Mechanisms of Weight Loss, Diabetes Control and Changes in Food Choices After Gastrointestinal Surgery
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- Papamargaritis, D., Panteliou, E., Miras, A.D. et al. Curr Atheroscler Rep (2012) 14: 616. doi:10.1007/s11883-012-0283-7
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The long-term effects of lifestyle changes, diet and medical therapy on obesity are limited. Bariatric surgery is the most effective long-term treatment with the greatest chances for amelioration of obesity-associated complications, including type 2 diabetes mellitus (T2DM). There is increasing evidence in the literature that bariatric operations have a profound effect on human physiology, by reducing hunger, increasing satiety, paradoxically increasing energy expenditure, and even promoting healthy food preferences. Some of these operations improve glucose homeostasis in patients with T2DM independently of weight loss. Changes in the gut hormone levels of glucagon-like peptide 1, peptide YY and ghrelin have been proposed as some of the mediators implicated in changing physiology. The aim of this review is to critically explore the current knowledge on the putative mechanisms of the change in weight and improvement in T2DM glycaemic control after the most commonly performed bariatric operations.
KeywordsGut hormonesEnergy expenditureFood preferencesTaste
Obesity is a global epidemic and its prevalence is predicted to rise even further in the future. It is related to a wide range of adverse health consequences, such as type 2 diabetes mellitus (T2DM); cardiovascular, respiratory, musculoskeletal, reproductive and psychological complications; as well as cancer .
Lifestyle changes and the currently available pharmacotherapy have been shown to have limited efficacy on long-term weight loss and its maintenance [2, 3]. Patients who complete a comprehensive program of a low-calorie diet or very low-calorie diet can expect to lose, at best, 5 % of the initial weight at 4 years . The current choices for the pharmacological treatment of obesity are limited to Orlistat. In the Xendos trial, patients treated with Orlistat and lifestyle measures over 4 years attained a mean weight loss of 5.8 kg . Nevertheless, even small amounts of sustained weight loss can be sufficient to reduce the incidence of type 2 diabetes and improve the metabolic syndrome.
Bariatric surgery is the most effective treatment for severe obesity in terms of magnitude of weight loss and long-term weight loss maintenance. In the Swedish Obese Subjects study, a cohort study among patients with a body mass index (BMI) > 34 kg/m2 with follow-up of more than 20 years, the surgical group achieved 18–23 % weight loss compared to a 1 % weight loss for patients receiving conventional treatment . Bariatric surgery is also the most effective treatment for some of the obesity-associated comorbidities, predominantly T2DM. Three randomised controlled trials have demonstrated that in obese patients with T2DM, bariatric surgery resulted in better glucose control and higher percentages of T2DM remission than did conservative medical therapy [5••, 6••, 7].
It was formerly thought that bariatric surgery induced weight loss and improved T2DM control simply by restricting meal size and/or by macronutrient malabsorption. However, there is increasing evidence in the literature that bariatric operations have profound effects on physiology by reducing hunger, increasing satiety, increasing energy expenditure and promoting healthier food preferences . Moreover, some of these operations improve glucose homeostasis in patients with T2DM, independent of weight loss. In this review, we will discuss the main physiological mechanisms through which the most commonly performed obesity surgery procedures facilitate weight loss, weight loss maintenance, and improvements in T2DM glyceamic control.
Bariatric Surgery Techniques
The Roux-en-Y gastric bypass (RYGB) is considered by many to offer the best balance of weight loss and comorbidity resolution against the risk of surgical complication. In the RYGB design, the stomach is divided into the upper stomach pouch, which is 15–30 mL in volume and the lower, gastric remnant. The stomach pouch is then anastomosed to the jejunum through a gastrojejunal anastomosis in a Roux-en-Y fashion. The continuity of the bowel is restored via a jejuno-jejunal anastomosis, between the excluded biliary limb and the alimentary limb, performed 75–150 cm distally to the gastrojejunostomy.
The Sleeve gastrectomy (SG) is a relatively new procedure increasing in popularity. It originated as part of the duodenal switch operation and is now used as a single stage procedure for the very obese and/or high-risk patients. In the SG, the stomach is transected vertically, creating a gastric tube and leaving a 150–200 mL pouch. The remaining stomach is excised.
The biliopancreatic diversion (BPD) includes a partial gastrectomy, leaving a 400 mL gastric pouch. The small bowel is divided 250 cm proximally to the ileocaecal valve and the alimentary limb is connected to the gastric pouch to create a Roux–en–Y gastroenterostomy. An anastomosis is performed between the excluded biliopancreatic limb and the alimentary limb at 50 cm proximally to the ileocaecal valve.
