H Ashrafian, The Department of Surgery and Cancer, Imperial College London, 10th Floor, Queen Elizabeth the Queen Mother (QEQM) Building, Imperial College Healthcare NHS Trust at St Mary's Hospital, Praed Street, London W2 1NY, UK. E-mail: email@example.com
The global prevalence of type 2 diabetes mellitus and impaired glucose metabolism continues to rise in conjunction with the pandemic of obesity. The metabolic Roux-en-Y gastric bypass operation offers the successful resolution of diabetes in addition to sustained weight loss and excellent long-term outcomes in morbidly obese individuals. The procedure consists of the physiological BRAVE effects: (i) Bile flow alteration; (ii) Reduction of gastric size; (iii) Anatomical gut rearrangement and altered flow of nutrients; (iv) Vagal manipulation and (v) Enteric gut hormone modulation. This operation provides anti-diabetic effects through decreasing insulin resistance and increasing the efficiency of insulin secretion. These metabolic outcomes are achieved through weight-independent and weight-dependent mechanisms. These include the foregut, midgut and hindgut mechanisms, decreased inflammation, fat, adipokine and bile metabolism, metabolic modulation, shifts in gut microbial composition and intestinal gluconeogenesis. In a small minority of patients, gastric bypass results in hyperinsulinaemic hypoglycaemia that may lead to nesidioblastosis (pancreatic beta-cell hypertrophy with islet hyperplasia). Elucidating the precise metabolic mechanisms of diabetes resolution and hyperinsulinaemia after surgery can lead to improved operations and disease-specific procedures including ‘diabetes surgery’. It can also improve our understanding of diabetes pathogenesis that may provide novel strategies for the management of metabolic syndrome and impaired glucose metabolism.
The escalating epidemic of obesity has resulted in a concomitant rise in worldwide type 2 diabetes mellitus. The World Health Organization and the International Diabetes Federation each project a rising prevalence of both obesity (1) and diabetes (2) by approximately 7 million per year. This problem will be confounded by the worldwide increase in pre-diabetes which will reflect the dramatic rise of overweight individuals by 70 million adult cases every year. Obesity and diabetic insulin resistance together form the foundation elements of metabolic syndrome resulting from impaired glucose metabolism. The patients who suffer from both conditions are therefore considered to suffer from ‘obesity associated diabetes mellitus’, more recently termed ‘diabesity’(3). This condition leads to considerable mortality, multisystem comorbidity and mounting healthcare costs. Diabesity and other obesity-related disorders are now considered as a critical concern for global health care and have been the subject of a worldwide call to action (4,5).
A number of treatment strategies have been introduced to decrease obesity including prevention, lifestyle, behavioural therapy and pharmacotherapy. The results of these strategies have only been marginally beneficial (6), which led to the development of a surgical approach to achieve sustained weight loss (7,8). These operations which were traditionally known as bariatric procedures are successful in achieving and maintaining long-term (more than 15 years) weight loss (9,10). However, in addition to their weight-loss effects, these procedures also achieve diabetes resolution in many of the patients with diabesity. As a result, these procedures are now considered as metabolic operations (7,8,11) which can sometimes provide such significant physiological augmentation that they can be considered as ‘bionic’ procedures (12).
The Roux-en-Y gastric bypass is the most commonly performed metabolic bypass operation (Fig. 1) accounting for 40% of over 344 000 metabolic operations worldwide in 2008 (13). This procedure offers successful diabetes resolution independent to its weight-loss effects and in a small subgroup of patients, it ‘overshoots’ to result in hyperinsulinaemic hypoglycaemia (14). In this review, we describe the effects and potential mechanisms of both diabetes resolution and hyperinsulinaemia after the Roux-en-Y gastric bypass procedure.
Roux-en-Y gastric bypass
The Roux-en-Y gastric bypass was first developed in the late 1960s (7,15) by combining the lessons learned from jejuno-ileal bypass, Billroth II operations and Y anastomoses from ulcer surgery. This procedure rearranges the gastrointestinal tract so that ingested nutrients directly enter the small bowel after passing through a small stomach pouch. By doing so, the nutrients bypass a large part of the stomach and duodenum (thus the procedure is termed ‘bypass’). Anatomically, this is achieved by rearranging the small bowel and stomach by initially dividing the stomach to form a small stomach pouch and larger stomach remnant. The jejunum that follows the stomach and duodenum is incised and the distal ‘cut’ segment of jejunum is then anastomosed to the small stomach pouch (the alimentary limb). The remaining stomach remnant and duodenum are then anastomosed at the distal end to an area lower down the jejunum (biliopancreatic limb) (Fig. 1).
