4. Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/ Metabolic Surgery

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1 4. Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/ Metabolic Surgery David E. Cummings, MD Francesco Rubino, MD Rationale for Understanding the Mechanisms of Bariatric Surgery Obesity, impaired glucose homeostasis, hypertension, and dyslipidemia are all tightly related with one another and strongly predict the development of type 2 diabetes mellitus (T2DM), cardiovascular disease, and death. Dubbed the metabolic syndrome when occurring together, these disorders may arise from common, not just inter-related, mechanisms. Medical treatment of any 1 component of the metabolic syndrome seldom improves, and in fact often worsens, other features. For example, many diabetes medications promote weight gain; some weight-reducing medications (eg, sibutramine and phentermine) can increase blood pressure. Niacin treatment for dyslipidemia increases insulin resistance, and beta-blockers used for hypertension can blunt hypoglycemia responses. Bariatric surgery is the only intervention that consistently promotes major improvements in all components of the metabolic syndrome (1). Weight-loss surgery performed among severely obese individuals is associated with long-term reductions in all major cardiovascular disease (CVD) risk factors (1). These changes yield clear reductions in actual CVD events (ie, fatal and nonfatal myocardial infarctions and strokes) over a period of up to 20 years (2), as well as decreased long-term, all-cause mortality (3, 4). Bariatric surgery is the only weight-loss intervention that has been demonstrated to be associated with decreased CVD events and overall mortality (2 4); no medical or lifestyle weight-loss strategy to date has demonstrated such benefits in hard clinical outcomes. Several recent randomized clinical trials directly comparing various bariatric operations to medical/behavioral interventions have all found that surgery promoted superior weight loss, glycemic improvement, and remission of T2DM (5 8). Translational Endocrinology & Metabolism, Volume 3, Number 2,

2 Several lines of evidence indicate that these benefits of surgery on CVD risk factors and events do not result simply from the known salutary consequences of weight loss. For example, there are no relationships between baseline body weight or the amount of postoperative weight loss and the ensuing reduction in CVD events (2). Rather, among 20 baseline patient characteristics examined, the only 1 that predicted (and strongly) the benefits of surgery on CVD was high fasting insulin concentration, with a trend towards similar findings for high fasting glucose (2). Similarly, the degree of reduction in glycemia and T2DM after surgery often does not correlate with either baseline body weight or the magnitude of postoperative weight loss (5, 9), and ample evidence indicates that some operations improve glucose homeostasis through mechanisms beyond just those resulting from reduced food intake and body weight (vide infra) (10). Hence, experts in the field are increasingly referring to bariatric operations as metabolic surgery, and most associated scientific societies across the globe have recently changed their names to reflect this (11, 12). For example, the former American Society for Bariatric Surgery is now the American Society for Metabolic and Bariatric Surgery. Overall, it appears that the benefits of bariatric/metabolic surgery on CVD are more related to its effects on glucose homeostasis than on body weight, and/or that these effects are inter-related (13). A tantalizing possibility, consistent with extant evidence, is that some operations correct the core defects underlying the pathophysiology of the metabolic syndrome, thereby ameliorating all features of it. Whether this is true or not, elucidating the mechanisms that mediate the various beneficial effects of bariatric/metabolic surgery, especially its profound impact on body weight and glucose homeostasis, is a compelling research objective. Such understanding should help optimize surgical design, inform the development of endoscopic devices that recapitulate the effects of surgery, and possibly identify drug targets for novel pharmaceuticals that could replicate some of the benefits of surgery noninvasively. Mechanisms of Weight Loss After Bariatric/Metabolic Surgery The older, traditional view was that bariatric surgery promotes weight loss by reducing gastric capacity and/or causing nutrient malabsorption, and individual operations were formerly categorized according to which of these mechanisms they primarily engage. Restrictive procedures such as laparoscopic adjustable gastric banding (LAGB) and vertical sleeve gastrectomy (VSG) reduce functional stomach volume and, in the former 64 Translational Endocrinology & Metabolism: Metabolic Surgery Update

3 case, retard gastric emptying. Malabsorptive procedures such as biliopancreatic diversion (BPD) divert ingested food from the stomach to the ileum, allowing only a small segment of bowel to absorb nutrients. The typical proximal Roux-en-Y gastric bypass (RYGB) combines gastric restriction with nutrient bypass of most of the stomach and a short segment of proximal intestine (primarily the duodenum); the remaining intact small bowel is sufficient to prevent clinically significant malabsorption. Within the past decade, it has become clear that the emphasis on gastric restriction and malabsorption as mechanisms to explain the effects of bariatric surgery is incorrect, or at the very least incomplete. If gastric restriction were a primary determinant of weight loss, one would expect total gastrectomy to promote major weight loss; yet this operation is associated with only minor and mostly temporary changes in body weight over the long term (14). Although malabsorption certainly can cause weight loss, clinically significant macronutrient malabsorption is not observed after the most commonly used bariatric operations (ie, proximal RYGB, LAGB, and VSG), which nevertheless promote profound weight loss (15). Some bariatric operations It appears that at least some bariatric operations, such as RYGB, reduce body weight by activating physiologic changes reduce body weight by activating physiologic changes that mimic the that mimic the normal adaptive normal adaptive responses to excess energy responses to excess energy stores, even in the absence of such a surplus. These changes lead to weight loss and weight loss and the defense of stores, thereby leading to the defense of a new, reduced level of body a new, reduced level of adiposity. In other words, surgery resets the adiposity. body weight settling point at a lower level. Voluntary weight loss resulting from nonsurgical interventions, such as dieting or exercise, stimulates a compensatory increase in appetite and food intake, as well as a decrease in energy expenditure (eg, resting metabolic rate and the energy efficiency of muscular activity), all driven in part by decreased leptin and increased ghrelin levels (16). In contrast, weight loss resulting from RYGB is associated with the opposite physiological changes, which likely contribute causally to the effects of this operation on body weight. Contrary to nonsurgical weight loss, that following RYGB is paradoxically associated with decreased appetite and food intake (17). This may result in part from ghrelin levels that are inappropriately decreased, or at least constrained despite major weight loss (18, 19), which normally increases ghrelin levels (18). Usual meal size decreases after RYGB, as expected from reduced gastric capacity, but counter to predictions based Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 65

