Abstract
Increasing worldwide prevalence of type 2 diabetes mellitus and its accompanying pathologies such as obesity, arterial hypertension and dyslipidemia represents one of the most important challenges of current medicine. Despite intensive efforts, high percentage of patients with type 2 diabetes does not achieve treatment goals and struggle with increasing body weight and poor glucose control. While novel classes of antidiabetic medications such as incretin-based therapies and gliflozins have some favorable characteristics compared to older antidiabetics, the only therapeutic option shown to substantially modify the progression of diabetes or to achieve its remission is bariatric surgery. Its efficacy in the treatment of diabetes is well established, but the exact underlying modes of action are still only partially described. They include restriction of food amount, enhanced passage of chymus into distal part of small intestine with subsequent modification of gastrointestinal hormones and bile acids secretion, neural mechanisms, changes in gut microbiota and many other possible mechanisms underscoring the importance of the gut in the regulation of glucose metabolism. In addition to bariatric surgery, less-invasive endoscopic methods based on the principles of bariatric surgery were introduced and showed promising results. This review highlights the role of the intestine in the regulation of glucose homeostasis focusing on the mechanisms of action of bariatric and especially endoscopic methods of the treatment of diabetes. A better understanding of these mechanisms may lead to less invasive endoscopic treatments of diabetes and obesity that may complement and widen current therapeutic options.
Introduction
Increasing prevalence of type 2 diabetes mellitus (T2DM) worldwide and its close interconnection with other pathologies such as obesity, arterial hypertension, dyslipidemia and many others commonly referred to as metabolic or insulin resistance syndrome (Reaven 2002) makes T2DM one of the most significant therapeutic challenges of the 21st century (O’Rahilly 1997). This chronic disease currently affects more than 415 million people around the globe (Guariguata 2012, Ogurtsova et al. 2017). Majority (more than 90%) of all diabetic patients suffer from type 2 diabetes whose increased incidence is associated with unhealthy lifestyle, lack of physical activity, overeating and obesity. Moreover, another 193 million people worldwide are supposed to suffer from undiagnosed diabetes (Beagley et al. 2013). It is estimated that by 2040, the number of subjects diagnosed with diabetes mellitus will reach 642 million (Whiting et al. 2011). However, the main socioeconomic problem of diabetes is neither its high prevalence nor its direct treatment costs, but the fact that its unsatisfactory control leads to the development of chronic macrovascular (accelerated atherosclerosis of large arteries) and microvascular (alteration of microcirculation in kidney, eye and peripheral nerves) complications that are responsible for the majority of diabetes-related treatment costs (Chatterjee et al. 2017). As a result, patients with T2DM have a 2- to 3-fold increased risk of development of cardiovascular complications including myocardial infarction, stroke and peripheral arterial disease (Haffner et al. 1998).
Numerous studies have shown that bariatric surgery, in particular, the operations based on exclusion of the proximal part of duodenum from the contact with food, not only effectively decrease body weight but also markedly improve glucose control beyond the positive metabolic effects of weight loss (Rubino & Marescaux 2004, Pournaras et al. 2012). In fact, high percentage of diabetics can achieve diabetes remission after bariatric surgery making this approach the only therapeutic intervention capable of modification of the course of diabetes (Pories 2008, O’Brien 2010). Consequently, endoscopic methods mimicking some of the effects of bariatric surgery were introduced and have shown some promises as well (Sullivan et al. 2017). The aim of this review is to discuss the current bariatric and endoscopic methods for the treatment of diabetes with a special focus on the mechanisms behind their effects. In particular, we will outline the potential mechanisms behind novel endoscopic procedures.
The role of the gut in glucose control and development of diabetes
Although its importance has not been fully appreciated until recently, gut has the ability to affect glucose homeostasis on multiple levels. It is essential for nutrient absorption and its delivery to different organs and tissues of human body (Kiela & Ghishan 2016). It utilizes a significant amount of energy to cope with its considerable size and constant turnover of epithelial cells, and it is responsible for the thermic effect of food, which contributes to total energy expenditure and energy homeostasis (van Baak 2008). Most importantly, the information regarding nutritional content, transluminal nutritional flux and other characteristics of ingested food is communicated to other organs and tissues, in particular, to the central nervous system. This information can markedly affect metabolic regulations including glucose metabolism and its modulation by bariatric surgery is the most likely explanation for the profound effects of bariatric surgery on type 2 diabetes control.
Nutrient sensing is a very important part of the regulatory loop whereby central nervous system is provided with accurate information regarding the amount and composition of ingested food (Tolhurst et al. 2012). Primary elements responsible for nutritional sensing within the gastrointestinal tract are specialized endothelial cells referred to as enteroendocrine cells or enteroendocrine system (Psichas et al. 2015). These cells have the ability to sense the nutritional content and the transluminal nutritional flux and consequently secrete gastrointestinal tract hormones that in turn provide the feedback loop to central nervous system and peripheral tissues. The original notion that there are distinct (single hormone-secreting) types of enteroendocrine cells producing distinct hormones has been challenged by recent data suggesting that multiple hormonal precursors are expressed within one cell (Egerod et al. 2012). However, the expression of different gastrointestinal hormones exhibits a characteristic pattern within the gastrointestinal tract with ghrelin, somatostatin and gastrin primarily produced in the stomach; GLP1 in jejunum, ileum and colon; GIP in duodenum; CCK in duodenum and jejunum and PYY in distal ileum and colon, respectively (Meek et al. 2016). With the exception of ghrelin-producing cells, which do not come into direct contact with gastric lumen (referred to as closed-type structures), other enteroendocrine cells are open-type structures with a narrow apical part facing the lumen (Steinert & Beglinger 2011). The gastrointestinal hormones are then typically released in the basolateral side where they either enter into the circulation (endocrine action), act on the neighboring epithelial cells (paracrine action) or activate vagal, enteric or spinal sensory neurons (neural action).
Gut chemosensing is a complex process involving a plethora of nutrient-specific receptors. Its detailed description is beyond the scope of the current paper and numerous excellent reviews on this topic have been recently published (Tolhurst et al. 2012, Psichas et al. 2015). In brief, carbohydrates are primarily sensed as glucose via the sodium glucose cotransporter 1 receptor (SGLT1) with subsequent stimulation of GLP1 and GIP secretion (Nguyen et al. 2012). The principal importance of SGLT1 receptors in mediating glucose-stimulated GLP1 and GIP secretion has been demonstrated in SGLT1-knockout mice where secretion of both hormones in response to glucose was markedly impaired (Kellett 2012). Dietary proteins strongly stimulate CCK secretion and secretion of GLP1 and GIP with underlying mechanism being only partially understood. The candidate receptors include G-coupled calcium-sensing receptor, TIR1/TIR3 and GPRC6A receptors (Reimann et al. 2004, Greenfield et al. 2009). Lipid sensing is mediated through numerous G-coupled receptors including GPR120, GPR119 and FFAR1 activating GLP1 and GIP secretion (Akiba et al. 2015, Kleberg et al. 2015).
Non-nutrient stimuli of enteroendocrine cells include bile acids and inflammatory cytokines (Psichas et al. 2015). Bile acids are in addition to their role in lipid digestion important signaling molecules that act primarily through G-coupled receptor GPBAR1 (also known as TGR5) with high expression in L-cells of distal intestine, being thus a stimulus of GLP1 and PYY secretion (Thomas et al. 2009, Tan et al. 2017). Out of the inflammatory cytokines, interleukin-6 (IL6) has been shown to increase GLP1 secretion from GLUTag cells (Ellingsgaard et al. 2011). Interestingly, IL6 has been demonstrated to increase GLP1 secretion in cardiac surgery patients suggesting a direct link between inflammation and GLP1 secretion in humans (Kahles et al. 2014).
Various gut-derived nutritional signals are then transferred to central nervous system through neural (vagal, enteric or spinal sensory neurons) or endocrine pathways. Nutrient passage through the digestive tract is thoroughly sensed by enteroendocrine cells and converted into gut-derived neural and hormonal signals acting on both central nervous system and peripheral tissues (Latorre et al. 2016). This complex network is a much more likely candidate for the explanation of the effects of bariatric surgery on glucose metabolism as compared to simplified theories postulating changes in single hormonal factors or mechanistic explanations based on the surgery-induced changes of digestive tract anatomy.
Proximal part of the small intestine, in particular the duodenum, appears to be the key metabolic signaling center contributing to metabolic disturbances in T2DM (Cherrington et al. 2017). Experimental studies have demonstrated morphological changes of duodenal mucosa in diabetic vs nondiabetic rats with a tendency toward increased expression of GIP-producing L cells possibly contributing to hyperinsulinemia typical for initial stages of T2DM (Bailey et al. 1986, Gniuli et al. 2010). Another study demonstrated impaired sensing and downstream neural signaling in the gut of diabetic rats (Lee et al. 2012). Interestingly, extracts from duodena of diabetic db/db mice impaired insulin signaling and caused insulin resistance in cultured muscle cells (Salinari et al. 2013b ). Human studies show similar morphological changes of duodenal mucosa with mucosal hypertrophy and hyperplasia of enteroendocrine cells (Theodorakis et al. 2006). Functional studies using a balloon catheter for nutrient delivery to duodenum, proximal jejunum and mid-jejunum, respectively, have shown that bypassing the duodenum with a direct delivery of nutrients to jejunum markedly increased insulin sensitivity in both healthy and T2DM subjects (Salinari et al. 2013a ). Breen and colleagues studied the role of bypassing duodenum and redirection of nutrients into jejunum (duodeno-jejunal bypass procedure) in the regulation of glucose metabolism (Breen et al. 2012). Intrajejunal nutrient administration decreased endogenous glucose production in normal rats through a gut-brain-liver network in the presence of unchanged plasma insulin concentrations. The glucose-lowering effect of intrajejunal nutrient administration was attenuated by the inhibition of jejunal glucose uptake or formation of long chain fatty acyl-coA in both normal rats and diabetic animals with streptozotocin-induced diabetes. These findings suggest a critical role of nutrient sensing in the jejunum for early improvements of glucose homeostasis after duodenal-jejunal bypass and possibly also after other bariatric or endoscopic procedures bypassing the duodenum.