This operation improves quality of life in the majority of patients (16) and carries a 30-d mortality of 0.3% (17,18). It is recognized as a leading metabolic procedure in view of its low morbidity compared with other bypass procedures such as biliopancreatic diversion (19,20) and its metabolic superiority compared with non-bypass procedures such as gastric banding (21).
Roux-en-Y gastric bypass achieves a number of physiological effects which include (7,11): (i) Bile flow alteration; (ii) Reduction of gastric size; (iii) Anatomical gut rearrangement and altered flow of nutrients; (iv) Vagal manipulation and (v) Enteric gut hormone modulation. The so-called ‘BRAVE’ effects (7) (Fig. 2).
The decrease in obesity results from decreasing energy intake (from decreased food intake) but also through increased energy expenditure (22). The operation also demonstrates a number of dramatic effects on systemic metabolism working through the established entero-insular axis (23) and the proposed entero-cardiac (8) and entero-renal axes (24).
Resolution of diabetes
In the early 1980s, gastric bypass programmes revealed that successful surgical weight loss was also associated with diabetes resolution (25–27). Units that subsequently followed up large cohorts of patients with type 2 diabetes (>100 cases) demonstrated successful diabetes resolution in 74–83% of patients at up to 14 years post-operatively (Table 1).
Table 1. The resolution of type 2 diabetes mellitus after Roux-en-Y gastric bypass
In these studies, diabetes resolution was measured using the oral glucose tolerance test, intravenous glucose tolerance tests (IVGTT), homeostasis model assessment of insulin resistance (HOMA-IR) and glycosylated haemoglobin (HbA1c) (33,34).
In comparison to surgery, only half of diabetic patients achieve a satisfactory HbA1c level on medical treatment (35). The prospective case-matched Swedish Obese Subjects (SOS) study revealed that the 2-year incidence of diabetes was 16% in medically treated individuals compared to 0% in those undergoing metabolic surgery (10,36).
A recent systematic review and meta-analysis assessed the effects of metabolic surgery on diabetes incorporating 221 studies of gastric bypass (34). In 553 patients from 22 treatment groups, diabetes was resolved in 80.3% of patients. The mean weight loss for diabetic patients was 42.65 kg with a decrease in body mass index (BMI) of 16 kg m−2 and a reduction of excess body weight by 66.7%. This is associated with significant decreases in HbA1c (2.18%), fasting insulin levels as a measure of insulin resistance (40.2 units) and fasting glucose levels (3.91 mmol L−1). Although the resolution or improvement of diabetes was greater for patients undergoing biliopancreatic diversion with or without duodenal switch (95.1%), this procedure has not been performed as widely as gastric bypass in view of its increased mortality and morbidity (33).
It was initially considered that much of the diabetes-reversing effects of gastric bypass were purely as a result of weight loss; however, it is now established that the beneficial effects of diabetes occurred within days after surgery, well before any weight loss (28). This therefore led to research studying the weight-loss dependent and independent effects of diabetes resolution of this procedure.
Timing of diabetic resolution
The resolution of diabetes after gastric bypass typically occurs within days to weeks after surgery. This takes place before any evidence of noticeable weight loss which can take between 3 months and 1 year to develop (28). Both IVGTT and HOMA-IR are markedly improved within 6 d of surgery (37). This results in 30% of diabetic patients being discharged from hospital on average 2.8 d after surgery with no anti-diabetic medication and normal plasma glucose levels (30). Although the percentage of diabetic patients being discharged without anti-diabetic medication depends heavily on the initial diabetic characteristics of the patients undergoing surgery (including disease duration and pancreatic reserve), such a rapid resolution of diabetes is not observed in gastric band patients (21,38) but is also seen in the similar bypass procedure of biliopancreatic diversion. The incretin (insulin releasing) effects of gastric bypass and biliopancreatic diversion have been proposed to contribute to their anti-diabetic effects. Such an incretin release is not noted in gastric band patients and therefore may reveal a differential effect of these operations on diabetes, which can occur by decreasing insulin resistance mainly through increased hepatic and muscle insulin sensitivity. Although a role for the resolution of diabetes through increased insulin release is recognized in some studies, it requires further validation (37,39,40). It is however clear in a small subgroup of patients that gastric bypass results in a hyperinsulinaemia which presents as symptomatic hypoglycaemia (41). Such an augmented release of insulin can result from the surgically induced condition of ‘nesidioblastosis’ and is discussed later in this text.