4 on stomach anatomy, there is also a voluntary reduction in the frequency of meals and snacks (20, 21). Equally counterintuitive is the observed decrease in preference for and consumption of calorie-dense (eg, high-fat or high-sugar) and rewarding foods (20 25). Similar changes in food choice are seen after VSG in rats (25). These changes are unlikely to be related simply to behavioral modifications due to dumping symptoms after high-carbohydrate meals, because such symptoms do not correlate at all with the efficacy of weight loss (15). In short, after RYGB, individuals experience a generalized reduction in hunger, which is not predicted from their gastrointestinal anatomy, in addition to early satiety, as expected from that anatomy. Although the exact mechanisms mediating reduced appetite after bariatric surgery are not fully defined, functional magnetic resonance imaging studies in people demonstrate post-rygb reductions of brain activation in key regions of mesolimbic reward pathways, especially in response to visual cues related to high (vs low) caloric density (17). These changes mirror concurrent postsurgical reductions in the desire to eat, both overall and especially regarding calorie-dense foods (17). appetite, in contrast to Analogous to the situation with Reduced appetite after RYGB could help non-surgical methods, weight explain why this operation typically promotes greater weight loss than does LAGB bypass causes a paradoxical loss resulting from gastric or vertical-banded gastroplasty, both of which increase in energy expenditure, can render similar or even greater degrees which contributes to its impact of gastric restriction. on body weight. Analogous to the situation with appetite, in contrast to nonsurgical methods, weight loss resulting from RYGB causes a paradoxical increase in energy expenditure, which contributes to its impact on body weight (22, 26 28). Overall daily energy expenditure is the sum of several discrete types of energy output. Those that drive the increased thermogenesis observed after RYGB include resting energy expenditure and the energetic cost of feeding (ie, diet-induced thermogenesis). The candidate molecular mediators of postsurgical changes in energy homeostasis overlap extensively with those thought to underlie improvements in glucose homeostasis, which will be described in greater detail below. In brief, they include the following. First, some operations (eg, RYGB, VSG, and BPD), cause very large, durable increases in postprandial secretion of anorexic distal intestinal L-cell peptides, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and oxyntomodulin (29, 30). Second, levels of the orexigenic upper gastrointestinal hormone ghrelin are invariably decreased by VSG, and typically decreased by RYGB, as well as 66 Translational Endocrinology & Metabolism: Metabolic Surgery Update

5 some types of BPD (10, 18, 29 30). Third, RYGB increases circulating levels of bile acids (31, 32), which could conceivably enhance energy expenditure via the TGR-5 receptor, elevating 5-deiodinase-mediated conversion of thyroid hormone from inactive T4 to bioactive T3, and enhancing brown adipose tissue thermogenesis. Finally, LAGB may decrease appetite via a presumed vagal-stimulation mechanism, as subjects in 1 study reported increases in not only postprandial but also fasting satiety ratings when, unbeknownst to them, their band was optimally constricted, compared with another occasion when it was not (33). Leptin, which is arguably the most important single molecule governing energy homeostasis, does not appear to explain the effects of bariatric surgery on body weight. As expected with any nonsurgical method of weight loss, leptin levels fall commensurate with weight loss resulting from all bariatric operations, a change that should elicit a compensatory increase in appetite and decrease in energy expenditure. The fact that at least some operations elicit the opposite responses, despite a drop in leptin levels, indicates that other mechanisms underlie the effects of these procedures and are powerful enough to overcome homeostasis is still active, and After gastric bypass, energy the influence of decreased leptin signaling. body weight still regulated, but In summary, after RYGB, the energy homeostasis system pertaining to both food intake content. at a greatly reduced body fat and energy expenditure resembles the condition normally activated as a compensatory response to forced weight gain. It therefore reduces appetite and increases energy expenditure, both of which lead to weight loss and the defense of a new, much lower level of body adiposity. Energy homeostasis is still active, and body weight still regulated, but at a greatly reduced body fat content. Mechanisms of Improved Glucose Homeostasis and Remission of Diabetes After Bariatric/Metabolic Surgery The impact on T2DM of bariatric/metabolic operations, especially those involving an intestinal bypass component, is truly amazing. At least in the short term to medium term, approximately 80% of obese patients with T2DM who undergo RYGB experience remission of their disease, thereafter maintaining nondiabetic glucose levels without diabetes medications, and remission rates are even higher after BPD (5, 34 37). These changes are associated with an overall reduction in long-term mortality and a remarkable 92% decline in diabetes-related deaths (3, 4). Although the Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 67

