-2 influences the gut hypertrophic response13. In humans GLP-1 acts as an incretin, releasing insulin14, and has been reported to inhibit food intake15. GLP-1 has also been shown to improve pancreatic β-cell function in rodents16. Increased GLP-1 levels are thought to mediate the improvements in glycaemic control that occur after RYGB in patients with type 2 diabetes mellitus17, 18.

This prospective study examined changes in gut hormones in human subjects after RYGB.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

All human studies were performed according to the principles of the Declaration of Helsinki. The research and ethics committee at King's College Hospital, London approved the study. Exclusion criteria included pregnancy, substance abuse, more than two alcoholic drinks per day and aerobic exercise for more than 30 min three times per week. Written informed consent was obtained from all six participants. A single surgeon performed the RYGBs using the omega loop technique described by Olbers et al.19. The Roux limb was 112 cm long with a 30-ml stomach pouch and a cut omega loop. The surgery was completed laparoscopically in five patients. One patient required conversion to an open procedure owing to technical difficulties. The subjects included in the study had very similar outcomes in terms of excess weight loss compared with the authors' surgical cohort as a whole (data not shown).

Patients were admitted to the research centre before surgery, and at 1, 3 and 6 months after operation. Venous blood was collected after a 12-h fast, immediately after consumption of a mixed 420-kcal meal, 15 and 30 min later, and at 30-min intervals thereafter up to 3 h. Plasma levels of the gut hormones PYY, enteroglucagon, GLP-1, insulin and ghrelin were compared at each time point. Insulin sensitivity was calculated using the Homeostasis Model Assessment (HOMA) Calculator version 2.2, available from the Diabetes Trials Unit website (http://www.dtu.ox.ac.uk). Satiety, fullness, nausea and aversion to food were measured immediately after consumption of the meal and 60, 120 and 180 min later using a visual analogue scale (VAS).

All samples were assayed in duplicate. Specific and sensitive radioimmunoassays were used to measure PYY-like immunoreactivity10, 20, plasma GLP-114, ghrelin21 and enteroglucagon22. The enteroglucagon assay provides a composite estimate of the products of the preproglucagon gene. Commercial assays were used to measure plasma leptin (Linco Research, St Charles, Missouri, USA), insulin (Abbott Laboratories, Abbott Park, Illinois, USA) and glucose (Olympus, Hamburg, Germany) levels.

Hormone levels were expressed as mean(s.e.m.). Values for area under the curve (AUC) were calculated by application of the trapezoidal rule. Basal levels and AUCs were compared by ANOVA (GraphPad Prism®, GraphPad, San Diego, CA, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

The results for the six patients are summarized in Table1. Mean(s.e.m.) preoperative body mass index was 48·3(1·4) kg/m2, and there was a mean weight loss of 31·9 kg at 6 months after operation (Table1, Fig.1a). All subjects were insulin resistant and two had established diabetes before surgery. Patients had markedly reduced fasting insulin levels (Table1, Fig.1b) and thus improved insulin sensitivity after RYGB, while still remaining in the World Health Organization grade II obesity category. Despite the improved insulin sensitivity, an early rise in plasma insulin was observed at 15 min compared with the preoperative profile (Table1). Total insulin secretion after RYGB, as assessed by the postprandial AUC, showed an overall trend towards reduction. Patients did not have symptoms of early or late dumping syndrome following the test meal and all postprandial glucose values were above 4 mmol/l. Postoperative fasting leptin levels showed a significant decrease at 1, 3 and 6 months compared with preoperative values (Table1, Fig.1c).

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Figure 1. Mean(s.e.m.) a body mass index, b fasting insulin and c fasting leptin levels before and after Roux-en-equation image gastric bypass. *P < 0·010, †P < 0ċ001 versus baseline (ANOVA)

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Table 1. Body mass index and hormone profile before and at 1, 3 and 6 months after Roux-en-equation image gastric bypass
 Preop.1 month postop.3 months postop.6 months postop.P*
  • Values are mean(s.e.m.). HOMA, Homeostasis Model Assessment; AUC, area under the curve; PYY, peptide YY; GLP-1, glucagon-like peptide 1.

  • *

    Baseline (preop.) versus 6 months (ANOVA).

Body mass index (kg/m2)48·3(1·4)41·9(1·4)39·6(1·6)36·4(1·5)< 0·001
Fasting leptin (ng/ml)44·7(8·1)29·4(7·7)19·8(4·0)14·0(2·9)< 0·001
Fasting insulin (munits/l)19·5(2·3)14·0(2·0)8·3(2·1)6·5(1·1)0·021
HOMA (insulin resistance)5·9(2·3)4·0(1·0)2·0(0·5)1·5(0·2)0·030
Change in insulin at 15 min (munits/l)17·2(6·6)43·1(10·8)73·1(17·7)49·0(14·5)0·035
Insulin AUC (munits per litre per min)4627(1316)3531(1079)2971(879)2300(410)0·372
Fasting PYY (pmol/l)21·6(1·4)23·4(6·5)27·4(7·8)20·3(2·6)0·753
PYY AUC (pmol per litre per min)3783(366)4994(1014)6521(903)6980(933)< 0·001
Enteroglucagon AUC (pmol per litre per min)16 628(2074)19 912(2776)25 217(3440)28 923(3260)0·045
Fasting GLP-1 (pmol/l)33·2(4·7)40·6(6·6)31·6(10·8)21·8(2·2)0·381
GLP-1 AUC (pmol per litre per min)6276(863)9640(927)8942(1154)16 917(4445)0·042
Fasting ghrelin (pmol/l)232(72)287(82)239(46)331(95)0·144

Despite this fall in leptin levels and improvement in insulin sensitivity in response to weight loss, VAS scores were indicative of reduced postprandial hunger at 180 min after a meal (P = 0·032). The reduced hunger was preserved at 3 and 6 months, despite progressive weight loss (Fig.2a). Satiety scores demonstrated reciprocal changes to hunger (Fig.2b). There was no difference in nausea scores before and after RYGB, and the patients did not demonstrate an aversion to food (data not shown).