Weight-loss independent effects
Although weight loss through lifestyle, diet and pharmacotherapy can all achieve improvements in glucose homeostasis and diabetes (42–45), the intentional weight-loss effects are difficult to maintain in the long term (44). Furthermore, the anti-diabetic effects of gastric bypass are much more pronounced than weight-loss effects, even when factoring for equivalent weight loss to non-surgical cases (8,33,34). In a rodent model of gastric bypass in fat diabetic Zucker rats, both glucose tolerance and insulin sensitivity are superior to the diabetic effects observed in sham operated rats with equivalent dietary weight loss (46). In order to compare whether the extent of diabetes resolution and incretin levels are greater after gastric bypass compared with a low caloric diet, Laferrere et al. studied morbidly obese patients with diabetes (matched for severity) in surgical and diet patients after equivalent weight loss. Both groups had approximately 10 kg of weight loss, although the diet group had no post-operative incretin (insulin releasing) effect whereas the surgery group had a significant decrease of their post-prandial glucose coupled with a fivefold increase in their incretin release (47).
The anti-diabetic effects of gastric bypass are also greater than the effects of other metabolic operations. The results of glucose tolerance and post-meal glucose excursion in weight-matched individuals undergoing gastric bypass are superior to patients undergoing other metabolic procedures such as adjustable gastric banding or vertical banded gastroplasty (48–50). In randomized patients matched for the severity of diabetes and weight loss, gastric bypass offers superior diabetes control to individuals undergoing sleeve gastrectomy (51).
These weight-loss independent effects have promoted a number of animal models of gastric bypass in non-obese diabetic rats to reveal improvements in both glucose homeostasis and diabetes resolution. As a result, trials of gastric bypass have been performed in non-morbidly obese human patients with lower BMIs (<35 kg m−2). Here the rate of diabetes resolution at up to 48 months varies between 76.5% and 97% (52,53). Some units have successfully performed Roux-en-Y gastric bypass in patients with BMI's as low as 22 and 25 kg/m2 (metabolic gastric bypass) in order to specifically treat diabetes and not obesity (in the absence of excessive weight loss in some series) (54,173). The long-term benefits of surgery at these lower weight categories require further investigation. A worldwide ‘Diabetes Surgery’ Summit was held in 2007 which provided a consensus position statement specifying that ‘gastric bypass was deemed a reasonable treatment option for patients with poorly controlled diabetes and a body mass index ≥30 kg m−1’(55).
Preventive effects on diabetes, morbidity and mortality
The beneficial effects of surgery are not only limited to patients with established type 2 diabetes mellitus, but also have a clear role in preventing the development of diabetes in morbidly obese patients with normoglycaemia. A multi-centre study in Sweden known as the SOS study was developed with a prospective case-matched intention-to-treat protocol to compare metabolic procedures (2037 subjects) with medical therapy for morbidly obese individuals (4047 subjects) (10,56). Four treatment arms were included (i) medical controls and three surgical strategies: (ii) Roux-en-Y gastric bypass, (iii) vertical banded gastroplasty and (iv) gastric banding. Within the three surgical arms, gastric bypass consisted of approximately 5% of all surgical patients compared to a majority undergoing vertical banded gastroplasty (≈70%) and gastric banding (≈25%) at both 2- and 10-year follow-up periods (9,10). In this study, at 2-year follow-up, 5% of control patients had developed diabetes compared to 0% in the surgical arm. In the surgical group, the overall incidence of diabetes had increased from 1% at 2-year follow-up to 7% at 10-year follow-up whereas in the control group the incidence increased from 8% at 2-year follow-up to 24% at 10-year follow-up.
These effects coupled to the other systemic effects of metabolic surgery result in a significant decrease in both overall morbidity and mortality in metabolic surgical patients. Although non-surgical intentional weight loss can reduce diabetes-related mortality in overweight patients by one-third (57) and overall mortality in diabetic patients also by one-third (58), one observational study of gastric bypass patients revealed a relative risk reduction of overall mortality by 89% in surgical patients compared to non-surgical controls (59). Both the SOS study (9) and a large retrospective follow-up study of approximately 20 000 patients from Utah (60) (divided equally into gastric bypass patients and controls) compared the effects of surgery with obese-matched controls. In the SOS cohort with an average follow-up of 10.9 years, there were 101 deaths in surgery group compared with 129 deaths in a medically treated obese control group (9). In the Utah study with an average follow-up of 7.1 years, the adjusted long-term mortality from the surgery group decreased by 40% when compared with a general population of matched obese patients. The surgical reduction of mortality after gastric bypass was in part because of a decreased mortality of cancer by 60% (primarily in women) and a decreased mortality from coronary artery disease by 56% which was driven by a profound decrease in diabetes, which also resulted in the decrease of deaths attributed to diabetes by 92% (60).