6 duration of diabetes remission is not fully known for each type of bariatric/ metabolic operation, a recent prospective study reported a sustained 88% remission of T2DM for at least 6 years following RYGB, including among patients with a body mass index (BMI) less than 35 kg/m 2, the currently accepted threshold for use of bariatric surgery among patients with T2DM (9). What could cause such profound effects on diabetes, which is generally regarded as a chronic, progressive disease wherein delay of end-organ complications through glycemic management is the primary treatment goal, and remission is seldom a realistic expectation? Available evidence indicates that numerous mechanisms are involved, related both to the known effects of weight loss to improve glycemia as well as more novel, weight-independent processes. Weight-Dependent Antidiabetes Mechanisms of Gastrointestinal Surgery Over the long term, surgical weight loss causes increased insulin sensitivity, as expected with weight loss achieved via any other intervention. Several months to years after RYGB, for example, increases of insulin sensitivity are clearly observed in muscle, liver, and adipose tissue (10, 38, 39). The insulin sensitivity index increases The profound effects of several-fold, as measured by either hyperinsulinemic clamps or intravenous glucose metabolic surgery on diabetes result from numerous tolerance testing and minimal modeling mechanisms, related both to (40, 41). This is associated with many hormonal and molecular changes that would the known effects of weight loss to improve glycemia as be predicted to contribute to improved well as more novel, weightindependent processes. insulin signaling. For example, there is an increase in levels of the insulin-sensitizing hormone adiponectin, especially the important high molecular weight form, which rises in proportion to the decrease of fat mass and predicts the degree of improvement in insulin sensitivity estimated by Homeostasis Model Assessment (HOMA) (42). In muscle, the concentration of insulin receptors and markers of insulin signaling increase (41, 43), as does expression of the mitochondrial transcription cofactor PGC-1 and its target MFN2 (44). Both insulin signaling and PGC-1 activity stimulate fatty acid metabolism in muscle, changes predicted to reduce intramyocellular lipids. Indeed, lipid content decreases after RYGB in both muscle and liver (45). Because lipid accumulation in these tissues causes insulin resistance, the reduction in intracellular lipids in them after RYGB should increase insulin sensitivity. 68 Translational Endocrinology & Metabolism: Metabolic Surgery Update

7 Complementary observations have been made in people following the malabsorptive procedure BPD (38, 39). After this operation, there are increases in muscle glucose uptake, expression of genes controlling glucose and fatty acid metabolism, and insulin-induced glucose oxidation and nonoxidative glucose disposal (44, 46). The resulting increase in insulin sensitivity occurs by 6 months following BPD and peaks at 2 years, with no further change thereafter (47). A critical limitation of these observations is that they were made months to years following surgery, after profound weight loss had occurred. Most of these findings are expected consequences of weight loss and thus do not necessarily reflect direct, weight-independent antidiabetes effects of the gastrointestinal operations per se. Clearly, however, the typical increase of insulin sensitivity (especially in muscle) that occurs with nonsurgical means of voluntary weight loss also occurs after bariatric/metabolic operations. This undoubtedly plays a role in their antidiabetes effects, at least in consolidating them in the long term. Evidence for Weight-Independent Antidiabetes Mechanisms of Gastrointestinal Surgery Mounting evidence shows that certain intestinal diversionary operations, as well as VSG, ameliorate T2DM through mechanisms beyond just weight loss and reduced caloric intake. Data favoring this assertion derive from the following observations ( Table 4-1 ). First, there is often extremely rapid postoperative T2DM remission (before substantial weight loss). Second, there are greater improvements in glucose homeostasis after RYGB than with equivalent weight loss from other interventions. Third, there are inconsistent correlations between the magnitude of post-rygb weight loss and diabetes remission. Fourth, there is improved glucose tolerance following experimental intestinal procedures that cause little or no weight loss. Finally, there is occasional development of late-onset beta-cell hyperactivity. Rapid Postoperative T2DM Remission Following RYGB and BPD, T2DM typically resolves within days to weeks, long before major weight loss has occurred (34). In a study of 1160 patients undergoing RYGB, one-third of those with T2DM were discharged from their surgical hospitalization with normal blood glucose levels off of all diabetes medications, after an average inpatient stay of <3 days (35). Postprandial insulin secretion increases markedly within a few days after RYGB, presumably related to an equally rapid enhancement of postprandial Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 69