The laparoscopic adjustable gastric banding (LAGB) involves the insertion of an adjustable plastic and silicone ring around the proximal aspect of the stomach, immediately below the gastrooesophageal junction, creating a small proximal pouch.
Mechanisms of Weight Loss
The intestinal bypass procedures such as the BPD and RYGB were initially designed to induce calorie malabsorption. Indeed, the BPD causes calorie malabsorption, as the patients can consume large amount of food post-BPD (between 2850 and 3418 kcal daily) and are still able to maintain their weight loss in the long term . The increased faecal fat and the higher incidence of hypoalbuminaemia after BPD confirm the malabsorptive effect of this procedure . As a result of the fat malabsorption after BPD, one of the most common postoperative complications is diarrhoea.
On the other hand, the RYGB was initially designed to combine malabsorption and restriction. It was also thought that the RYGB causes malabsorption because pancreatic and biliary secretions only mix with food in the short common segment of the small bowel. However, findings on the serum markers of nutritional status, such as albumin and faecal fats, have suggested that calorie malabsorption does not contribute to weight loss post-RYGB. Some studies have reported normal levels of albumin and faecal fat when other studies have reported only slightly increased levels of faecal fats [10•, 11]. It is believed that the appearance of malabsorption post-RYGB may depend on the length of the intestinal limbs, as well as the food choices of the patient.
Reduction of Stomach Size
The RYGB, SG and LAGB procedures were designed to significantly reduce stomach volume. The presence of food within the smaller stomach pouch may result in early gastric distension, and subsequently lead to early satiety and reduced meal size . However, if that were the dominant mechanism reducing food intake, then the body would generate a compensatory increased intake of calorie-dense food and/or increased meal frequency in an attempt to resist weight loss.
On the contrary, after RYGB the patients report reduced hunger, increased satiety, and a lower consumption of energy-dense foods compared to preoperatively . Randomised controlled trials have shown that operations that create similar gastric pouch sizes to the RYGB have completely different effects on food preferences and weight loss . The vertical banded gastroplasty (VBG) for example, results in significantly less weight loss, “unhealthier” food preferences and failure in many cases to maintain long-term weight loss as compared to RYGB . The latter is the main reason why the VGB is not performed any more.
Regarding the LAGB, the lack of compensatory, high calorie seeking behaviour in the majority of patients, suggests that gastric restriction is not a dominant physiological mechanism and others may be at play. Currently, a preferred hypothesis is that the band exerts pressure on the vagus nerve, which reduces hunger and increases satiety. Restriction does, however, remain a significant side effect in many, especially if the band is over-inflated. The rapid weight gain seen after reversal of the LAGB also argues for the physiological attenuation of appetite when the band is optimally adjusted .
Mechanisms of Weight Loss Independent of Malabsorption and Restriction
The main question to answer is how bariatric surgery overcomes the evolutionarily robust homeostatic compensatory mechanisms that resist weight loss, and manages to achieve weight loss maintenance. Changes in gut hormones and their effects on energy and glucose homeostasis have been proposed as possible mechanisms for the long-term maintenance of weight loss, as well as for the immediate improvement in glucose homeostasis after some of these procedures. The main hormones that are implicated in this entero–endocrine axis and affect both in energy and glucose homeostasis are Glucagon like Peptide-1 (GLP-1), Peptide YY (PYY) and ghrelin.
GLP-1 is synthesized by the L-cells located mainly in the ileum. It is an incretin and stimulates the insulin release in response to nutrient ingestion. GLP-1 exerts its glucose-lowering effects through inhibition of gastric emptying, which delays digestion and blunts postprandial glycaemia, restoration of insulin sensitivity, and inhibition of glucagon secretion. It also plays a significant role in the regulation of energy homeostasis, as it acts on the central nervous system to induce satiety and decrease food intake. It is released after food intake and differences have been observed between normal weight and obese individuals .
PYY is a peptide released into the circulation by intestinal endocrine L-cells of the distal gut following food ingestion along with GLP-1. PYY is released postprandially in proportion to the calories ingested and has an inhibitory effect on gastrointestinal mobility. It increases satiety, reduces food intake, and delays gastric emptying. In addition to regulating appetite and body weight, PYY exerts glucoregulatory properties, especially in rodents .