Mechanisms of resolution
The dramatic effects of Roux-en-Y gastric bypass on diabetes resolution has led to the study of the mechanisms through which these effects take place. Over the past decade, there has been an exponential increase in the analysis of the metabolic effects of surgery primarily for two reasons: (i) understanding the surgical modulation of glucose homeostasis may offer novel treatments for diabetes and (ii) it may allow current surgical practice to be optimized for improved diabetes resolution in a broader cohort of patients. Our current understanding of mechanisms of diabetes resolution through Roux-en-Y gastric bypass include (Fig. 3).
According to this hypothesis (61,62), bypassing segments of the foregut (duodenum and proximal jejunum) and altering the ‘flow’ of ingested food after gastric bypass results in the release of a signal or signals that have anti-diabetic properties. Evidence for this hypothesis was demonstrated in a non-obese diabetic rodent model (Goto-Kakizaki) where rats underwent duodenal-jejunal bypass. This operation is similar to gastric bypass except here only the duodenum is bypassed. Compared to sham controls, there was no weight reduction or altered food intake, although diabetes resolution was fast and effective which was demonstrated through glucose tolerance blood glucose concentration (63). This is likely to occur through nutrient exclusion in the upper gut and has been hypothesised to decrease the release of so-called ‘anti-incretins’ which may be constitutionally expressed by the native foregut (64). Possible examples could include undiscovered foregut hormones that inhibit the activity of incretins in a similar manner to somatostatin inhibiting insulin (65); once the foregut is bypassed through surgery, the anti-incretin activity would be diminished as the subsequent increase of incretin release may result in the resolution of diabetes. As yet, no anti-incretins have been discovered; however, human studies have been performed where duodenal-jejunal bypass achieves improved glucose homeostasis in the absence of weight loss (66,67).
It has been suggested that gastric bypass can prevent the increase in blood glucose levels by decreasing the circulating level of glucagon post-operatively (68). Conversely, it has been proposed that glucagon administration could maintain normal postprandial plasma glucose concentrations by stimulating hepatic glucose output (69). Blood hormone assays reveal an early increase in glucagon levels after a test meal (50) despite the finding that the level of incretins such as Glucagon-like peptide-1 (GLP-1) are also elevated after surgery and can inhibit glucagon secretion (70). As a result, the contribution of glucagon in decreasing glucose levels after surgery has been questioned and may reflect the experimental variance in glucagon assays used.
These foregut effects are unlikely to occur through ‘increased food transit’ after surgery, as although there is no pylorus in the gastric pouch after gastric bypass, the pylorus is left intact for the duodenal-jejunal bypass. This work has led to the development of ‘endoluminal duodenal sleeves’, where the placement of an endoscopically positioned, artificial duodenal barrier can offer weight loss and improved glucose homeostasis in experimental models and early studies (71–74).
Glucose is an important signalling molecule when present in the portal vein (hepato-portal sensing), where portal afferents communicate with the vagus nerve to decrease hunger through hypothalamic centres. This results in improved glycaemic control through the suppression of hepatic glucose production by insulin and improved insulin sensitivity. The ingestion of proteins results in the increased expression of enzymes to result in increased intestinal (midgut) gluconeogenesis (75).
In a rodent of gastric bypass, intestinal gluconeogenesis was enhanced as a likely result of altered nutrient presentation to the small bowel. This physiological effect located in the midgut resulted in improved glucose homeostasis and insulin resistance compared to gastric band/sham subjects. These effects are dependent on intact portal glucose signalling and are not necessarily mediated by gut hormones, as their effect was not significantly diminished by the GLP-1 antagonist exendin-9 (76,77).
Hindgut mechanism and gut hormones
An alternative premise to the foregut and midgut mechanisms is the hindgut mechanism, where the transport of ingested nutrients that have not been exposed to the bypassed foregut induce a signal in the hindgut that leads to improved glucose homeostasis. Gastric bypass operations provide long-term plasma increases of gut hormones secreted from the hindgut (terminal ileum, colon and rectum) within hours after surgery. These hormones include GLP-1 and peptide YY that are released from gastrointestinal L-cells (11). The role for these gut hormones in contributing to diabetes resolution has been increasingly recognized. In other metabolic procedures such as gastric banding where diabetes resolution is not as pronounced, there is less modulation of hindgut hormones. These gut hormones contribute to inducing decreased appetite through both ‘ileal-brake’ and anorectic mechanisms (11) and are activated by both direct nutrient and indirect neural pathways (such as those from the duodenum) (78). GLP-1 has receptors in the central nervous system such as the hypothalamus and the nucleus tractus solitarius where it mediates calorific intake, anorectic activity and satiety. It can even induce malaise through the amygdala which may provide for food aversion effects (11). Further evidence for the hindgut hypothesis has been derived from studies where the placement of segments of hindgut higher up in the gastrointestinal tract through the procedure of ileal interposition can enhance the release of gut hormones and achieve improved glycaemic control in humans (79–83) and animal models (84).