8 TABLE 4-1. Bodies of Evidence Supporting Weight-Independent Antidiabetes Mechanisms of Metabolic Surgery Evidence Rapid improvements in glucose homeostasis and remission of T2DM, before substantial weight loss has occurred with some operations Greater improvements of glucose homeostasis and remission of T2DM after intestinal bypass operations than occur with equivalent weight loss following lifestyle interventions or gastric banding Inconsistent relationship between the magnitude of weight loss and the degree of T2DM improvement with some operations Experimental intestinal bypass operations can markedly decrease T2DM with little or no weight loss Occasional cases of severe, late-onset hyperinsulinemic hypoglycemia after RYGB References (34, 35, 48 51) (49, 52 56) (2, 5, 9, 57) (58 86) (87 93) GLP-1 response (vide infra) (48, 49). Insulin sensitivity measurements in some studies also improve within several days after RYGB (50, 51), and interestingly, this finding may be limited to patients with diabetes, not those without it. Very rapid diabetes remission is not observed following purely restrictive operations such as LAGB and vertical-banded gastroplasty, which appear to improve T2DM simply by promoting weight loss (1, 7, 49). Greater Diabetes Remission with RYGB-Induced Weight Loss than with Equivalent Weight Loss from Purely Gastric-Restrictive Operations or Nonsurgical Interventions Several studies have documented greater improvements in glucose homeostasis and diabetes following RYGB than after equal weight loss from purely gastric-restrictive operations (eg, LAGB) or lifestyle modifications. For example, studies comparing patients with equivalent weight loss following either RYGB or LAGB have shown that glucose tolerance and rates of T2DM remission are much better following RYGB (49, 52). Similarly, among matched diabetic patients undergoing either RYGB or low-calorie dieting, after an equivalent magnitude of weight loss, the surgical group displayed much greater improvements of glucose tolerance, accompanied by elevated postprandial GLP-1 levels, insulin levels, and incretin effect (53, 54). Analogous animal experiments confirm these results and implicate increases in both incretin effect and insulin sensitivity to improve glucose tolerance (55). In another study, matched diabetic patients randomized to 70 Translational Endocrinology & Metabolism: Metabolic Surgery Update

9 either VSG or gastric bypass with an equivalent degree of reduced gastric volume, despite equal weight loss in both groups at 6 months, diabetes remission was far greater among the intestinal-bypass patients (93% vs 47%) (56). Inconsistent Relationship Between the Magnitude of Post-RYGB or BPD Weight Loss and Diabetes Remission Although the degree of reduction in glycemia correlates well with the amount of weight loss after LAGB (7), which probably does not engage weightindependent antidiabetes mechanisms, there is an inconsistent relationship between the magnitude of weight loss after RYGB and the degree to which diabetes and glucose homeostasis improve. For example, in a prospective study of 66 patients with T2DM and a BMI of 30 to 35 kg/m 2, there was no hint of correlation between changes in BMI and changes in any measure of improved glycemia (ie, HbA1c, fasting plasma glucose, HOMA-IR, or insulinogenic index during a standardized meal test) at any of 7 time points assessed from 3 months through 6 years after RYGB (9). The sole exceptions were mildly significant correlations between delta BMI and delta fasting glucose at 5 and 6 years; however, glycemic improvements had reached their maximum by 6 months, and all of the 88% of patients who achieved diabetes remission had done so by just 3 months after surgery. Similar negative correlations were observed in a study of Asian Indians with T2DM and a BMI of 22 to 35 kg/m 2, where despite extremely severe, longstanding diabetes at baseline, the rate of remission (100%) was at least as good or better than would be expected following RYGB in more obese, traditional bariatric surgery patients (ie, 80%), despite considerably less percent and absolute weight loss in the former study (57). Likewise, in 20-year follow-up data from the Swedish Obese Subjects study (2), as well as in a recent randomized trial of either RYGB or BPD versus conventional medical care to treat T2DM in obese patients (5), neither baseline weight nor the amount of postsurgical weight loss correlated with the degree of glycemic improvement, diabetes remission, or reduction in CVD events. Experimental Intestinal Bypass Procedures that Improve Glucose Homeostasis Disproportionately to Weight Loss Several new experimental operations and devices that replicate some of the intestinal physiology of RYGB, but without the gastric restriction, can cause major improvements in glucose homeostasis with little or no weight loss, providing convincing evidence for weight-independent antidiabetes Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 71

10 mechanisms. For example, duodenal-jejunal bypass (DJB) diverts nutrients around the proximal intestine in a manner similar to RYGB, but with no reduction in stomach volume. In lean and obese rat models of T2DM, DJB rapidly and durably improves fasting glucose and glucose tolerance (58 68). Control experiments have demonstrated that these effects occur independently of changes in food intake or body weight, without malabsorption, and via mechanisms specifically involving removal of the proximal intestine from digestive continuity, rather than just enhanced distal-intestinal nutrient delivery. These findings have been replicated using DJB in several rodent models and in people (58 73). Mimicking the effects of DJB with an endoscopically implanted device, the endoluminal duodenal bypass sleeve prevents contact between ingested nutrients and duodenal mucosa. Like DJB, this device markedly lowers fasting glucose levels and improves glucose tolerance in diabetic rats and people (74 80). These improvements in glucose homeostasis begin before clinically meaningful weight loss occurs, and they later persist to a greater degree than with equivalent weight loss achieved nonsurgically. Such findings support the notion that preventing nutrient stimulation of the upper intestinal mucosa can exert antidiabetes effects. Another experimental operation, ileal interposition (formerly called ileal transposition or IT), also improves glucose homeostasis out of proportion to weight loss, but via different mechanisms (81). Animals and people with IT show exaggerated GLP-1, peptide-yy, and enteroglucagon responses to gastric nutrient loads (81 83). Increases in these satiety peptides are associated with reductions in food intake and body weight, without malabsorption or gastric restriction (84, 85). Interposed rats also display improved glucose homeostasis apparently from increases in insulin secretion and sensitivity benefits that cannot be explained by body weight changes alone but involve additional weight-independent mechanisms (82, 86). Enhanced GLP-1 secretion is an obvious candidate to explain at least some of these effects. Late-Onset Post-RYGB Beta-Cell Hyperactivity Further hints of weight-independent antidiabetes mechanisms of RYGB come from increasing (although still rare) reports of life-threatening post- RYGB hyperinsulinemic hypoglycemia (87 92). This problem, which sometimes requires pancreatectomy to save patients lives, arises very late: 1 to 9 years postoperatively. Thus, it does not result from an acute mismatch between obesity-associated beta-cell hypertrophy and postoperative improvements of insulin sensitivity during dynamic weight loss, 72 Translational Endocrinology & Metabolism: Metabolic Surgery Update