Ghrelin is a peptide mainly produced from the X/A-like cells of the stomach and, to a lesser degree, from the small intestine and acts on the hypothalamus to regulate appetite. It is an orexigenic hormone that stimulates appetite and food intake. Additionally, ghrelin stimulates insulin counter-regulatory hormones, suppresses the insulin-sensitising hormone adiponectin, and inhibits insulin secretion, all of which acutely elevate blood glucose levels. Circulating ghrelin concentrations increase with fasting and decrease following nutrient ingestion .
Changes in Hunger and Satiety
Changes in appetite are reported within days following bariatric surgery. Increased satiety and decreased hunger postoperatively have been reported after the RYGB, SG and LAGB [16•, 17, 18]. The changes in the postprandial levels of gastrointestinal hormones that induce satiety, such as GLP-1 and PYY, have been proposed as one of the possible mechanisms for the reduced food intake and long-term maintenance of weight loss after bariatric procedures such as the RYGB and SG [16•, 17, 18].
A causative link between the enhanced postprandial PYY and GLP-1 response and the increased satiety and long-term maintenance of weight loss after RYGB has been proposed . Increased postprandial PYY and GLP-1 responses are observed from the second postoperative day after RYGB, prior to any significant weight loss. Furthermore, PYY and GLP-1 responses correlate with different levels of weight loss post-RYGB; patients with 20 % weight loss had lower PYY and GLP-1 levels compared to patients that lost 40 % of their weight after surgery . Moreover, in a randomised double-blind controlled study of patients after RYGB and LAGB, inhibition of the gut hormone responses with octreotide (a somatostatin analogue) increased food intake in the RYGB group, but not in the LAGB group, suggesting that gut hormones play a role in the reduced food intake after RYGB, but not after LAGB . As a result, although an optimally adjusted gastric banding also reduces hunger and induces early satiation , changes in appetite after LAGB appear to be independent of gut hormone changes.
The vagal nerve plays an important role in the regulation of food intake and body weight . Vagal afferents are activated by the presence of nutrients in the stomach and the intestine. The release of gut hormones, as well as mediation of their effects, is influenced by the functionality of the vagus. Indeed, the preservation of vagal fibres during surgery leads to greater and more sustained body weight loss in animal models of the RYGB . It is also possible that LAGB exerts its effects on satiety by neural signalling arising from the stomach . Pressure generated in the proximal alimentary limb of the RYGB by a 20 mL balloon appears to predict the meal size of a patient. Thus, the rapid entry of food from the oesophagus through the small gastric pouch and the large gastric jejunal stoma may trigger neural signals in the alimentary limb, which may contribute to long-term weight loss maintenance .
Changes in Energy Expenditure
Chronic caloric deprivation is normally accompanied by a decrease in resting energy expenditure as the body strives to conserve energy . Paradoxically, energy expenditure has been shown to increase in rodents after RYGB, and this has been suggested as a mechanism contributing to the enhanced and maintained postoperative body weight loss [21, 22]. However, the data on energy expenditure in humans are controversial. Flancbaum et al. demonstrated that resting energy expenditure decreased over time in patients with a normal preoperative metabolic rate , whereas patients who were “hypometabolic” before RYGB exhibited increases in their resting energy expenditure after the operation . These changes occurred despite the reduced energy intake comparable to a very low-calorie diet. Other studies have found lower resting energy expenditure after RYGB (e.g.). These discrepant results may stem from differences in the methodology used to measure energy expenditure.
Resting energy expenditure in humans decreases significantly, to the level of normal weight controls, after BPD . Measurements of energy expenditure in rat models of the SG and LAGB, in which the only anatomical alteration is the reduction of stomach size, did not reveal significant changes in energy expenditure [26, 27].
Changes in Food Preferences
Eating behaviour is thought to be influenced by internal signals (substrates, hormonal and neural) and external non-homeostatic hedonic signals (food cues, palatability, availability, cost/benefit ratio and social conditions). The orbitofrontal cortex in the brain receives information through all sensory modalities and is involved in food searching, smelling, tasting and reward. Neural circuits regulating energy homeostasis (hypothalamus, brainstem and corticolimbic areas) are also involved in cognition, decision making, memory, reward, attention and emotion. In humans, higher cortical centres are implicated in psychological and emotional factors, which can drive food intake beyond homeostatic requirements . Neuroimaging studies using functional magnetic resonance imaging (MRI) or Positron emission tomography (PET) scanning in obesity have yielded mixed results; in some studies this reward network in the brain is hyperactive, therefore promoting overeating, and in others it is hypofunctioning, again leading to overeating to compensate for this reward deficiency [29••].