Changes of intestinal gluconeogenesis were suggested to play a role in the glucose control after bariatric surgery (in particular gastric bypass) (Mithieux 2014). Troy and colleagues have demonstrated in mice with diet-induced obesity that under fasting conditions, intestinal gluconeogenesis is a major contributor to portal vein glucose levels and its detection via a GLUT2 and hepatoportal sensor pathway (Troy et al. 2008). Intestinal gluconeogenesis was significantly increased after gastric bypass procedure, and this increase in portal vein glucose could trigger the portal sensor to change insulin resistance thus contributing to quick improvements in glucose metabolism. Hayes and colleagues measured fasting glucose levels in portal and central venous blood in patients before and after gastric bypass (Hayes et al. 2011). They found no significant difference in glucose levels in these two sites in diabetic patients before and after surgery thus not supporting the hypothesis that intestinal gluconeogenesis contributes to the resolution of T2DM seen after Roux-en-Y gastric bypass (RYGB).
Collectively, these data along with well-known effects of bariatric surgery involving duodenal exclusion on glucose homeostasis suggest an important and multifaceted role of the proximal gut in the regulation of glucose homeostasis.
Gut microbiota, nutritional sensing and metabolism
Gut microbiota has recently been suggested as an important player involved in metabolic regulations and modulation of local and systemic inflammatory reactions (Burcelin et al. 2013). Obesity and T2DM were associated with changes in the amount and composition of gut bacteria as well as their biological diversity (Koren et al. 2012, Bouter et al. 2017). The exact mechanisms by which intestinal microbiota influences metabolic traits are largely unknown but might include products of gut bacterial fermentation of ingested dietary fiber, especially short-chain fatty acids (SCFA – butyrate, propionate and acetate), which were shown to affect energy homeostasis (Kim et al. 2014). The recent discovery of receptors across a wide range of cell and tissue types, for which SCFA appear to be natural ligands, further highlights their potential central role in the gut microbiota–metabolism interactions (Zhang et al. 2016). Another potentially important mechanism of direct influence of gut microbiota on metabolic regulations may lie in its interconnection with the initiation and development of subclinical inflammation that in turn contributes to the development of insulin resistance/type 2 diabetes (Haffner 2003). It has been postulated that obesity and T2DM are associated with increased penetration of lipopolysaccharide from gut bacteria into circulation with subsequent activation of innate immune system in adipose tissue (Creely et al. 2007).
While modulation of gut microbiota effectively prevented obesity and improved metabolic status in rodent models of obesity and type 2 diabetes (Di Luccia et al. 2015), human data supporting such strong effects in obese diabetic patient are much less convincing. A recent study exploring the effect of lean donor fecal microbiota transplantation has shown modest improvements in insulin sensitivity in male recipients with the metabolic syndrome 6 but not 18 weeks after transplantation (Kootte et al. 2017).
As changes in the gut microbiota have been studied only in some types of bariatric surgeries and in none of the endoscopic methods of diabetes treatment, we do not cover this topic in detail in this paper (for extensive reviews please see (Wahlstrom et al. 2016, Magouliotis et al. 2017)).
From bariatric to metabolic surgery
Bariatric surgery is the only therapeutic strategy proven to sustainably reduce body weight along with accompanying complications in patients with higher degree of obesity (Sjostrom et al. 2007, Pories 2008). Furthermore, it not only markedly reduces body weight but also radically improves diabetes control or leads to its complete remission in a high percentage of patients. Although substantial metabolic improvements are present in all patients after bariatric surgery, different types of operations differ in the rate of diabetes remission as well as in the timing of metabolic improvements (Dixon et al. 2012). In this part of the paper, we describe the principles of various bariatric procedures with respect to changes of gastrointestinal anatomy. Mechanisms of action of these operations are discussed along with mechanisms of action of endoscopic procedures in the section ‘How do bariatric or endoscopic procedures improve glucose control’.
Traditional classification of bariatric operations into restrictive and malabsorptive is considered inadequate by some leaders in the field (Dixon et al. 2012) and may be misleading as far as the mechanism of action is concerned (Haluzik 2013). For example, recent data suggest that typical ‘restrictive’ operations such as sleeve gastrectomy in fact do not restrict the passage of the food into the duodenum but rather speed it up (Sista et al. 2017). Nevertheless, traditional classification into restrictive, malabsorptive and mixed operations can still provide a good base to understanding the degree of alteration of gastrointestinal tract anatomy and in some cases also the mechanism of weight loss achievement.
Restrictive procedures including gastric banding, gastric plication and sleeve gastrectomy are all based on the restriction of gastric volume as the primary anatomical alteration (Ashrafian et al. 2010) – see Fig. 1 for different types of surgeries. In case of gastric banding, it is achieved by an adjustable band that creates an artificially small upper portion of the stomach restricting the amount of food that can be consumed in one portion (Burton & Brown 2011). Gastric plication works on a similar premise restricting stomach size by 70% owing to repeated folding (plicating) of the stomach wall inwards (Abdelbaki et al. 2012). Laparoscopic sleeve gastrectomy involves resection of two-thirds of the stomach including the gastric fundus – an important source of the orexigenic hormone ghrelin (Shi et al. 2010). In gastric banding and gastric plication, the decreased food intake and long-term weight loss are indeed achieved mainly by the restriction of the stomach size without any further weight loss-independent mechanisms in place. In contrast, sleeve gastrectomy appears to induce more complex responses resulting in better body weight-reducing and glucose control-improving efficacy than previous two procedures (Chambers et al. 2011).
Different types of bariatric operations.
Citation: Journal of Endocrinology 237, 1; 10.1530/JOE-17-0438
In most of the malabsorptive procedures (e.g., biliopancreatic diversion (BPD), RYGB), stomach size is also partially restricted, and at the same time, a direct connection between the stomach and the lower part of the small intestine is created (Pournaras et al. 2010). Traditionally, bypass of a significant portion of the intestine was thought to decrease the absorption of nutrients, resulting in weight loss. Most recent data suggest that it may be only a partial explanation and that more complex mechanisms are in place (Kohli et al. 2013).
In any case, all bariatric procedures induce diabetes remission in a significant number of patients ranging from 30 to 95% of cases, with procedures involving the exclusion of a part of small intestine being generally more effective (Buchwald et al. 2004). The metabolic improvements after bariatric operations occur rather rapidly within the first days or weeks after the procedure when only negligible weight reduction is achieved. This suggests that other mechanisms partially or completely independent of weight loss are playing a role (Ashrafian & le Roux 2009, Jackness et al. 2013).
The concept of metabolic surgery refers to clinical and scientific evidence that bariatric operations are able to cure or at least markedly improve type 2 diabetes by mechanisms only partially related to weight loss (Rubino & Cummings 2012). Bariatric surgery has traditionally been used for the treatment of 3rd degree (BMI > 40 kg/m2) or 2nd degree obesity with complications (BMI 35–40 kg/m2) (Fried et al. 2014). Metabolic/bariatric surgery is according to the latest consensus advocated for the treatment of diabetes even in patients with BMI > 30 kg/m2 and poor glucose control (Rubino et al. 2016).
Endoscopic methods that mimic bariatric surgery
While bariatric surgery has proven high efficacy in improving glucose control and reducing body weight, it has still numerous disadvantages including the risks of general anesthesia, the operation itself and short-term and long-term postoperative complications (Bal et al. 2011). Furthermore, many patients are reluctant to have their diabetes treated by surgery when there are still possibilities of conservative therapy. To minimize the risks associated with the invasiveness of bariatric surgery while trying to maintain its favorable metabolic effects, endoscopic procedures mimicking some of the principles of bariatric surgery have been introduced (Kumar 2016, Sullivan et al. 2017, Vairavamurthy et al. 2017). Here, we describe the principles and the efficacy of endoscopic procedures targeting pathophysiological mechanisms identified by bariatric operations. We intentionally leave out gastric balloons and aspiration therapy as short-term mechanistic procedures primarily intended for the treatment of obesity.
Duodenal-jejunal bypass liner (DJBL)
Duodenal-jejunal by-pass liner (DJBL) is an endoscopically implantable device that mimics some of the effects of gastric bypass operations (Patel et al. 2012). The principle of this device is based on the early animal (Rubino & Marescaux 2004) and human studies (Cohen et al. 2007) showing that surgical duodenal-jejunal bypass markedly improves glucose homeostasis without a marked effect on weight loss. In this operation, duodenum is transected and closed distally 1–2 cm below pylorus, creating pylorojejunostomy. Biliopancreatic limb is divided 30 cm from ligament of Treitz and anastomosed end-to-side 50 cm downstream in the jejunum (Cohen et al. 2007).