11 since that scenario would cause hypoglycemia early after surgery. The implication of such late-onset hyperinsulinemia is that the post-rygb milieu stimulates beta-cell function and possibly growth for many years. This phenomenon is undoubtedly beneficial for the vast majority of diabetic patients, but it occasionally goes too far. Such diabetes overshoot never occurs with weight loss achieved by other means. RYGB also restores the normal beta-cell acute insulin response to glucose, indicating that the loss of this response characteristic of T2DM is reversible (93). Candidate Mechanisms to Explain Weight-Independent Antidiabetes Effects of Metabolic Surgery Several mechanisms may explain weight-independent antidiabetes effects of metabolic surgery ( Table 4-2 ). The following sections will describe them in greater detail. Decreased Circulating Ghrelin Levels An early observation that helped propel the concept of metabolic surgery was that 24-hour plasma ghrelin profiles were markedly reduced in post- RYGB patients compared with either normal-weight or matched obese nonsurgical controls (18). This finding introduced the view, which has since become popular, that some forms of bariatric surgery represent endocrine interventions whose effects are mediated in part via hormonal and/or metabolic mechanisms (11, 12). Because ghrelin is prodiabetic via numerous means, compromised secretion following some operations (eg, RYGB, VSG, possibly BPD) could contribute to improved glycemic control. Although most authors concur that ghrelin levels are reduced after RYGB, or at least constrained in the face of weight loss that would otherwise stimulate ghrelin, there is considerable heterogeneity among published reports regarding the impact of RYGB on ghrelin concentrations (10, 39). In contrast, the effects of this operation on glycemia are extremely robust and consistent. Thus, despite its historic importance for the field, ghrelin is unlikely to be a dominant factor mediating post-rygb diabetes remission. Increased Postprandial GLP-1 Levels An intuitively appealing model posits that operations that expedite delivery of ingested nutrients to the distal intestine (eg, intestinal bypass operations such as RYGB and BPD) should enhance postprandial secretion of nutrient-stimulated distal intestinal L-cell peptides, including GLP-1, PYY, Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 73

12 TABLE 4-2. Some Candidate Mechanisms for Weight-Independent Antidiabetes Effects of Metabolic Surgery Proposed Mechanism References Compromised ghrelin secretion (10 12, 18, 39) Increased postprandial GLP-1 secretion, enhancing the incretin effect and insulin secretion Glucose-lowering effects of proximal intestinal nutrient exclusion (9, 29, 48, 51, 53, 54, 95 98, 100, 101, 107) (58 80, 108) Changes in bile acids (31, 32, 109, 131 ) Alterations in gut-brain-liver neurocircuits that regulate hepatic insulin sensitivity Changes in branched-chain amino acids and mtor signaling (67, 68, 110, 111) (112) Modulation of gut microbiota ( ) Decreases in intestinal glucose uptake via SGLT-1 (116) Decreases in glucagon levels (117) Changes in amylin levels (118) Changes in ceramides (119) Reduced inflammation and oxidative stress ( ) and oxyntomodulin. All of these should enhance postprandial satiety signaling, and GLP-1 should also improve glucose tolerance through its insulin-secretagogue effects as an incretin. Despite conceptual reasons to question this model with some operations (eg, RYGB, DJB, and VSG) (94), empiric observations confirm major, rapid, and long-lasting increases in postprandial GLP-1 excursions after RYGB, BPD, VSG, IT, and possibly DJB, but not after LAGB (29, 48, 51, 95 98). Similar increases in postprandial PYY, oxyntomodulin, and cholecystokinin also occur (29, 48, 99), at least after RYGB, and together with increased GLP-1, these would be expected to help promote weight loss as well. Increasing evidence indicates that the enhanced postprandial GLP-1 responses seen after various operations do not result solely from increased distal-intestinal nutrient delivery due to mechanical shortcuts. Regardless of exact mechanisms, however, the impact of these operations on GLP-1 levels is impressive. Moreover, the GLP-1 that is secreted in excess following surgical manipulations is poised to engage key vagal neural circuits to maximize impact on insulin secretion, likely yielding far greater effects than would arise with equivalent increases in GLP-1 signal strength in the systemic circulation rendered by treatment with GLP-1 analogues or DPP4 inhibitors. 74 Translational Endocrinology & Metabolism: Metabolic Surgery Update