Of the hindgut hormones discovered to date, GLP-1 seems to be a contributor to diabetes resolution. This peptide may augment insulin secretion and enhances pancreatic beta-cell proliferation while also decreasing beta-cell apoptosis. A synthetic analogue of GLP-1 (exendin-4) sharing 52% homology to natural GLP-1 has been derived from the Gila lizard (Heloderma suspectum), and has been successfully introduced to treat type 2 diabetic patients (85,86).
When comparing foregut and hindgut mechanisms of diabetes resolution, a recent study revealed that bypassing the hindgut results in better glucose tolerance than foregut bypass when both procedures have been performed sequentially in an experimental model (87).
Ghrelin and other gut hormones
Ghrelin is a 28-amino acid gut hormone predominantly secreted from the stomach. It is known as an orexigen as it increases hunger. Its circulating levels are decreased in correlation with weight gain, and its levels rise following dietary weight-loss. Ghrelin's effects take place both peripherally and directly within the central nervous system. Plasma levels of Ghrelin have been demonstrated to decrease in 42% of studies after gastric bypass, increased in 23% of cases and had no significant changes in 35%. Such a variation of effects may be because of changes in surgical technique on the vagus nerve. The fact that Ghrelin levels remain unchanged or even decrease in the majority of cases after surgically induced weight loss is paradoxical, and contributes to the decreased appetite seen after these procedures (11).
In addition to its effects on food intake, Ghrelin can also play a role in glucose homeostasis as it has a reciprocal relationship to insulin. It is expressed in pancreatic beta-cells, and pharmacological and genetic blockade of islet-derived Ghrelin in mice leads to increases glucose-induced insulin secretion and improved peripheral insulin sensitivity (88,89). Ghrelin also decreases levels of the anti-diabetic fat hormone adiponectin. A reduction of Ghrelin after gastric bypass may therefore contribute to the positive effects seen on glucose homeostasis.
Gastric bypass can also modulate a number of other glucose regulating gut hormones. These include glucose-dependent insulinotropic peptide or gastric inhibitory peptide and pancreatic polypeptide. Although increased release of these gut hormones can improve glucose homeostasis and contribute to diabetes resolution, the majority of gastric bypass studies reveal non-significant modulation or even a decrease in their levels (11).
Starvation, caloric restriction and weight loss
Gastric bypass offers successful weight loss in the long term that can be associated with an improvement in glucose homeostasis (49); however, this does not account for the rapid improvements in glucose homeostasis. Patients undergoing metabolic surgery undergo a required decrease in food-intake preoperatively (which can contribute to decreased liver dimensions) to optimise visceral anatomy for laparoscopic surgery. Furthermore, these patients have a modified post-operative diet of liquids that only later progresses to solids. As a result, some hypotheses ascribe the improved glucose homeostasis from surgery to be associated with the effects of dieting followed by that of full weight loss.
Although standard dieting and caloric restriction have been demonstrated to improve diabetes for over 90 years (90,91), the beneficial effects of dieting on glucose homeostasis do not occur to the extent seen after gastric bypass, even in the early period (10,26,28,33,36). Extreme caloric restriction can achieve significant improvements in glucose homeostasis, where one study demonstrated that a 330 cal d−1 diet achieved a drop of fasting plasma glucose from 297 mg dL−1 (16.5 mmol L−1) to 138 mg dL−1 (7.66 mmol L−1) over 40 d (92). Here 87% of this effect occurred in the first 10 d (92). However, such diets are impractical and difficult to sustain long-term as their caloric provision is comparable to starvation (93,94). Furthermore, all patients undergoing metabolic surgery are exposed to the same pre- and post-operative diets. However, the effects on diabetes resolution are significantly higher for bypass procedures as opposed to other restrictive procedures such as gastric banding, which resolves diabetes in 28–36% of cases (21,33,34). This adds to the evidence for a weight-independent anti-diabetic effect provided by bypass procedures.
Nerve mediated effects
Vagal dissection during gastric bypass can contribute to some of the early weight-loss effects after surgery (95). The vagus nerve has been classically recognized as an important mediator of pancreatic exocrine function (96). Although vagal manipulation may result in poor glucose homeostasis (97) and impair the cephalic phase insulin release (98), it may paradoxically also improve glucose tolerance. This may occur through the suppression of Ghrelin release (99). Furthermore, there are unstudied effects of how gastric bypass may modulate vagal afferents and efferents in the increasingly recognized gut-brain-liver axis (100) which may contribute to augmented hepatic insulin sensitivity.