DJBL is a 60 cm long impermeable fluoropolymer sleeve that is inserted endoscopically into the small intestine for up to 12 months (Fig. 2) (Patel et al. 2012, Rohde et al. 2016). The ingested food is thus prevented from the contact with the proximal part of small intestine (duodenum, proximal jejunum) as it passes through the impenetrable liner. As a result, the food that reaches directly the medium part of jejunum is less digested. Both the exclusion of the proximal part of small intestine and the presence of less digested food in its distal parts are thought to be at least partially responsible for the weight loss and improvement of diabetes control seen in obese patients with T2DM after DJBL implantation (Cohen et al. 2013).
Duodenal-jejunal bypass liner.
Citation: Journal of Endocrinology 237, 1; 10.1530/JOE-17-0438
In general, the efficacy of DJBL varies among different studies (Kavalkova et al. 2016, Rohde et al. 2017, Vilarrasa et al. 2017). In a recently published meta-analysis of 5 randomized and 10 observational studies a DJBL implantation was accompanied by excess weight loss of 5.1 kg and a decrease of HbA1c of 0.9% and fasting plasma glucose by 3.7mmol/L (Rohde et al. 2016). Adverse events consisted mainly of abdominal pain, nausea and less frequently vomiting. While most of the trials with DJBL demonstrated its good efficacy and safety, the pivotal US-based trial with this device has been terminated prematurely owing to higher rate of hepatic abscesses that was about 3.5%. Interestingly, this rate was almost 5 times higher than the rate of this complication in the centers outside the United States in other trials. Based on these safety data, DJBL has been withdrawn from the market in the USA and its safety is currently under close scrutiny by the European Medicines Agency as well.
Endoscopic duodenal mucosal resurfacing
Duodenal mucosal resurfacing is a minimally invasive endoscopic procedure based on the hydrothermal ablation of duodenal mucosa (Fig. 3 – reviewed in Cherrington et al. (2017)). Preclinical testing was performed on Goto-Kakizaki rats – a model of type 2 diabetes. In this study, hydrothermal ablation of duodenal mucosa significantly reduced postprandial glucose (unpublished data mentioned in Rajagopalan et al. (2016)). Phase I human study was performed as a single arm, non-randomized trial at a single center in Santiago de Chile. 44 patients with poorly controlled type 2 diabetes were included and underwent a single application of thermal energy ablation over 3–12 cm of duodenum (Rajagopalan et al. 2016). The procedure was well tolerated with no major acute side effects and good tolerance of oral diet by all patients after procedure. The most common side effect was abdominal pain and three patients developed duodenal stenosis that was successfully treated by a single endoscopic dilation. After 6 months, HbA1c was reduced by 1.2% from the baseline value of 9.6%. Patients with ≥9 cm ablation had HbA1c reduced by 2.5% at three months and by 1.4% at six months as compared to 1.2% reduction in <6 cm of duodenum ablation after three and 0.7% reduction of HbA1c after 6 months, respectively. Both fasting and postprandial blood glucose levels were significantly lowered in both subcohorts along with reduction or no change in antidiabetic medication in the long segment cohort while in some patients from the short segment cohort treatment intensification was needed. In a combined group of all patients, body weight was reduced by 3.9 kg at three months and by 2.5 kg at 6 months, respectively.
Hydrothermal ablation of the duodenal mucosa (reproduced, with permission, under the terms of the original Creative Commons licence from Cherrington et al. (2017)).
Citation: Journal of Endocrinology 237, 1; 10.1530/JOE-17-0438
Minimally invasive entero-enteral dual-path bypassing using self-assembling magnets
This method uses an incisionless system based on the miniature self-assembling magnets, which create large-caliber anastomoses (Fig. 4). The incisionless magnet anastomosis system is preloaded into the biopsy channels of two endoscopes, and a simultaneous colonoscopy and enteroscopy are performed (Ryou et al. 2016a ). After endoscopic deployment, the magnets self-assemble to form octagons in the jejunum and ileum. Subsequently, they couple to create a compression anastomosis allowing a portion of the ingested nutrients to bypass a part of the small bowel. Mated magnets then pass into the stool after the compression anastomosis is formed, typically in 1–2 weeks. The system has been successfully tested in two studies in 5 and 8 Yorkshire pigs, respectively (Ryou et al. 2016a , b ). The procedure was safe with all animals surviving with anastomosis present three months after the procedure.
Minimally invasive entero-enteral dual-path bypassing using self-assembling magnets.
Citation: Journal of Endocrinology 237, 1; 10.1530/JOE-17-0438
First human data with this approach have been presented recently. Simonson and colleagues studied 10 obese patients (4 with T2DM and 3 with prediabetes) who underwent dual-path enteral diversion using an incisionless magnet anastomosis system at baseline and 6, 12 and 18 months after the procedure, respectively (Machytka et al. 2017a ). The mean weight loss after 18 months was 16.6 kg. In patients with diabetes, HbA1c decreased from 7.8 to 6.0% despite reduction or cessation of antidiabetic medication. All 3 prediabetic patients returned to normal glucose tolerance. No major side effects were reported with diarrhea being the most frequent minor side effect. The interim 12-months results of this procedure have recenty been published (Machytk et al. 2017b ).
How do bariatric or endoscopic procedures improve glucose control?
Many possible explanations of metabolic improvements after bariatric surgery have been formulated with ‘foregut’ and ‘hindgut hypotheses’ being often mentioned (Dixon et al. 2012). The foregut hypothesis is based on the observation that bariatric procedures excluding the proximal part of the small intestine from the ingestion, such as gastric bypass or biliopancreatic diversion, are the most effective in the improvement or remission of type 2 diabetes. According to this hypothesis, exclusion of foregut from nutrient passage may inhibit the production of the postulated factor that impairs insulin secretion and possibly induces other metabolic disturbances. The hindgut hypothesis suggests that expedited delivery of nutrients to the distal parts of small intestine promotes metabolic improvements and weight loss by accentuation of ileal brake – a primary inhibitory feedback mechanism that regulates the transit of food through digestive tract to ensure optimal nutrient digestion and absorption (Maljaars et al. 2008).
It is now increasingly clear that simplified mechanistic explanations looking for a single hormonal factor or single mechanism are not capable of explaining the complex effects of bariatric surgery. The improvement of glucose homeostasis after surgery may include a plethora of mechanisms from pure restriction of food intake or malabsorption leading to weight loss to modulation of gastric emptying; the digestion of carbohydrates, lipids and proteins; modification of absorption of glucose and its utilization by the intestine; changes in nutrient sensing and modulation of gastrointestinal hormone secretion, modulation of gut microbiota and many others (Fig. 5).
Complex changes induced by bariatric surgery. Gastric bypass is pictured as an example of the operation combining weight-dependent and weight-independent effects. Exclusion of distal part of duodenum combined with accelerated entry of less digested food into jejunum increases GLP1 secretion that subsequently acts on the brain to decrease food intake and modify food preferences. Further input into the brain is mediated through nutrient sensing and other multiple mechanisms transferred by neural and endocrine pathways. Adapted, with permission, from Madsbad et al. (2014). Copyright 2014 Elsevier Ltd.
Citation: Journal of Endocrinology 237, 1; 10.1530/JOE-17-0438
Weight loss and energy expenditure
Weight loss is an important part of the metabolic effects of bariatric surgery. For example, in the meta-analysis published by Buchwald and colleagues, the percentage of excess weight loss was 47% for gastric banding, 62% for RYGB and 79% after biliopancreatic diversion with duodenal switch (Buchwald et al. 2004). In the recently published 5-year results of the STAMPEDE trial comparing surgical vs medical therapy of T2DM, patients BMI decreased from 36.4 to 34 in the medical group, while it was lowered from 37 to 28.9 in gastric bypass and from 36 to 29.3 in sleeve gastrectomy group, respectively (Schauer et al. 2017). Similar results were reported in another study comparing surgical vs conservative treatment of type 2 diabetes (Mingrone et al. 2015).
By contrast in endoscopic procedures, relatively modest body weight decrease has been reported ranging mostly between 5 and 10 kg or even less with duodenal mucosal resurfacing (Rohde et al. 2016). Changes in energy expenditure have not been systematically measured in most of the bariatric procedures. Available data suggest that energy expenditure decreases after bariatric surgery similar to changes seen in weight loss achieved by caloric restriction (Benedetti et al. 2000). There are no data available with respect to energy expenditure changes in patients after endoscopic procedures. Nevertheless, it is unlikely that major changes of energy expenditure after endoscopic procedures can be expected.
Gastric volume restriction
Gastric volume restriction and malabsorption have been extensively discussed in connection with the mechanism of metabolic effects of bariatric surgery. Laparoscopic gastric banding markedly restricts the size of the upper pouch of the stomach preventing the patients from eating large quantities of solid food. Smaller meal sizes are sufficient to create intraluminal pressure able to induce satiation probably through gastric sensory receptors and vagus nerve (Burton & Brown 2011). On the contrary, anorexigenic gastrointestinal hormones such as GLP1 and PYY are not affected by gastric banding, and ghrelin levels increase similarly to patients losing weight by dieting (Wang & Liu 2009). No data are available with respect to gastric plication and food passage or gastric emptying. Similar to gastric banding, gastric plication does not appear to consistently affect GLP1, GIP and PYY, and majority of the studies suggest increased ghrelin levels after this procedure similarly to changes after gastric banding or hypocaloric diet (Buzga et al. 2015).