13 Several additional observations make GLP-1 an appealing candidate to explain some of the effects of metabolic surgery on glycemia. For example, the increase in postprandial GLP-1 responses after RYGB occurs immediately, lasts for years, and is associated with equally fast and longlasting increases in beta-cell function (eg, meal-stimulated insulin and C-peptide secretion, beta-cell sensitivity to glucose) (9, 29, 48, 51). Hence, these changes could explain the very rapid, sustained improvement in glucose homeostasis that occurs with RYGB. Furthermore, increased GLP-1 levels after RYGB are associated with the expected increase in incretin effect, which also ensues rapidly and durably after surgery, and is not a secondary consequence of weight loss (53, 54). In fact, equivalent weight loss from dieting or purely gastric-restrictive operations does not render any of the previously described effects on GLP-1 or insulin secretion (51, 53). Direct demonstration that enhanced nutrient stimulation of the distal intestine can render beneficial metabolic effects derives from observations with ileal interposition surgery (100). In this operation, a segment of the L-cell-rich terminal ileum is surgically interposed into the proximal small intestine, near the duodenum-jejunum border, greatly increasing its exposure to ingested nutrients. As expected, this intervention substantially augments postprandial GLP-1 and PYY responses, changes that are associated with improvements in glucose homeostasis occurring before substantial weight loss and to a greater degree than in nonsurgical equivalent weight-loss controls, all in the absence of any gastric restriction or malabsorption (100). In the short term, GLP-1-dependent increases in glucosestimulated insulin secretion are observed. Over a longer term in animals, the operation appears to increase beta-cell mass. This, too, could result from GLP-1, which can promote beta-cell proliferation and differentiation, while inhibiting apoptosis, at least in animals (101). Like ghrelin, glucose-dependent insulinotropic peptide (GIP), the other incretin besides GLP-1, is unlikely to be a major contributor to the effects of RYGB, because the impact of surgery on GIP levels is highly heterogeneous, variably reported as increased, decreased, or unchanged postoperatively (30), whereas surgical effects on glucose homeostasis are extremely consistent. Despite considerable evidence indicating that GLP-1 contributes to some of the effects of metabolic surgery, other evidence clearly shows that it is not the sole effector. For example, this incretin cannot explain improvements in intravenous glucose tolerance that are observed very soon after RYGB (102). Similarly, GLP-1 does not easily explain effects of surgery on insulin sensitivity, which increases prior to meaningful weight loss after BPD (103, 104) and appears to increase weight-independently soon after Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 75

14 RYGB among patients with T2DM, although not in patients without T2DM (29, 49, 51, 105, 106). The latter paradox suggests a possible pathogenic role for the gut in the etiology of T2DM. Importantly, loss-of-function experiments in which GLP-1 signaling is blocked indicate that some, but not all, of the effects of RYGB on insulin secretion and glucose tolerance are GLP-1-dependent (107). Antidiabetes Effects from Proximal Intestinal Nutrient Exclusion Several lines of evidence indicate that isolating the proximal small intestine, especially the duodenum, from contact with ingested nutrients, exerts beneficial effects on glycemic control, independent of food intake and body weight. This concept was first conceived based on experiments in rats with DJB, which creates a modest proximal intestinal bypass (mostly the duodenum) equivalent to that in a standard, conservative RYGB, but with no reduction in gastric capacity. In other words, it is essentially a stomach-sparing gastric bypass. DJB promotes major, rapid, and longlasting improvements in fasting glucose and oral glucose tolerance, without reducing food intake or body weight compared with sham-operated controls, in different animal models of T2DM including polygenic nonobese Goto-Kakizaki rats, monogenic obese ZDF rats, and animals with chemically- or immunologically-mediated insulin deficiency (58 68). Overall, similar results apply in people undergoing DJB (69 73). Interestingly, these beneficial effects on glucose homeostasis are only seen in individuals with T2DM. In those with normal glycemia, oral glucose tolerance worsens slightly after DJB, as predicted from the reduction in nutrient-stimulated secretion of the incretin GIP from the proximal intestine. These findings suggest that the proximal intestine might be involved in the pathogenesis of T2DM, perhaps by producing a pro diabetes molecule only in diabetic individuals, one that is silenced by DJB (or RYGB). Theoretically, the glycemic benefits of DJB might result simply from expedited delivery of ingested nutrients to the distal intestine, hyperstimulating GLP-1 secretion. Additional studies, however, demonstrate that other antidiabetes effects arise directly from nutrient exclusion of the proximal small intestine. For example, in diabetic Goto-Kakizaki rats, a variation of DJB, in which ingested food passes from the stomach not only into the proximal jejunum (as in a standard DJB) but also into the proximal duodenum through the pylorus, had no impact on glycemia, whereas the regular DJB largely eliminated diabetes (59). Individual animals serially subjected to DJB with duodenal exclusion followed by DJB without duodenal exclusion, or vice versa, experienced reversible remission and reconstitution of 76 Translational Endocrinology & Metabolism: Metabolic Surgery Update