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Figure 2. Mean(s.e.m.) scores on a visual analogue scale (VAS) in response to the questions a ‘How hungry do you feel?’ and b ‘How full are you?’ after a 420-kcal meal. aP = 0·042, 6 months versus baseline (preop.); bP < 0·001, 6 months versus baseline (ANOVA)

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In response to a 420-kcal meal, there was a progressive increase in the AUC for PYY after surgery (Table1, Fig.3a). Enteroglucagon levels similarly rose progressively following the RYGB, as evident from the AUC (Table1, Fig.3b). Before surgery the GLP-1 concentration rose by only 10 per cent in response to the 420-kcal test meal (P = 0·600). However, at 1, 3 and 6 months after operation, an exaggerated GLP-1 response was observed (Table1, Fig.3c). There was no difference between preoperative and postoperative fasting or postprandial ghrelin levels (Table1).

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Figure 3. Mean(s.e.m.) area under the curve (AUC) following a 420-kcal meal for a peptide YY (PYY), b enteroglucagon and c glucagon-like peptide 1 (GLP-1) before and after Roux-en-equation image gastric bypass. *P < 0·050, †P < 0ċ010, ‡P < 0ċ001 versus baseline (ANOVA)

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

RYGB results in significant weight loss in morbidly obese individuals, with the anticipated changes in fuel homeostasis, but without the compensatory increased appetite that usually leads to weight regain after non-surgical forms of intentional weight loss. Decreased appetite and calorie intake lead to weight loss following RYGB23, whereas calorie malabsorption does not appear to be a significant contributory factor24. This prospective study showed a pleiotropic endocrine response to obesity surgery, which may contribute to the enhanced postprandial satiety that results in long-term weight loss.

After surgery PYY responses were increased to levels previously shown to have appetite-reducing effects in humans9, 10. Chronically raised fasting levels of PYY have been described previously in several gastrointestinal diseases associated with loss of appetite25, 26. Other established actions of PYY include reduced gastric emptying and delayed gastrointestinal transit27. All of these actions could be considered an appropriate response to acute small intestinal disease or shortened small bowel as they increase the contact time of the nutrient load with the absorptive lining, thus increasing absorption time. Increased PYY secretion and the accompanying effects on food intake suggest that PYY mediates, at least in part, the increased satiety noted after RYGB.

In addition to PYY, high levels of enteroglucagon and GLP-1 were observed after RYGB. The enteroendocrine cells (L cells) that contain PYY also secrete GLP-1, enteroglucagon and other members of the enteroglucagon family. Consistent with previous findings, after RYGB in the present study there was no difference in fasting GLP-1 levels17, but an exaggerated GLP-1 response following a 420-kcal meal. GLP-1 concentrations have previously been shown to be raised after jejunoileal bypass28, 29. This increased GLP-1 response may act both as an incretin effect and as a satiety signal following RYGB.

Fasting insulin sensitivity (HOMA) improved after operation and was similar to that expected in a lean, insulin-sensitive cohort. However, patients were noted to have significantly higher insulin levels 15 min after the meal. Overall, there was a trend towards a reduction in insulin secretion as assessed by AUC calculation. This progressive increase in first-phase insulin secretion has been observed previously in patients undergoing malabsorptive bariatric surgery30. Such changes in insulin sensitivity and release might have contributed to the improvement in glycaemic control noted in other studies17, 18, 31. Rapid and sustainable improvements in glycaemic control were observed independent of weight loss after duodenal–jejunal exclusion in a non-obese diabetic rodent32. Insulin has been proposed as a satiety hormone33 and the high postprandial peak level of insulin after RYGB might also influence food intake. The dissociation of first-phase insulin secretion and whole-body insulin resistance requires further study.

Consistent with previous reports34–36, postoperative ghrelin levels did not show the rise that would be predicted by diet-induced weight loss5, 34. This may partly explain the reduced appetite following gastric bypass. It is uncertain what causes this abrogation of the anticipated compensatory rise in ghrelin levels. The degree of hyperinsulinaemia is a major determinant of suppression of ghrelin in obese patients and postoperative changes may depend on the patient's preoperative insulin resistance and any postoperative improvement in insulin sensitivity. The variable degree of vagal disconnection of the gastric pouch after RYGB may also play a role in some patients.

Alterations in several peripheral signals potentially contribute to the reduced appetite and weight loss after RYGB for morbid obesity. Increased postprandial PYY and GLP-1 levels might combine to enhance satiety, leading to a long-term reduction in calorie intake without an increase in ghrelin levels. Increased GLP-1 and insulin levels may contribute to improvements in glycaemic control. The progressive rise in enteroglucagon levels suggests that these phenomena might be a consequence of a gut adaptive response. The data indicate that a hormonal response has evolved to counter the effects of intestinal dysfunction triggered by RYGB. This adaptive response promotes satiety and is responsible for a major component of the weight loss that follows RYGB.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
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