Gastric volume is restricted in both RYGB and sleeve gastrectomy; nevertheless, this size restriction does not slow down the food passage into intestine but rather accelerates its entry (Sista et al. 2017). Consequently, nutrient sensing can be significantly altered and could thus explain some of the metabolic effects of surgery. Another possible consequence of accelerated food transit could be the modulation of hormonal secretion of enteroendocrine cells, which can attenuate food intake through neural mechanisms (le Roux et al. 2007).
Out of the endoscopic procedures, gastric emptying has only been studied in patients after DJBL implantation (de Moura et al. 2015). De Moura and colleagues found delayed gastric emptying after DJBL implantation that was reversible after its removal. Nevertheless, the changes in gastric emptying did not correlate with weight loss or T2DM control suggesting that other mechanisms were responsible for improved diabetes compensation (de Moura et al. 2015).
Malabsorption
Malabsorption of macronutrients is not seen with restrictive operations or RYGB while it is common in patients after BPD (Madsbad et al. 2014). In BPD, partial fat malabsorption is intended and considered part of the weight-reducing mechanism (O’Brien 2010). On the contrary, micronutrient deficiencies are often seen especially after RYGB and BPD where parenteral supplementation of some vitamins (in particular vitamin D) may be needed (Pournaras & le Roux 2009). In our study with 10-month DJBL implantation in patients with poorly controlled T2DM, we noticed a decrease in serum concentrations of zinc, vitamin B12 and iron that were reversed three months after DJBL removal (Kavalkova et al. 2016). Overall, malabsorption of macronutrients only appears to play some role in the weight loss and metabolic improvements in patients after BPD while it is not present in other procedures. Micronutrient changes seen after some procedures are unlikely to have a significant role in alterations of glucose metabolism.
Changes in classical gastrointestinal hormones
Changes of circulating levels of gastrointestinal and pancreatic peptide hormones have been intensively discussed as important players potentially explaining the metabolic effects of bariatric surgery and some excellent reviews focused on this topic are available (Meek et al. 2016, Cavin et al. 2017). In general ghrelin, cholecystokinin and both incretins (GLP1 and GIP), and PYY have been studied most frequently with less information available with respect to other hormones.
Ghrelin is produced by the stomach and the pancreas and its elevated concentrations increase hunger and stimulate food intake (Tschop et al. 2000). Decreased ghrelin levels are present in patients with obesity, and they increase in response to diet-induced weight loss and restrictive bariatric surgeries that do not involve stomach resection (gastric banding, gastric plication) (Cummings et al. 2002, Dostalova & Haluzik 2009). Ghrelin levels were reported to increase after DJBL (de Jonge et al. 2015) while no information about its levels is available in patients after other endoscopic procedures.
Cholecystokinin is primarily secreted by I cells in duodenum and stimulates bile and pancreatic juice secretion into gut lumen, slows down gastric emptying and promotes satiety (Miyasaka & Funakoshi 2003). Cholecystokinin levels rise after RYGB or sleeve gastrectomy and decrease after DJBL (de Jonge et al. 2015) while no data are available for other bariatric or endoscopic procedures (Peterli et al. 2012, Dirksen et al. 2013b ).
GLP1 is secreted from L cells mainly in the distal ileum and colon (Holst et al. 2008). Its well-known effects such as increased insulin and decreased glucagon secretion, inhibition of food intake and slowing of gastric emptying are used therapeutically in patients with type 2 diabetes via DPP4 inhibitors and GLP1 receptor agonists commonly referred to as incretin-based therapies (Drucker et al. 2010).
Early experimental studies demonstrated an important role for increased GLP1 secretion as an important mediator of metabolic improvements after various types of bariatric surgery including not only gastric bypass (Shin et al. 2010), but also ileal transposition (Strader et al. 2005) and sleeve gastrectomy (Chambers et al. 2011). Interestingly though, the effects of RYGB on body weight and glucose homeostasis were preserved even in two mouse models of functional glucagon-like peptide-1 deficiency (Mokadem et al. 2014).
In human studies, RYGB markedly increases GLP1 levels that are undoubtedly responsible for some of the positive metabolic effects of this operation (Holst & Madsbad 2016) by multiple mechanisms including increased insulin and decreased glucagon secretion, slowed gastric emptying and central anorexigenic effects (Holst et al. 2008). Other bariatric procedures, even the restrictive ones, can also transiently increase GLP1 levels (Bradnova et al. 2014). Nevertheless, the concentrations are much lower as compared to the marked increase after RYGB. Postprandial GLP1 levels were reported to be either significantly increased (Rohde et al. 2017) or unchanged after DJBL implantation (Kavalkova et al. 2016, Vilarrasa et al. 2017) with no data available with respect to GLP1 changes after other endoscopic procedures. GIP is secreted from K cells in the proximal part of small intestine (Drucker 2006). It has an important insulinotropic and lipogenic effect and acts in concert with GLP1 to maintain normal insulin secretion. In contrast to GLP1, the effect of different bariatric operations on circulating GIP levels appears to be modest or none at all (Mingrone et al. 2009, Salinari et al. 2009). We noticed a small decrease in postprandial GIP peak after DJBL implantation while no data for other endoscopic procedures are available (Kavalkova et al. 2016).
PYY is produced by L-cells in the distal part of small intestine and in the colon (Batterham et al. 2003). It promotes satiety, delays gastric emptying, slows down colonic motility and reduces postprandial insulin production. In experimental studies, PYY appears to play an important role in mediating weight loss after bariatric surgery. Its importance was directly demonstrated in PYY-knockout mice that in contrast to control animals did not lose weight after gastric bypass (Chandarana et al. 2011). Restoration of normal glucose homeostasis in the diabetic Goto-Kakizaki (GK) rat model was mediated by PYY and neutralization of PYY reversed these effects in diabetic rat islets in vitro (Ramracheya et al. 2016). In humans, some studies reported increased postprandial PYY levels after different types of bariatric operations (Dirksen et al. 2013a , Tsoli et al. 2013), which could theoretically contribute to increased satiety in patients after bariatric surgery. DJBL implantation and creation of a dual-path enteral diversion by incisionless magnetic anastomotic system, respectively, was also accompanied by increased PYY concentrations (Rohde 2016, Machytka et al. 2017a , Vilarrasa et al. 2017) while no data on PYY were reported for duodenal mucosal resurfacing.
Glucagon is produced by the alpha cells of pancreatic islets. It is a major counter regulatory hormone to insulin being released during fasting and promoting gluconeogenesis and glycogenolysis (Lund et al. 2014). Chronically increased glucagon concentrations contribute to hyperglycemia and excessive liver glucose production in patients with T2DM and its amelioration by incretin-based therapies is an important part of their mechanism of antidiabetic action (Martin et al. 2011). Weight loss is in general accompanied by decreased glucagon levels and a similar finding was reported in patients undergoing RYGB (Korner et al. 2006). In our study, DJBL decreased glucagon concentrations and this effect was abolished after DJBL removal (Kavalkova et al. 2016). No data are available with respect to glucagon changes after other endoscopic or bariatric procedures.
Changes in bile acids
Bile acids not only contribute to lipid digestion but also act as important signaling molecules in the liver through stimulation of farnesoid X receptor (FXR) (Prawitt et al. 2011) and TGR5 receptors (Thomas et al. 2009). These receptors have an important role in the regulation of numerous metabolic processes including glucose and lipid homeostasis. Therefore, modulation of circulating bile acids is a plausible mechanism to explain some of the metabolic effects of bariatric or endoscopic interventions. Bile acid-dependent changes after vertical sleeve gastrectomy (VSG) were studied in a mouse model with diet-induced obesity comparing mouse with intact vs targeted genetic disruption of FXR (Ryan et al. 2014). VSG increased circulating bile acids regardless of intact FXR signaling. However, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance was substantially reduced. In another study, diversion of bile flow to the ileum induced metabolic changes similar to RYGB including weight loss and improvements in glucose tolerance and hepatic steatosis underscoring the significance of bile acid signaling in the metabolic effects of bariatric surgery (Flynn et al. 2015).
Numerous studies have indicated that malabsorptive operations markedly affect the systemic concentrations of bile acids (Pournaras & le Roux 2013). Increased systemic levels of total bile acids have been described in patients after both gastric bypass and biliopancreatic diversion (Pournaras et al. 2012). In patients after sleeve gastrectomy, total bile acids were reported to be unchanged (Haluzikova et al. 2013) or increased (Escalona et al. 2016). Only transient elevation of the majority of circulating bile acids was found after gastric banding with only glycolithocholic acid being elevated chronically (Thoni et al. 2017). Out of the endoscopic interventions, bile acids were only measured after DJBL. In our study, we found a marked elevation in total circulating bile acid levels 10 months after DJBL implantation (Kavalkova et al. 2016).
Changes in fibroblast growth factor 19
Fibroblast growth factor-19 (FGF19) was originally discovered in human brain during embryonic and fetal development (Nishimura et al. 1999). Later studies have shown its important role in the regulation of bile acid synthesis and transportation and an important interplay between bile acids and FGF19 (Lundasen et al. 2006). Bile acids stimulate FGF19 expression and synthesis in enterocytes through stimulation of FXR (Wistuba et al. 2007). FGF19, on the other hand, inhibits the expression of Cyp7a1 – a rate-limiting enzyme in bile acids synthesis (Song et al. 2009). Numerous experimental studies have shown that administration of FGF19 or its transgenic expression prevented the development of obesity and insulin resistance in mice (Tomlinson et al. 2002). Furthermore, a recent study has demonstrated that administration of FGF15/19 and FGF19-based chimeric molecule protected from diet-induced hepatic steatosis and promoted liver regeneration after partial hepatectomy in a mouse model (Alvarez-Sola et al. 2017).