RYGB patients tend to have reduced meal size but increased meal frequency, while reducing snacking on high-fat, high-sugar food . In a randomized controlled trial, patients after VBG consumed a higher proportion of fat and carbohydrates, compared to the RYGB patients that preferred fruit and vegetables and “consciously” avoided fat . In another study, RYGB patients consumed 45 % less solid and liquid sweets and 37 % less dairy products compared to VBG patients . The majority of published studies support this healthy shift away from calorically dense foods to low-fat and sweet options [32••]. Some of the inconsistencies in the literature on this topic and the longevity of these observations may be due to the methodology employed in the available studies. This has been heavily based on food diaries and scaling techniques, both of which have inherent limitations. The limited neuroimaging literature is more consistent and has shown that, the reward areas of the brain are activated less after RYGB in response to high calorie food [33•, 34]. The use of direct behavioural techniques, like those used in animal experimentation, may provide more consistency in the human literature [32••]. Indeed, animal models of RYGB and SG show a clear preference away from high concentrations of sweet and fat compared to sham animals [35•, 36, 37•].
Mechanisms Underlying the Changes in Food Preference Following Bariatric Surgery
Taste is the result of the interaction between the chemical stimulus and the taste receptor cells on the tongue, palate and small intestine. Taste function can be better understood if broken down into three domains : a) the sensory domain which incorporates the detection and assessment of intensity of tastants; b) the hedonic domain which incorporates the reward value of tastants; and c) the physiological domain which involves the physiological processes taking place in response to a tastant (i.e. salivation).
In terms of the sensory domain, two out of the three published studies are in agreement that detection threshold for sweet is decreased after RYGB in humans [35•, 39, 40]. The study of the reward domain of taste is more difficult, due to the dietary advice that obese patients have been given throughout their lives. This inevitably leads to significant bias in patients’ responses. The secondary taste cortex, located in the orbitofrontal cortex and the amygdala, activate areas that influence behaviour and are responsible for the reward of taste . Taste reward has two components: the consummatory component, which reflects the experience when the tastant meets the receptor when eating/tasting and is predominantly mediated by opioidergic and GABAergic pathways; and the appetitive, which reflects motivation and drive for a reward and relies on mesolimbic dopaminergic transmission . Studies using the visual analogue scaling methodology have not shown any changes in the consummatory reward value of sweet food after RYGB [35•]. There is no behavioural literature on whether RYGB affects the appetitive reward of sweet or fat taste in humans.
In the animal literature, using the taste reactivity test, which measures the number of positive orofacial responses to a stimulus, it has been shown that RYGB increased consummatory responses for low concentrations of sweet and decreased them for high concentrations [43•]. Similar results were obtained using the brief access test, which assesses the appetitive and consummatory affective value of a reinforcer. The RYGB models exhibited increased appetitive responses for low concentrations of sweet and fat, and decreased responses for high concentrations [43•]. However, the latter finding has not been replicated by other investigators . In another study, which used a different rat strain, licking responses were similar for low and medium sucrose concentrations, and significantly lower for high sucrose concentrations in the RYGB model, compared to the sham operated obese rats . This finding correlated with attenuated neural firing to high sucrose concentrations in the parabrachial nucleus of the RYGB rats. Differences in salivation after bariatric surgery have not been investigated yet.
Dumping syndrome can occur when sugary foods are consumed, and it has been suggested as a possible cause for changes in food preferences and weight loss after RYGB and SG. The rapid gastric emptying and the increased secretion of gut hormones are the main mechanisms implicated in dumping syndrome. Sugary foods are rapidly ‘dumped’ into the small intestine, where they exert an intense osmotic effect, drawing fluid from the circulation into the intestine. Dumping syndrome could be quite unpleasant for the sufferer, eliciting a post-ingestive feedback which may lead the patients to avoid consuming high-energy, sugar dense foods, and therefore may contribute to weight loss. Despite this theory, there is no significant evidence in the literature that the severity of dumping syndrome after bariatric procedures is correlated with weight loss.
Metabolic Surgery and T2DM
Whilst a healthy diet and exercise remain the cornerstones of T2DM treatment, bariatric surgery is more effective in the improvement of T2DM compared to lifestyle modifications and pharmacotherapy [5••, 6••, 7]. This has led to the labelling of bariatric surgery procedures as “metabolic” operations. Three randomised controlled trials have compared bariatric surgery (LAGB, BPD, RYGB and SG) to lifestyle and medical interventions, demonstrating that bariatric surgery was much more effective in controlling glycaemia compared to conventional treatments [5••, 6••, 7].