It has been increasingly recognized that gastric bypass can alter food intake through the modulation of taste (101–103) in addition to its effects on appetite (so-called ‘I don't like burgers anymore syndrome’) (11,104). The effects on taste are likely to include both vagal and gut hormonal mechanisms. A relationship between changes in taste, the gustatory nervous system (chorda tympani) and insulin release has recently been identified (105). Gastric bypass may therefore potentially alter insulin release although some of the operative effects on taste. Although diet-induced obesity can compromise gut submucosal nerve function (106) and diabetes can result in the loss of enteric neurons (107), rodents models of gastric bypass reveal compensatory sympathetic nervous system activation driven by increased peptide YY and orexin signalling (108). Recent evidence also supports the potential role of increased post-operative GLP-1 in offering neuroprotection against peripeheral neuropathy (109,110) and providing anti-diabetic effects through increased skeletal muscle sympathetic nerve activity (111).
Roux-en-Y gastric bypass modulates a number of adipose derived hormones (adipokines) including leptin, adiponectin and resistin (112,113) which are likely mediated through weight-loss effects. Increasing leptin and decreasing adiponectin levels are associated with poor insulin resistance in obese individuals. Although the post-surgical modulation of leptin has conflicting results and only a few studies address the role of resistin after surgery, it is clearly demonstrated that the plasma levels of adiponectin rise post-operatively (114–116). An increase in adiponectin is associated with a lower risk of type 2 diabetes across diverse populations, consistent with a dose-response relationship (117). Circulating levels of adiponectin are inversely related to visceral body fat, and it acts on the liver, muscles and vasculature. The high molecular weight form predominantly acts on the liver, typically through the AdipoR2 receptor to increase insulin sensitivity and decrease steatosis via activation of AMP-activated protein kinase and increased peroxisome-proliferator-activated receptor alpha ligand activity (118).
Inappropriate lipid load (or lipotoxicity) contributes to insulin resistance (119,120). The biliopancreatic diversion which is a related bypass procedure induces malabsorption of fats, so that there is glucose normalization via decreased intramyocellular fat content, improved muscular glucose transporter gene expression and enhanced insulin signalling that may work through malonyl-CoA pathway (39). Roux-en-Y gastric bypass, however, does not result in significant nutrient malabsorption (48), and there is currently little data to reveal that its effect on diabetes works through alterations in intramyocellular fat. The effects on fat metabolism are likely to be strongly mediated through weight-loss dependent mechanisms (49).
Altering bile flow and release can be beneficial in the treatment of diabetes as bile sequestrants (cholestyramine, colestipol, colestimide and colesevelam) can reduce fasting glucose levels in patients with type 2 diabetes mellitus (121). Bile acids are derived from cholesterol or oxysterols in the liver and mediate fat absorption in the enterohepatic cycle. They can act on bile acid receptors in the liver and intestine (including Farnesoid X receptor, Fibroblast growth factor receptor and TGR5) to modulate glucose homeostatic genes and homeostasis (122,123). Bile sequestrants promote the excretion of bile acids from the gastrointestinal tract, which subsequently leads to an increased synthesis of bile acids from cholesterol thereby reducing hepatic cholesterol levels. The mechanisms of glucose control provided by these pharmacological agents are not yet fully understood, but include the modulation of farnesoid X receptor (FXR)-dependent signalling pathways regulating hepatic gluconeogenesis enzymes such as Phosphoenolpyruvate Carboxykinase (PEPCK) (124) and the TGR-5-dependent secretion of incretin gut hormones such as GLP-1 (125). Few studies have considered the role of bile metabolism after gastric bypass, although initial data reveals that serum bile acids are elevated after surgery to mimic the effects of bile sequestrants, and this is correlated with both anti-diabetic GLP-1 and adiponectin levels (126).
There is increasing evidence that systemic inflammation is associated with insulin resistance (120,127–129). Metabolic surgery results in a decrease of oxidative stress and attenuated levels of systemic inflammatory markers such as Interleukin-6, C-reactive protein, sialic acid, plasminogen activator inhibitor-1, malondialdehyde and von Willebrand factor (115,116,130–132). The reduction in inflammatory markers is more pronounced in patients with normal glucose tolerance when compared to insulin resistant patients (115,131). Multiple regression analysis has revealed that the decrease in insulin resistance after surgery is independently associated with a decrease in Interleukin-6 concentrations (132).
Metabolic and metagenomic effects
The techniques of studying patients and their diseases at a systems biology level has recently been enhanced through metabonomics, which provides information via the generation of metabolic profiles based on nuclear magnetic resonance spectroscopy, mass spectrometry and multivariate chemometrics. This ‘top-down’ systems biology approach (as opposed to the bottom-up approach of studying single-gene effects, proteins and metabolites in individual cell types) can offer a broader overview of each individuals disease state (133,134), and can also identify new disease mechanisms, novel therapeutic targets and personalized health care through characterizing the metabolic status of an individual at a metabolically detailed level. Roux-en-Y gastric bypass surgery can alter the metabolic profile of subjects by modulating metabolites such as asparagine, lysophosphatidylcholine (C18:2), nervonic (C24:1) acid, p-Cresol sulfate, lactate, lycopene, glucose and mannose. The changes in nervonic acid have been signifcantly and negatively correlated with the HOMA-IR estimation of insulin resistance (135).