In humans, circulating FGF19 concentrations were decreased or unchanged in patients with type 2 diabetes and obesity relative to healthy subjects (Mraz et al. 2011, Gomez-Ambrosi et al. 2017). Similarly, FGF19 concentrations were reduced in obese adolescents with nonalcoholic fatty liver disease and were inversely related to the probability of development of nonalcoholic steatohepatitis and fibrosis (Gallego-Escuredo et al. 2015). Bariatric surgery including RYGB, LSG and gastric banding consistently increased FGF19 (Haluzikova et al. 2013; Pournaras & le Roux 2013). FGF19 concentrations were also increased in our study after DJBL implantation in patients with T2DM (Kavalkova et al. 2016) while no data on FGF19 levels are available for other bariatric or endoscopic procedures. Taken together, available data suggest that increased FGF19 concentrations may play a role in metabolic improvements after bariatric surgery and DJBL implantation. This factor may also have an interesting potential in the treatment of obesity and related metabolic complications.
Conclusions and future directions
With steadily increasing prevalence of T2DM, novel therapeutic approaches are needed that are capable of not only achieving a temporary improvement of glucose control but also modifying the course of diabetes development, i.e. slowing down its progression or achieving its complete remission. Bariatric surgery is, at the moment, the only approach able to accomplish this goal. It is quite clear that the operations with highest metabolic efficacy act by multiple mechanisms with many of them being partially or completely independent of weight loss. Endoscopic methods mimicking some of the principles of bariatric surgery have been introduced and tested in patients with T2DM. Although promising, most of these methods are still in the early stages of clinical development. It can be expected that better understanding of the mechanisms of action of bariatric surgery will eventually lead to novel pharmacological therapies of T2DM possibly acting through modifications of nutritional sensing, manipulation of number or phenotype of enteroendocrine cells or alterations of signal transduction from enteroendocrine cells to central nervous system. Many hopes are also put into modification of gut microbiota as potential adjuvant therapy of T2DM although little data supporting the viability of this concept in humans is available to date. Refined endoscopic methods based on the principles of bariatric surgery could in the future complement and possibly even replace some of the methods of bariatric surgery. Collectively, treatment of diabetes by targeting the gastrointestinal tract appears to be one of the most promising approaches, we currently have to battle the emerging threat of type 2 diabetes mellitus and many interesting developments can be expected in this field in the near future.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by RVO-VFN64165 and DRO IKEM 000023001.
References
Abdelbaki TN, Huang CK, Ramos A, Neto MG, Talebpour M & Saber AA 2012 Gastric plication for morbid obesity: a systematic review. Obesity Surgery 22 1633–1639. (https://doi.org/10.1007/s11695-012-0723-z)
Akiba Y, Inoue T, Kaji I, Higashiyama M, Narimatsu K, Iwamoto K, Watanabe M, Guth PH, Engel E, Kuwahara A, et al. 2015 Short-chain fatty acid sensing in rat duodenum. Journal of Physiology 593 585–599. (https://doi.org/10.1113/jphysiol.2014.280792)
Alvarez-Sola G, Uriarte I, Latasa MU, Fernandez-Barrena MG, Urtasun R, Elizalde M, Barcena-Varela M, Jimenez M, Chang HC, Barbero R, et al. 2017 Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut 66 1818–1828. (https://doi.org/10.1136/gutjnl-2016-312975)
Ashrafian H & le Roux CW 2009 Metabolic surgery and gut hormones – a review of bariatric entero-humoral modulation. Physiology and Behavior 97 620–631. (https://doi.org/10.1016/j.physbeh.2009.03.012)
Ashrafian H, Bueter M, Ahmed K, Suliman A, Bloom SR, Darzi A & Athanasiou T 2010 Metabolic surgery: an evolution through bariatric animal models. Obesity Reviews 11 907–920. (https://doi.org/10.1111/j.1467-789X.2009.00701.x)
Bailey CJ, Flatt PR, Kwasowski P, Powell CJ & Marks V 1986 Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets. Acta Endocrinologica 112 224–229. (https://doi.org/10.1530/acta.0.1120224)
Bal BS, Finelli FC & Koch TR 2011 Origins of and recognition of micronutrient deficiencies after gastric bypass surgery. Current Diabetes Reports 11 136–141. (https://doi.org/10.1007/s11892-010-0169-4)
Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA & Bloom SR 2003 Inhibition of food intake in obese subjects by peptide YY3-36. New England Journal of Medicine 349 941–948. (https://doi.org/10.1056/NEJMoa030204)
Beagley J, Guariguata L, Weil C & Motala AA 2013 Global estimates of undiagnosed diabetes in adults for 2013 for the IDF diabetes atlas. Diabetes Research and Clinical Practice 103 150–160. (https://doi.org/10.1016/j.diabres.2013.11.001)
Benedetti G, Mingrone G, Marcoccia S, Benedetti M, Giancaterini A, Greco AV, Castagneto M & Gasbarrini G 2000 Body composition and energy expenditure after weight loss following bariatric surgery. Journal of the American College of Nutrition 19 270–274. (https://doi.org/10.1080/07315724.2000.10718926)
Bouter KE, van Raalte DH, Groen AK & Nieuwdorp M 2017 Role of the gut microbiome in the pathogenesis of obesity and obesity-related metabolic dysfunction. Gastroenterology 152 1671–1678. (https://doi.org/10.1053/j.gastro.2016.12.048)
Bradnova O, Kyrou I, Hainer V, Vcelak J, Halkova T, Sramkova P, Dolezalova K, Fried M, McTernan P, Kumar S, et al. 2014 Laparoscopic greater curvature plication in morbidly obese women with type 2 diabetes: effects on glucose homeostasis, postprandial triglyceridemia and selected gut hormones. Obesity Surgery 24 718–726. (https://doi.org/10.1007/s11695-013-1143-4)
Breen DM, Rasmussen BA, Kokorovic A, Wang R, Cheung GW & Lam TK 2012 Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nature Medicine 18 950–955. (https://doi.org/10.1038/nm.2745)
Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K & Schoelles K 2004 Bariatric surgery: a systematic review and meta-analysis. JAMA 292 1724–1737. (https://doi.org/10.1001/jama.292.14.1724)
Burcelin R, Serino M, Chabo C, Garidou L, Pomie C, Courtney M, Amar J & Bouloumie A 2013 Metagenome and metabolism: the tissue microbiota hypothesis. Diabetes, Obesity and Metabolism 15 (Supplement 3) 61–70. (https://doi.org/10.1111/dom.12157)
Burton PR & Brown WA 2011 The mechanism of weight loss with laparoscopic adjustable gastric banding: induction of satiety not restriction. International Journal of Obesity 35 (Supplement 3) S26–S30. (https://doi.org/10.1038/ijo.2011.144)
Buzga M, Holeczy P, Svagera Z & Zonca P 2015 Laparoscopic gastric plication and its effect on saccharide and lipid metabolism: a 12-month prospective study. Wideochir Inne Tech Maloinwazyjne 10 398–405. (https://doi.org/10.5114/wiitm.2015.54103)
Cavin JB, Bado A & Le Gall M 2017 Intestinal adaptations after bariatric surgery: consequences on glucose homeostasis. Trends in Endocrinology and Metabolism 28 354–364. (https://doi.org/10.1016/j.tem.2017.01.002)
Chambers AP, Jessen L, Ryan KK, Sisley S, Wilson-Perez HE, Stefater MA, Gaitonde SG, Sorrell JE, Toure M, Berger J, et al. 2011 Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 141 950–958. (https://doi.org/10.1053/j.gastro.2011.05.050)
Chandarana K, Gelegen C, Karra E, Choudhury AI, Drew ME, Fauveau V, Viollet B, Andreelli F, Withers DJ & Batterham RL 2011 Diet and gastrointestinal bypass-induced weight loss: the roles of ghrelin and peptide YY. Diabetes 60 810–818. (https://doi.org/10.2337/db10-0566)
Chatterjee S, Khunti K & Davies MJ 2017 Type 2 diabetes. Lancet 389 2239–2251. (https://doi.org/10.1016/S0140-6736(17)30058-2)
Cherrington AD, Rajagopalan H, Maggs D & Deviere J 2017 Hydrothermal duodenal mucosal resurfacing: role in the treatment of metabolic disease. Gastrointestinal Endoscopy Clinics of North America 27 299–311. (https://doi.org/10.1016/j.giec.2016.12.002)
Cohen RV, Schiavon CA, Pinheiro JS, Correa JL & Rubino F 2007 Duodenal-jejunal bypass for the treatment of type 2 diabetes in patients with body mass index of 22–34 kg/m2: a report of 2 cases. Surgery for Obesity and Related Diseases 3 195–197. (https://doi.org/10.1016/j.soard.2007.01.009)
Cohen R, le Roux CW, Papamargaritis D, Salles JE, Petry T, Correa JL, Pournaras DJ, Galvao Neto M, Martins B, Sakai P, et al. 2013 Role of proximal gut exclusion from food on glucose homeostasis in patients with type 2 diabetes. Diabetic Medicine30 1482–1486. (https://doi.org/10.1111/dme.12268)