15 T2DM. Diabetes was eliminated or restored based on the absence or presence, respectively, of nutrient passage through the duodenum, with an unchanging degree of minor shortcutting for nutrients to reach the lower bowel. In people, much greater reduction in HbA1c was demonstrated among patients who underwent VSG+IT with duodenal exclusion versus those who underwent the same operation without duodenal exclusion, despite equivalent weight loss (108). These studies indicate that enhanced delivery of nutrients to the distal intestine is unlikely to fully explain the early diabetes improvement following upper intestinal bypass. The work strongly implicates an additional role for the excluded proximal intestine per se, identifying a fundamentally novel physiologic effect of DJB and RYGB, possibly shedding light on diabetes pathogenesis. Further support for this upper intestinal hypothesis comes from experiments in which a flexible plastic sleeve is implanted in the proximal small bowel, causing food to move from the pylorus to the beginning of the jejunum without coming in contact with duodenal mucosa. Such endoluminal duodenal bypass sleeves, which have been tested in rats, pigs, and people, cause relatively minor or no weight loss, but they markedly improve oral glucose tolerance and fasting glucose levels (74 80). In people with T2DM, placement of this device caused substantial improvements in fasting and postprandial area under the curve (AUC) glucose levels starting as early as 1 week, long before weight loss had occurred (76 80). By 6 months, although minor weight loss (3.8 kg) had begun, glycemia was disproportionately improved, with a remarkable fall of HbA1c levels from 9.0 to 6.1% (80), a result better than would be expected with any T2DM medication except insulin. A very intriguing and unexpected feature of both DJB and upper intestinal sleeves is that they reduce fasting and postprandial blood glucose levels to approximately the same degree, and consistent with this continuous reduction in glycemia, they have a major impact on HbA1c levels (58 80). Thus, although these interventions appear only to reroute the flow of food through the gastrointestinal tract after meals, they exert salutary effects on glycemia that persist between meals. The fact that these interventions immediately reduce fasting glucose levels with long-lasting effect suggests that they may increase hepatic insulin sensitivity. This hypothesis was recently supported, and a role for a novel gut-brain-liver neurocircuit implicated, in a study using pancreatic clamps in animals (67). It is conceivable that the relevant mechanisms also involve insulinindependent glucose disposal, especially by the liver, perhaps involving changes in bile acid fluxes (vide infra). These are but a few of the important questions still to be addressed in future studies. Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 77

16 Changes in Bile Acids Very recent, evolving evidence implicates bile acids as potential mediators of some of the effects of gastrointestinal surgery on glucose and energy homeostasis. Although best known for their roles in lipid digestion, bile acids can improve glucose metabolism and may promote weight loss, via several mechanisms (32). The first mechanism is stimulation of TGR5 signaling in intestinal L-cells to increase secretion of peptides that enhance insulin secretion (GLP-1) and reduce food intake (GLP-1, PYY, oxyntomodulin). The second mechanism is engagement of TGR5 signaling in brown adipose tissue to activate 5 -deiodinase type 2 and increase energy expenditure, as well as possibly in beta cells to stimulate insulin secretion. The third mechanism is engagement of FXR α signaling in distal intestinal enterocytes to increase FGF19 secretion, thereby enhancing mitochondrial activity, insulin sensitivity, and insulin-independent hepatic glycogen and protein synthesis. The fourth mechanism is suppression of hepatic gluconeogenesis via FXR-dependent and FXR-independent mechanisms. The fifth mechanism is mimicking of insulin action in the liver to stimulate PI3kinase, AKT, and glycogen synthase. The final mechanism is reduction of endoplasmic reticulum stress, thereby ameliorating insulin resistance. Intestinal bypass operations and possibly VSG enhance delivery of bile acids to the distal intestine. In the former case, bile acids arrive distally in a state not complexed into mixed micelles, and as such, they should theoretically have greater signaling capabilities, accentuating several of the previously mentioned beneficial effects. Circulating bile acid levels are clearly elevated after RYGB, and these levels correlate with postprandial GLP-1 levels, rates of glucose and lipid oxidation, and overall glucose tolerance (31, 32, 109, 131). Portal vein levels and hepatic exposure should also theoretically be accentuated. The extent to which these changes contribute to the effects of metabolic surgery remains to be determined, but preliminary evidence suggests that they do make a meaningful contribution. Other Candidate Mechanisms for the Effects of Bariatric/Metabolic Surgery on Glucose Homeostasis and/or Body Weight It has recently been determined that the gut regulates not only insulin secretion (via incretins) but also insulin sensitivity, through a novel gut-brain-liver neurocircuit (110). Small intestinal sensing of minute amounts of ingested nutrients, signaling the onset of a meal, activate 78 Translational Endocrinology & Metabolism: Metabolic Surgery Update