Furthermore, obese subjects demonstrate a distinctive metagenomic profile associated with gut flora (136,137). It has been demonstrated that there is a clear differentiation between lean and obese individuals in terms of their microbiota with a shift towards a higher firmicute to bacteroidetes ratio that can be modulated by dietary intervention (138). By examining sequences of microbial 16S rRNA genes, it was demonstrated that gastric bypass surgery can modify the relative magnitude of bacterial colonies in the intestinal community to increase Gammaproteobacteria proportions (139). These bacterial shifts have been hypothesized to contribute to changes in food ingestion and digestion (139) and we propose further that it may also play a role in diabetes resolution. Our own experiments on metabonomic and microbiotic profiles after gastric bypass have confirmed these findings and further reveal an association between the shifts in the gut microbiome and systems metabolites after surgery (unpublished data).
Other unknown effects
Gastric bypass may mediate its anti-diabetic effects through a number of other mechanisms. These may include the modulation of currently undiscovered gut hormones (140), novel lipid metabolic pathways including ghrelin O-acyl transferase (141), cell death-inducing DFF45-like effector (142), angiopoietin-like protein 2 (143) and other as yet undiscovered mechanisms. Further research is required to clarify further mechanisms through which these operations can achieve diabetes resolution, and how much each mechanism contributes to the effects demonstrated.
Incidence after gastric bypass
In a minority of patients who have undergone gastric bypass, the raised blood glucose associated with diabetes is not only resolved, but is actually significantly decreased to result in hyperinsulinaemic hypoglycaemia. This condition is not associated with lifestyle or pharmacotherapeutic weight loss. The phenomenon of post-gastric bypass hypoglycaemia has been increasingly recognized by some units quoting a post-operative prevalence of at least 0.36% (144). This typically presents with symptoms of light headedness, confusion, dizziness and sweating.
Assessing the cause of hyperinsulinaemic hypoglycaemia can be complex (145), and includes inherited, sporadic, transient and surgical causes. Differentiating the surgical causes of hypoglycaemia seen in dumping syndrome from a variety of gastrointestinal operations from those specific to gastric bypass can be challenging.
The diagnosis of unregulated insulin release is achieved through measuring inappropriate insulin and C-peptide levels. Recently, selective arterial calcium-stimulation tests have been used to identify the anatomical areas of pancreas responsible for hyperinsulinism. Here calcium is injected sequentially into the splenic, superior mesenteric and gastroduodenal arteries. The changes of insulin levels in the right hepatic vein after each injection are used to identify areas of hyperinsulinism by matching the specific arterial blood supply to corresponding areas of the pancreas (41,145–147).
An increased number of studies have reported specific hyperinsulinaemic changes because of gastric bypass resulting from the condition of nesidioblastosis (Table 2). This condition is characterized by pancreatic beta-cell hypertrophy, islet hyperplasia and increased beta-cell mass. Nesidioblastosis was traditionally considered to be a condition largely limited to newborn infants and extremely rarely in adults presenting with significant hypoglycaemia that could only be managed by pancreatectomy (147,148). The finding that nesidioblastosis also occurs in adults after gastric bypass has added to the evidence for the weight-loss independent effects of diabetes resolution as a result of increased insulin release. Some authors controversially propose that nesidioblastosis does not exist after gastric bypass, and that the hyperinsulinism observed is resultant purely form the persistence of hyperfunctioning beta-cells persisting from the time of the patients obesity (149,150).
Table 2. Cases of nesidioblastosis after Roux-en-Y gastric bypass
Number of patients with nesidioblastosis
Presentation time after Roux-en-Y gastric bypass (months)
Mean age (years)
Excluding one patient whose symptoms were present 36 months preoperatively.
To date, 40 cases of nesidioblastosis have been reported after gastric bypass in the literature (Table 2) although 135 cases have been discussed at a recent conference (151). The nesidioblastosis in these patients after gastric bypass is considered as part of the non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS). Some authors have even regarded surgery controversially in these patients as possibly ‘too much of a good thing’(14), although these findings are likely to represent the extreme end of the metabolic spectrum seen in a small subgroup of patients after these operations.