Creely SJ, McTernan PG, Kusminski CM, Fisher FM, Da Silva NF, Khanolkar M, Evans M, Harte AL & Kumar S 2007 Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. American Journal of Physiology: Endocrinology and Metabolism 292 E740–E747. (https://doi.org/10.1152/ajpendo.00302.2006)
Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP & Purnell JQ 2002 Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New England Journal of Medicine 346 1623–1630. (https://doi.org/10.1056/NEJMoa012908)
de Jonge C, Rensen SS, Verdam FJ, Vincent RP, Bloom SR, Buurman WA, le Roux CW, Bouvy ND & Greve JW 2015 Impact of duodenal-jejunal exclusion on satiety hormones. Obesity Surgery26 672–678. (https://doi.org/10.1007/s11695-015-1889-y)
de Moura EG, Lopes GS, Martins Bda C, Orso IR, Coutinho AM, de Oliveira SL, Sakai P, Galvao-Neto Mdos P, Santo MA, Sapienza MT, et al. 2015 Effects of duodenal-jejunal bypass liner (EndoBarrier(R)) on gastric emptying in obese and type 2 diabetic patients. Obesity Surgery 25 1618–1625. (https://doi.org/10.1007/s11695-015-1594-x)
Di Luccia B, Crescenzo R, Mazzoli A, Cigliano L, Venditti P, Walser JC, Widmer A, Baccigalupi L, Ricca E & Iossa S 2015 Rescue of fructose-induced metabolic syndrome by antibiotics or faecal transplantation in a rat model of obesity. PLoS ONE 10 e0134893. (https://doi.org/10.1371/journal.pone.0134893)
Dirksen C, Bojsen-Moller KN, Jorgensen NB, Jacobsen SH, Kristiansen VB, Naver LS, Hansen DL, Worm D, Holst JJ & Madsbad S 2013a Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass. Diabetologia 56 2679–2687. (https://doi.org/10.1007/s00125-013-3055-1)
Dirksen C, Jorgensen NB, Bojsen-Moller KN, Kielgast U, Jacobsen SH, Clausen TR, Worm D, Hartmann B, Rehfeld JF, Damgaard M, et al. 2013b Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. International Journal of Obesity 37 1452–1459. (https://doi.org/10.1038/ijo.2013.15)
Dixon JB, le Roux CW, Rubino F & Zimmet P 2012 Bariatric surgery for type 2 diabetes. Lancet 379 2300–2311. (https://doi.org/10.1016/S0140-6736(12)60401-2)
Dostalova I & Haluzik M 2009 The role of ghrelin in the regulation of food intake in patients with obesity and anorexia nervosa. Physiological Research 58 159–170. (available at: http://www.biomed.cas.cz/physiolres/pdf/58/58_159.pdf)
Drucker DJ 2006 The biology of incretin hormones. Cell Metabolism 3 153–165. (https://doi.org/10.1016/j.cmet.2006.01.004)
Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS & Buse JB 2010 Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 33 428–433. (https://doi.org/10.2337/dbib9-1499)
Egerod KL, Engelstoft MS, Grunddal KV, Nohr MK, Secher A, Sakata I, Pedersen J, Windelov JA, Fuchtbauer EM, Olsen J, et al. 2012 A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP1, PYY, and neurotensin but not somatostatin. Endocrinology 153 5782–5795. (https://doi.org/10.1210/en.2012-1595)
Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, et al. 2011 Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nature Medicine 17 1481–1489. (https://doi.org/10.1038/nm.2513)
Escalona A, Munoz R, Irribarra V, Solari S, Allende F & Francisco Miquel J 2016 Bile acids synthesis decreases after laparoscopic sleeve gastrectomy. Surgery for Obesity and Related Diseases 12 763–769. (https://doi.org/10.1016/j.soard.2015.11.015)
Flynn CR, Albaugh VL, Cai S, Cheung-Flynn J, Williams PE, Brucker RM, Bordenstein SR, Guo Y, Wasserman DH & Abumrad NN 2015 Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery. Nature Communications 6 7715. (https://doi.org/10.1038/ncomms8715)
Fried M, Yumuk V, Oppert JM, Scopinaro N, Torres A, Weiner R, Yashkov Y, Fruhbeck G, International Federation for Surgery of O, Metabolic Disorders-European C, et al. 2014 Interdisciplinary European guidelines on metabolic and bariatric surgery. Obesity Surgery 24 42–55. (https://doi.org/10.1007/s11695-013-1079-8)
Gallego-Escuredo JM, Gomez-Ambrosi J, Catalan V, Domingo P, Giralt M, Fruhbeck G & Villarroya F 2015 Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. International Journal of Obesity 39 121–129. (https://doi.org/10.1038/ijo.2014.76)
Gniuli D, Calcagno A, Dalla Libera L, Calvani R, Leccesi L, Caristo ME, Vettor R, Castagneto M, Ghirlanda G & Mingrone G 2010 High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats. Diabetologia 53 2233–2240. (https://doi.org/10.1007/s00125-010-1830-9)
Gomez-Ambrosi J, Gallego-Escuredo JM, Catalan V, Rodriguez A, Domingo P, Moncada R, Valenti V, Salvador J, Giralt M, Villarroya F, et al. 2017 FGF19 and FGF21 serum concentrations in human obesity and type 2 diabetes behave differently after diet- or surgically-induced weight loss. Clinical Nutrition 36 861–868. (https://doi.org/10.1016/j.clnu.2016.04.027)
Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM, Blackwood A, Reimann F, Holst JJ & Gribble FM 2009 Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. American Journal of Clinical Nutrition 89 106–113. (https://doi.org/10.3945/ajcn.2008.26362)
Guariguata L 2012 By the numbers: new estimates from the IDF Diabetes Atlas Update for 2012. Diabetes Research and Clinical Practice 98 524–525. (https://doi.org/10.1016/j.diabres.2012.11.006)
Haffner SM 2003 Insulin resistance, inflammation, and the prediabetic state. American Journal of Cardiology 92 18J–26J. (https://doi.org/10.1016/S0002-9149(03)00612-X)
Haffner SM, Lehto S, Ronnemaa T, Pyorala K & Laakso M 1998 Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. New England Journal of Medicine 339 229–234. (https://doi.org/10.1056/NEJM199807233390404)
Haluzik M 2013 Bariatric surgery and the mechanism of diabetes remission: are we getting there? Journal of Clinical Endocrinology and Metabolism 98 4336–4338. (https://doi.org/10.1210/jc.2013-3698)
Haluzikova D, Lacinova Z, Kavalkova P, Drapalova J, Krizova J, Bartlova M, Mraz M, Petr T, Vitek L, Kasalicky M, et al. 2013 Laparoscopic sleeve gastrectomy differentially affects serum concentrations of FGF19 and FGF-21 in morbidly obese subjects. Obesity 21 1335–1342. (https://doi.org/10.1002/oby.20208)
Hayes MT, Foo J, Besic V, Tychinskaya Y & Stubbs RS 2011 Is intestinal gluconeogenesis a key factor in the early changes in glucose homeostasis following gastric bypass? Obesity Surgery 21 759–762. (https://doi.org/10.1007/s11695-011-0380-7)
Holst JJ & Madsbad S 2016 Mechanisms of surgical control of type 2 diabetes: GLP1 is key factor. Surgery for Obesity and Related Diseases 12 1236–1242. (https://doi.org/10.1016/j.soard.2016.02.033)
Holst JJ, Deacon CF, Vilsboll T, Krarup T & Madsbad S 2008 Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends in Molecular Medicine 14 161–168. (https://doi.org/10.1016/j.molmed.2008.01.003)
Jackness C, Karmally W, Febres G, Conwell IM, Ahmed L, Bessler M, McMahon DJ & Korner J 2013 Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and beta-cell function in type 2 diabetic patients. Diabetes 62 3027–3032. (https://doi.org/10.2337/db12-1762)
Kahles F, Meyer C, Mollmann J, Diebold S, Findeisen HM, Lebherz C, Trautwein C, Koch A, Tacke F, Marx N, et al. 2014 GLP1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 63 3221–3229. (https://doi.org/10.2337/db14-0100)
Kavalkova P, Mraz M, Trachta P, Klouckova J, Cinkajzlova A, Lacinova Z, Haluzikova D, Benes M, Vlasakova Z, Burda V, et al. 2016 Endocrine effects of duodenal-jejunal exclusion in obese patients with type 2 diabetes mellitus. Journal of Endocrinology 231 11–22. (https://doi.org/10.1530/JOE-16-0206)
Kellett GL 2012 Comment on: Gorboulev et al. Na+-D-glucose cotransporter SGLT1 Is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61 e4. (https://doi.org/10.2337/db11-1793)
Kiela PR & Ghishan FK 2016 Physiology of intestinal absorption and secretion. Best Practice and Research: Clinical Gastroenterology 30 145–159. (https://doi.org/10.1016/j.bpg.2016.02.007)
Kim S, Kim JH, Park BO & Kwak YS 2014 Perspectives on the therapeutic potential of short-chain fatty acid receptors. BMB Reports 47 173–178. (https://doi.org/10.5483/BMBRep.2014.47.3.272)
Kleberg K, Jacobsen AK, Ferreira JG, Windelov JA, Rehfeld JF, Holst JJ, de Araujo IE & Hansen HS 2015 Sensing of triacylglycerol in the gut: different mechanisms for fatty acids and 2-monoacylglycerol. Journal of Physiology 593 2097–2109. (https://doi.org/10.1113/jphysiol.2014.285635)
Kohli R, Bradley D, Setchell KD, Eagon JC, Abumrad N & Klein S 2013 Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. Journal of Clinical Endocrinology and Metabolism 98 E708–E712. (https://doi.org/10.1210/jc.2012-3736)
Kootte RS, Levin E, Salojarvi J, Smits LP, Hartstra AV, Udayappan SD, Hermes G, Bouter KE, Koopen AM, Holst JJ, et al. 2017 Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metabolism 26 611.e6–619.e6. (https://doi.org/10.1016/j.cmet.2017.09.008)