Mechanisms of Diabetes Remission After Bariatric Surgery
Weight loss and weight loss maintenance clearly play an important role in the remission of T2DM. This is evident by the restoration of glucose tolerance and improvement of insulin sensitivity by all types of bariatric surgery. However, each bariatric procedure has different effect on glycaemia, and the glucose homeostasis improvement in patient with T2DM is independent of weight loss after some operations . The weight-loss-independent mechanisms of T2DM remission after metabolic procedures include: a) reduction of caloric intake; b) changes in insulin secretion; and c) changes in hepatic insulin sensitivity.
Reduction of Caloric Intake
The enforced caloric restriction, negative energy balance and weight loss undoubtedly reduce insulin resistance after all bariatric procedures. The ability of acute caloric restriction to transiently improve glycaemia in T2DM is well known, and according to this model, by the time patients return to an unrestricted diet, they begin to experience the insulin-sensitizing effects of dynamic weight loss from their operation . These effects have been observed after all the bariatric procedures. However, if caloric restriction played the major role in mediating changes in glucose homeostasis, the rate of T2DM remission would be the same after all types of bariatric surgery. Yet, the effects on T2DM resolution are of significantly higher magnitude and much faster for bypass procedures compared to LAGB and SG [48•]. This adds to the evidence for a weight-independent glucose lowering effect.
Changing Insulin Secretion
Changing insulin secretion, also known as the “hindgut” hypothesis, postulates that the hindgut plays a major role in mediating the beneficial effects of bariatric surgery on metabolism and weight loss. According to this theory, rerouting of food through an anatomically altered and/or shorter gastrointestinal tract results in increased delivery of incompletely digested nutrients to the distal gut, which causes enhanced secretion of the insulinotropic and appetite-controlling gut hormones (i.e. GLP-1, PYY). The increased secretion of these hormones leads to increased weight loss and improved glucose homeostasis. This theory could partially explain the significant effectiveness of SG and RYGB on T2DM remission from the early postoperative period.
Further support for this hypothesis comes from experiments involving ileal interposition [47, 49]. In this operation, a segment of the L-cell-rich ileum is transplanted into the upper intestine, near the duodenum-jejunum boundary, thereby increasing its exposure to ingested nutrients . As predicted, this operation significantly increases the postprandial GLP-1 and PYY response, and results in improved glycaemic control without any malabsorption or gastric restriction .
Changing Hepatic Insulin Resistance
According to the hepatic insulin resistance or “foregut” hypothesis, bypass of the proximal small bowel reduces the secretion of unknown gastrointestinal factors that decrease insulin secretion and/or promote insulin resistance. The reduction of these putative anti-insulin factors (anti-incretins) leads to the increase of insulin action and/or secretion, thereby improving T2DM . Duodenal exclusion and correction of the anti-incretin dysfunction may explain the improvement of T2DM after bypass surgery. Further evidence for the “hindgut” theory comes from the procedure known as the Duodenal Jejunal Bypass (DJB). In rat models of the DJB, T2DM improved even in the absence of a reduction in food intake or body weight loss, compared to sham-operated controls . In rodent models of uncontrolled diabetes, DJB improved reduced hepatic glucose production through jejunal sensing mechanisms .
Additional evidence supporting the foregut exclusion hypothesis comes from studies examining the effects of preventing nutrient contact and absorption in the proximal gut by inserting a flexible, plastic endoluminal sleeve into the duodenum that extends into the jejunum, the duodenal–jejunal sleeve; this procedure results in early improvement in glucose homeostasis [53••].
This review has explored the mechanisms through which the most commonly performed bariatric surgery procedures cause weight loss and improvements in the glycaemia of T2DM. It has become apparent that anatomical rearrangements of the gut can cause powerful physiological perturbations that we are now just starting to begin to understand. In many cases, these are at play even before weight loss has taken place. Further indepth interrogation of these mechanisms may lead to the optimisation and personalisation of these procedures,and also the development of more effective and safe pharmacotherapy for the treatment of obesity and T2DM.
Alexander D. Miras is funded by the Medical Research Council Research Training Fellowship G0902002. There are no conflicts of interest in relation to this work.
No potential conflicts of interest relevant to this article were reported.