Possible mechanisms of nesidioblastosis
The mechanisms that lead to acquired nesidioblastosis after gastric bypass are likely to include some of those that are also responsible for the resolution of diabetes mellitus (Fig. 3). Specific hypotheses regarding nesidioblastosis consider it: (i) as an extreme case of dumping syndrome; (ii) to result from a condition of obesity-induced adaptive beta-cell hypertrophy that does not revert after weight loss; (iii) to result from a inappropriate growth factor release that is exposed by surgery and (iv) develops from altered gut hormonal signalling by surgery which persists after surgically induced weight loss (41,146,152–156).
The fact that gastric bypass increases plasma levels of gut hormonal incretins may be an important contributory factor (157), and GLP-1 has been implicated in increasing pancreatic beta-cell mass in rodent models (158–160). Conversely however, GLP-1 is considered to increase insulin output and decreases glucagon secretion in a glucose-dependent manner thus minimising the risk of hypoglycaemia (85). Furthermore, the GLP-1 mimetic exenatide (86,159) (approved April 2005) has not to date been reported to result in nesidioblastosis in humans.
The modulation of the gut hormone Ghrelin is another possible mechanism through which gastric bypass patients develop nesidioblastosis. Ghrelin has been implicated in a number of pancreatic hyperplastic and neoplastic states (161–163). It's release can also be affected by other upper gastrointestinal operations such as gastric banding (164) and oesophagectomy (165) where cases of nesidioblastosis and hyperinsulinaemic hyperglycaemia have been reported.
One study reported on growth factor expression in explanted pancreatic tissue from cases of nesidioblastosis (75% from gastric bypass and 25% idiopathic.) They identified an overexpression of Insulin-like growth factor 2, Insulin-like growth factor-1 receptor alpha and Transforming growth factor-beta receptor-3 (156). Various other pathways to hyperinsulinaemia pathways have yet to be determined including the precipitation of hypoglycaemia during pregnancy (166), and the associations of nesidioblastosis with other gut tumours (41,154). E.g. there are a number of cases of gastric bypass that have subsequently revealed the presence of an underlying insulinoma, which can be concurrent with the nesidioblastosis (41,154,167). There is also one report of a pancreatic side branch intraductal papillary mucinous tumour presenting with severe postprandial hypoglycaemia 26 years after gastric bypass (168). Some authors have reported on post-gastric bypass islet cell hyperplasia both with and without nesidioblastosis, which may allude to a spectrum of changes from initial hyperplasia to subsequent nesidioblastosis (152).
Treatment of hyperinsulinaemic hypoglycaemia
Treatment options for post-gastric bypass hyperinsulinaemic hypoglycaemia include distal, subtotal and near-total pancreatectomy in severe cases of nesidioblastosis and islet hyperplasia (Table 2) (41,146,152–155). The severity of NIPHS after gastric bypass has resulted in some units quoting a gradient-guided pancreatic resection in 62% of patients, where approximately 60% of the pancreas was removed (169). Other units, however, propose a treatment with a modified low-carbohydrate diet (144,170), octreotide, alpha-glucosidase inhibitors (such as Acarbose) (144,171), calcium-channel blockers (such as Verapamil and Nifedipine) (168,171), or post-operative feeding to the non-bypassed gut by gastrostomy tube (172).
Roux-en-Y gastric bypass offers superior diabetes resolution in morbidly obese individuals when compared with current medical strategies. It is a leading metabolic procedure that in some cases can offer ‘bionic’ physiological effects (12). This operation achieves improved glucose homeostasis through a variety of weight-independent and weight-dependent mechanisms. These include the foregut, midgut and hindgut mechanisms, decreased inflammation, fat, adipokine and bile metabolism, altered gut hormone release, metabolic modulation, shifts in gut microbial composition and intestinal gluconeogenesis. Further to diabetes resolution, a small minority of patients suffer from severe non-insulinoma hyperinsulinaemic hypoglycaemia. This may result in pathological pancreatic changes leading to nesidioblastosis. The future of this field relies on carrying out clinical trials and increased research into further clarifying the mechanisms of diabetes resolution and hyperinsulinaemic hypoglycaemia after these operations. Scientific methods to elucidate these mechanisms include further scrutinizing of genomic, transcriptomic and metabonomic profiles using systems biology approaches in addition to novel technologies that assess microbiomics and cellular energetics. Studying the mechanisms of diabetes resolution and hyperinsulinaemia after surgery can ultimately lead to improved operations and disease-specific procedures such as ‘diabetes surgery’. It can also improve our understanding of diabetes pathogenesis that may provide novel strategies for the management of metabolic syndrome and impaired glucose metabolism.
Conflict of Interest Statement
No conflict of interest was declared.
We are grateful for support from the Wellcome Trust and the NIHR Biomedical Research Centre Funding Scheme. We would like to thank Catherine Sulzmann for her artwork.