Korner J, Inabnet W, Conwell IM, Taveras C, Daud A, Olivero-Rivera L, Restuccia NL & Bessler M 2006 Differential effects of gastric bypass and banding on circulating gut hormone and leptin levels. Obesity 14 1553–1561. (https://doi.org/10.1038/oby.2006.179)
Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Backhed HK, Gonzalez A, Werner JJ, Angenent LT, Knight R, et al. 2012 Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150 470–480. (https://doi.org/10.1016/j.cell.2012.07.008)
Kumar N 2016 Weight loss endoscopy: development, applications, and current status. World Journal of Gastroenterology 22 7069–7079. (https://doi.org/10.3748/wjg.v22.i31.7069)
Latorre R, Sternini C, De Giorgio R & Greenwood-Van Meerveld B 2016 Enteroendocrine cells: a review of their role in brain-gut communication. Neurogastroenterology and Motility 28 620–630. (https://doi.org/10.1111/nmo.12754)
le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos A, Laurenius A, Lonroth H, Fandriks L, Ghatei MA, Bloom SR, et al. 2007 Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Annals of Surgery 246 780–785. (https://doi.org/10.1097/SLA.0b013e3180caa3e3)
Lee J, Cummings BP, Martin E, Sharp JW, Graham JL, Stanhope KL, Havel PJ & Raybould HE 2012 Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 302 R657–R666. (https://doi.org/10.1152/ajpregu.00345.2011)
Lund A, Bagger JI, Christensen M, Knop FK & Vilsboll T 2014 Glucagon and type 2 diabetes: the return of the alpha cell. Current Diabetes Reports 14 555. (https://doi.org/10.1007/s11892-014-0555-4)
Lundasen T, Galman C, Angelin B & Rudling M 2006 Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. Journal of Internal Medicine 260 530–536. (https://doi.org/10.1111/j.1365-2796.2006.01731.x)
Madsbad S, Dirksen C & Holst JJ 2014 Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes and Endocrinology 2 152–164. (https://doi.org/10.1016/S2213-8587(13)70218-3)
Magouliotis DE, Tasiopoulou VS, Sioka E, Chatedaki C & Zacharoulis D 2017 Impact of bariatric surgery on metabolic and gut microbiota profile: a systematic review and meta-analysis. Obesity Surgery 27 1345–1357. (https://doi.org/10.1007/s11695-017-2595-8)
Machytka E, Buzga M, Lautz DB, Ryou M, Simonson DC & Thompson CC 2017a A dual-path enteral bypass procedure created by a novel incisionless anastomosis system (IAS): 6-month clinical results. Gastroenterology 150 S26. (https://doi.org/10.1016/s0016-5085(16)30214-1)
Machytka E, Buzga M, Zonca P, Lautz DB, Ryou M, Simonson DC, Thompson CC2017b Partial jejunal diversion using an incisionless magnetic anastomosis system: 1-year interim results in patients with obesity and diabetes. Gastrointestinal Endoscopy 86 904– 912. (https://doi.org/10.1016/j.gie.2017.07.009)
Maljaars PW, Peters HP, Mela DJ & Masclee AA 2008 Ileal brake: a sensible food target for appetite control. A review. Physiology and Behavior 95 271–281. (https://doi.org/10.1016/j.physbeh.2008.07.018)
Martin JH, Deacon CF, Gorrell MD & Prins JB 2011 Incretin-based therapies – review of the physiology, pharmacology and emerging clinical experience. Internal Medicine Journal 41 299–307. (https://doi.org/10.1111/j.1445-5994.2011.02439.x)
Meek CL, Lewis HB, Reimann F, Gribble FM & Park AJ 2016 The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones. Peptides 77 28–37. (https://doi.org/10.1016/j.peptides.2015.08.013)
Mingrone G, Nolfe G, Gissey GC, Iaconelli A, Leccesi L, Guidone C, Nanni G & Holst JJ 2009 Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion. Diabetologia 52 873–881. (https://doi.org/10.1007/s00125-009-1288-9)
Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Nanni G, Castagneto M, Bornstein S & Rubino F 2015 Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 386 964–973. (https://doi.org/10.1016/S0140-6736(15)00075-6)
Mithieux G 2014 Nutrient control of energy homeostasis via gut-brain neural circuits. Neuroendocrinology 100 89–94. (https://doi.org/10.1159/000369070)
Miyasaka K & Funakoshi A 2003 Cholecystokinin and cholecystokinin receptors. Journal of Gastroenterology 38 1–13. (https://doi.org/10.1007/s005350300000)
Mokadem M, Zechner JF, Margolskee RF, Drucker DJ & Aguirre V 2014 Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency. Molecular Metabolism 3 191–201. (https://doi.org/10.1016/j.molmet.2013.11.010)
Mraz M, Lacinova Z, Kavalkova P, Haluzikova D, Trachta P, Drapalova J, Hanusova V & Haluzik M 2011 Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment. Physiological Research 60 627. (available at: http://www.biomed.cas.cz/physiolres/pdf/60/60_627.pdf)
Nguyen CA, Akiba Y & Kaunitz JD 2012 Recent advances in gut nutrient chemosensing. Current Medicinal Chemistry 19 28–34. (https://doi.org/10.2174/092986712803414033)
Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H & Itoh N 1999 Structure and expression of a novel human FGF, FGF19, expressed in the fetal brain. Biochimica et Biophysica Acta 1444 148–151. (https://doi.org/10.1016/S0167-4781(98)00255-3)
O’Brien PE 2010 Bariatric surgery: mechanisms, indications and outcomes. Journal of Gastroenterology and Hepatology 25 1358–1365. (https://doi.org/10.1111/j.1440-1746.2010.06391.x)
O’Rahilly S 1997 Science, medicine, and the future. Non-insulin dependent diabetes mellitus: the gathering storm. BMJ 314 955–959. (https://doi.org/10.1136/bmj.314.7085.955)
Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE & Makaroff LE 2017 IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Research and Clinical Practice 128 40–50. (https://doi.org/10.1016/j.diabres.2017.03.024)
Patel SR, Mason J & Hakim N 2012 The Duodenal-Jejunal bypass sleeve (EndoBarrier Gastrointestinal Liner) for weight loss and treatment of type II diabetes. Indian Journal of Surgery 74 275–277. (https://doi.org/10.1007/s12262-012-0721-3)
Peterli R, Steinert RE, Woelnerhanssen B, Peters T, Christoffel-Courtin C, Gass M, Kern B, von Fluee M & Beglinger C 2012 Metabolic and hormonal changes after laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy: a randomized, prospective trial. Obesity Surgery 22 740–748. (https://doi.org/10.1007/s11695-012-0622-3)
Pories WJ 2008 Bariatric surgery: risks and rewards. Journal of Clinical Endocrinology and Metabolism 93 S89–S96. (https://doi.org/10.1210/jc.2008-1641)
Pournaras DJ & le Roux CW 2009 After bariatric surgery, what vitamins should be measured and what supplements should be given? Clinical Endocrinology 71 322–325. (https://doi.org/10.1111/j.1365-2265.2009.03564.x)
Pournaras DJ & le Roux CW 2013 Are bile acids the new gut hormones? Lessons from weight loss surgery models. Endocrinology 154 2255–2256. (https://doi.org/10.1210/en.2013-1383)
Pournaras DJ, Jafferbhoy S, Titcomb DR, Humadi S, Edmond JR, Mahon D & Welbourn R 2010 Three hundred laparoscopic Roux-en-Y gastric bypasses: managing the learning curve in higher risk patients. Obesity Surgery 20 290–294. (https://doi.org/10.1007/s11695-009-9914-7)
Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, Bekker JH, Ghatei MA, Bloom SR, Walters JR, et al. 2012 The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 153 3613–3619. (https://doi.org/10.1210/en.2011-2145)
Prawitt J, Caron S & Staels B 2011 Bile acid metabolism and the pathogenesis of type 2 diabetes. Current Diabetes Reports 11 160–166. (https://doi.org/10.1007/s11892-011-0187-x)
Psichas A, Reimann F & Gribble FM 2015 Gut chemosensing mechanisms. Journal of Clinical Investigation 125 908–917. (https://doi.org/10.1172/JCI76309)
Rajagopalan H, Cherrington AD, Thompson CC, Kaplan LM, Rubino F, Mingrone G, Becerra P, Rodriguez P, Vignolo P, Caplan J, et al. 2016 Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes: 6-month interim analysis from the first-in-human proof-of-concept study. Diabetes Care 39 2254–2261. (https://doi.org/10.2337/dc16-0383)
Ramracheya RD, McCulloch LJ, Clark A, Wiggins D, Johannessen H, Olsen MK, Cai X, Zhao CM, Chen D & Rorsman P 2016 PYY-dependent restoration of impaired insulin and glucagon secretion in type 2 diabetes following Roux-En-Y gastric bypass surgery. Cell Reports 15 944–950. (https://doi.org/10.1016/j.celrep.2016.03.091)
Reaven G 2002 Metabolic syndrome: pathophysiology and implications for management of cardiovascular disease. Circulation 106 286–288. (https://doi.org/10.1161/01.CIR.0000019884.36724.D9)
Reimann F, Williams L, da Silva Xavier G, Rutter GA & Gribble FM 2004 Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells. Diabetologia 47 1592–1601. (https://doi.org/10.1007/s00125-004-1498-0)
Rohde U 2016 EndoBarrier gastrointestinal liner. Delineation of underlying mechanisms and clinical effects. Danish Medical Journal 63 B5309.
Rohde U, Hedback N, Gluud LL, Vilsboll T & Knop FK 2016 Effect of the endobarrier gastrointestinal liner on obesity and type 2 diabetes: a systematic review and meta-analysis. Diabetes, Obesity and Metabolism 18 300–305. (https://doi.org/10.1111/dom.12603)
Rohde U, Federspiel CA, Vilmann P, Langholz E, Friis SU, Krakauer M, Rehfeld JF, Holst JJ, Vilsboll T & Knop FK 2017 The impact of EndoBarrier gastrointestinal liner in obese patients with normal glucose tolerance and in patients with type 2 diabetes. Diabetes, Obesity and Metabolism 19 189–199. (https://doi.org/10.1111/dom.12800)
Rubino F & Marescaux J 2004 Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Annals of Surgery 239 1–11. (https://doi.org/10.1097/01.sla.0000102989.54824.fc)
Rubino F & Cummings DE 2012 Surgery: the coming of age of metabolic surgery. Nature Reviews Endocrinology 8 702–704. (https://doi.org/10.1038/nrendo.2012.207)
Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KG, Zimmet PZ, Del Prato S, Ji L, Sadikot SM, Herman WH, et al. 2016 Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care 39 861–877. (https://doi.org/10.2337/dc16-0236)
Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Perez HE, Sandoval DA, Kohli R, Backhed F, et al. 2014 FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509 183–188. (https://doi.org/10.1038/nature13135)
Ryou M, Agoston AT & Thompson CC 2016a Endoscopic intestinal bypass creation by using self-assembling magnets in a porcine model. Gastrointestinal Endoscopy 83 821–825. (https://doi.org/10.1016/j.gie.2015.10.023)
Ryou M, Aihara H & Thompson CC 2016b Minimally invasive entero-enteral dual-path bypass using self-assembling magnets. Surgical Endoscopy 30 4533–4538. (https://doi.org/10.1007/s00464-016-4789-x)
Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M & Mingrone G 2009 First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes Care 32 375–380. (https://doi.org/10.2337/dbib8-1314)
Salinari S, Carr RD, Guidone C, Bertuzzi A, Cercone S, Riccioni ME, Manto A, Ghirlanda G & Mingrone G 2013a Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects. American Journal of Physiology: Endocrinology and Metabolism 305 E59–E66. (https://doi.org/10.1152/ajpendo.00559.2012)
Salinari S, Debard C, Bertuzzi A, Durand C, Zimmet P, Vidal H & Mingrone G 2013b Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance. PLoS ONE 8 e56258. (https://doi.org/10.1371/journal.pone.0056258)
Shi X, Karmali S, Sharma AM & Birch DW 2010 A review of laparoscopic sleeve gastrectomy for morbid obesity. Obesity Surgery 20 1171–1177. (https://doi.org/10.1007/s11695-010-0145-8)
Shin AC, Zheng H, Townsend RL, Sigalet DL & Berthoud HR 2010 Meal-induced hormone responses in a rat model of Roux-en-Y gastric bypass surgery. Endocrinology 151 1588–1597. (https://doi.org/10.1210/en.2009-1332)
Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, Navaneethan SD, Singh RP, Pothier CE, Nissen SE, et al. 2017 Bariatric surgery versus intensive medical therapy for diabetes – 5-year outcomes. New England Journal of Medicine 376 641–651. (https://doi.org/10.1056/NEJMoa1600869)
Sista F, Abruzzese V, Clementi M, Carandina S, Cecilia M & Amicucci G 2017 The effect of sleeve gastrectomy on GLP1 secretion and gastric emptying: a prospective study. Surgery for Obesity and Related Diseases 13 7–14. (https://doi.org/10.1016/j.soard.2016.08.004)
Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, et al. 2007 Effects of bariatric surgery on mortality in Swedish obese subjects. New England Journal of Medicine 357 741–752. (https://doi.org/10.1056/NEJMoa066254)
Song KH, Li T, Owsley E, Strom S & Chiang JY 2009 Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology 49 297–305. (https://doi.org/10.1002/hep.22627)
Steinert RE & Beglinger C 2011 Nutrient sensing in the gut: interactions between chemosensory cells, visceral afferents and the secretion of satiation peptides. Physiology and Behavior 105 62–70. (https://doi.org/10.1016/j.physbeh.2011.02.039)
Strader AD, Vahl TP, Jandacek RJ, Woods SC, D’Alessio DA & Seeley RJ 2005 Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. American Journal of Physiology: Endocrinology and Metabolism 288 E447–E453. (https://doi.org/10.1152/ajpendo.00153.2004)
Sullivan S, Edmundowicz SA & Thompson CC 2017 Endoscopic bariatric and metabolic therapies: new and emerging technologies. Gastroenterology 152 1791–1801. (https://doi.org/10.1053/j.gastro.2017.01.044)
Tan JK, McKenzie C, Marino E, Macia L & Mackay CR 2017 Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation. Annual Review of Immunology 35 371–402. (https://doi.org/10.1146/annurev-immunol-051116-052235)
Theodorakis MJ, Carlson O, Michopoulos S, Doyle ME, Juhaszova M, Petraki K & Egan JM 2006 Human duodenal enteroendocrine cells: source of both incretin peptides, GLP1 and GIP. American Journal of Physiology: Endocrinology and Metabolism 290 E550–E559. (https://doi.org/10.1152/ajpendo.00326.2004)
Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, et al. 2009 TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metabolism 10 167–177. (https://doi.org/10.1016/j.cmet.2009.08.001)
Thoni V, Pfister A, Melmer A, Enrich B, Salzmann K, Kaser S, Lamina C, Ebenbichler CF, Hackl H, Tilg H, et al. 2017 Dynamics of bile acid profiles, GLP1 and FGF19 after laparoscopic gastric banding. Journal of Clinical Endocrinology and Metabolism102 2974–2984. (https://doi.org/10.1210/jc.2017-00235)
Tolhurst G, Reimann F & Gribble FM 2012 Intestinal sensing of nutrients. Handbook of Experimental Pharmacology 207 309–335. (https://doi.org/10.1007/978-3-642-24716-3_14)
Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, et al. 2002 Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143 1741–1747. (https://doi.org/10.1210/endo.143.5.8850)
Troy S, Soty M, Ribeiro L, Laval L, Migrenne S, Fioramonti X, Pillot B, Fauveau V, Aubert R, Viollet B, et al. 2008 Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap-band in mice. Cell Metabolism 8 201–211. (https://doi.org/10.1016/j.cmet.2008.08.008)
Tschop M, Smiley DL & Heiman ML 2000 Ghrelin induces adiposity in rodents. Nature 407 908–913. (https://doi.org/10.1038/35038090)
Tsoli M, Chronaiou A, Kehagias I, Kalfarentzos F & Alexandrides TK 2013 Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study. Surgery for Obesity and Related Diseases 9 667–677. (https://doi.org/10.1016/j.soard.2012.12.006)
Vairavamurthy J, Cheskin LJ, Kraitchman DL, Arepally A & Weiss CR 2017 Current and cutting-edge interventions for the treatment of obese patients. European Journal of Radiology 93 134–142. (https://doi.org/10.1016/j.ejrad.2017.05.019)
van Baak MA 2008 Meal-induced activation of the sympathetic nervous system and its cardiovascular and thermogenic effects in man. Physiology and Behavior 94 178–186. (https://doi.org/10.1016/j.physbeh.2007.12.020)
Vilarrasa N, de Gordejuela AG, Casajoana A, Duran X, Toro S, Espinet E, Galvao M, Vendrell J, Lopez-Urdiales R, Perez M, et al. 2017 Endobarrier(R) in grade I obese patients with long-standing type 2 diabetes: role of gastrointestinal hormones in glucose metabolism. Obesity Surgery 27 569–577. (https://doi.org/10.1007/s11695-016-2311-0)
Vitek L & Haluzik M 2016 The role of bile acids in metabolic regulation. Journal of Endocrinology 228 R85–R96. (https://doi.org/10.1530/JOE-15-0469)
Wahlstrom A, Sayin SI, Marschall HU & Backhed F 2016 Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metabolism 24 41–50. (https://doi.org/10.1016/j.cmet.2016.05.005)
Wang Y & Liu J 2009 Plasma ghrelin modulation in gastric band operation and sleeve gastrectomy. Obesity Surgery 19 357–362. (https://doi.org/10.1007/s11695-008-9688-3)
Whiting DR, Guariguata L, Weil C & Shaw J 2011 IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice 94 311–321. (https://doi.org/10.1016/j.diabres.2011.10.029)
Wistuba W, Gnewuch C, Liebisch G, Schmitz G & Langmann T 2007 Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR. World Journal of Gastroenterology 13 4230–4235. (https://doi.org/10.3748/wjg.v13.i31.4230)
Zhang X, Zheng X & Yuan Y 2016 Treatment of insulin resistance: straight from the gut. Drug Discovery Today 21 1284–1290. (https://doi.org/10.1016/j.drudis.2016.06.016)