17 this parasympathetic circuit to increase liver insulin sensitivity, thereby suppressing hepatic glucose output. Hence, the gut serves as a first responder to meals, preventing the excessive surges of blood glucose that might occur with profligate mobilization of endogenous fuel stores in the postprandial state, saving those stores instead for future needs (111). Because the site of relevant nutrient sensing to activate this neurocircuit includes the duodenum (67), it is conceivable that the type of proximal intestinal bypass rendered by RYGB, DJB, or endoluminal duodenal bypass sleeves might hyperstimulate it, contributing to glycemic improvements. Indeed, the ability of DJB to lower blood glucose levels (without affecting food intake) in 2 different models of insulin-deficient rodent diabetes requires intact jejunal nutrient sensing and is attributable to reduced hepatic glucose production, without increased insulin secretion (67). An additional role for altered intestinal carbohydrate metabolism, specifically changes in intestinal gluconeogenesis, has also been proposed to mediate some of the effects of RYGB and/or DJB on diabetes (68). Via weight-independent means, RYGB decreases circulating levels of total and branched-chain amino acids (112). This should down-regulate mtor/s6k/irs pathways, which are normally activated by weight loss as an adaptive response to starvation, decreasing insulin sensitivity. Consistent with this prediction, changes in these amino acid levels after RYGB correlate inversely with measures of insulin sensitivity and secretion (112). It has recently been determined that constituents of the vast gut microbiome (ie, all microorganisms inhabiting the gastrointestinal tract) vary widely between lean and obese individuals, and gut microbiota have been implicated as regulators of host energy balance and possibly glucose homeostasis (113). Because gastrointestinal operations and devices alter intestinal nutrient exposure, ph, osmolarity, and many other features of the internal milieu, it seems likely that such interventions would modulate gut microbiome composition, and indeed, this has been clearly demonstrated (114, 115). At present, however, it is unclear how much such changes might contribute to the effects of metabolic surgery on clinical outcomes. It is also a difficult challenge to clarify whether various microbiome shifts cause alterations in the host (such as weight loss), or whether they are secondary consequences of such alterations. Nevertheless, this is a rich arena for future research. Additional roles in the effects of bariatric/metabolic surgery have been proposed to be played by changes in a variety of other entities, including the intestinal glucose transporter SGLT-1 (116), glucagon (117), amylin (118), ceramides (119), inflammation, and oxidative stress ( ). Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 79

18 Clinical Implications: Use of Metabolic Surgery to Treat T2DM in Less Obese or Even Nonobese Patients Because metabolic surgery typically promotes complete remission of T2DM in severely obese patients (34 36), and because mounting evidence indicates that, in the case of several operations, this results from hormonal and metabolic mechanisms beyond just the consequences of weight loss (10 12, 39), evaluating the use of such operations to treat diabetes in less obese patients is logical (11, 12). Bariatric surgery is currently restricted to patients with a BMI greater than 40 kg/m 2, or BMI greater than 35 kg/m 2 with obesity-related comorbidities such as T2DM. These guidelines derive from a 21-year-old National Institutes of Health (NIH) consensus statement (123), which was written before the impact of metabolic surgery on diabetes was widely known, and before the development of many recent advances in minimally invasive techniques that have greatly improved safety. Recently, worldwide experts in the field have offered new consensus suggestions carefully crafted, but unofficial as articulated by delegates of the Diabetes Surgery Summit, the World Congress on Interventional Therapies for Type 2 Diabetes, and the International Diabetes Federation (11, 12, 124). These thought leaders recommended that bariatric/metabolic surgery be considered to treat poorly controlled T2DM in patients with a BMI as low as 30 to 35 kg/m 2. That recommendation was based primarily on relatively short-term, nonrandomized data then available, but subsequent studies, including randomized controlled trials (6, 7) and prospective investigations with long-term follow-up (9) continue to help affirm this new guideline. Although lowering the BMI threshold for surgery in patients with T2DM from 35 to 30 kg/m 2 would be a modest numerical change, it would affect a very large population, because the BMI distribution peak among diabetic patients lies within this range (125). In the United States, more than 25% of people with diabetes have class 1 obesity (BMI 30 to 35 kg/m 2 ) (125, 126). Thus, a modest alteration of surgical criteria to include this population would have far-reaching implications for diabetes care. Insufficient data exist at present to judge the utility of surgery to treat diabetes in patients with a BMI less than 30 kg/m 2. Although the literature on use of metabolic surgery to treat diabetes in patients with a BMI less than 35 kg/m 2 is still in a relatively early stage of development, to date it appears that the safety and efficacy of these operations in less obese patients are relatively similar to what has been 80 Translational Endocrinology & Metabolism: Metabolic Surgery Update

19 observed in severely obese, traditional bariatric surgery patients ( ). Importantly, excessive weight loss has not been observed after LAGB or the standard, proximal RYGB, even when performed in less obese patients. Overall, available evidence suggests that a BMI cutoff of 35 kg/m 2 is not an accurate parameter to predict the potential of gastrointestinal surgery to induce glycemic and metabolic control (2, 11, 12). Mounting data support a conceptual paradigm shift to view these operations as metabolic surgery, rather than merely bariatric surgery. Conclusion Although the precise mechanisms mediating weight loss and T2DM remission after bariatric/metabolic procedures have not been fully elucidated, it is apparent that rearrangements of gastrointestinal tract anatomy can promote weight loss via mechanisms other than just gastric restriction and malabsorption, and several procedures exert endocrine/metabolic antidiabetes effects in addition to those related to reduced food intake and body weight. Various gastrointestinal manipulations engage these mechanisms to differing degrees, and it is likely that operations with dramatic antidiabetes impact, such as RYGB, activate several of them in complementary ways. Beyond the few hormones whose changes after gastrointestinal surgery have been studied, the gut produces over 100 known bioactive peptides (130) and possibly also undiscovered relevant factors. Fully clarifying the molecules responsible for the benefits of gastrointestinal surgery on glucose homeostasis is a compelling research objective that promises to help optimize surgical and device design, as well as to inform research toward novel pharmaceuticals. References 1. Sjöström L, Lindroos AK, Peltonen M, et al; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351(26): Sjöström L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307(1): Sjöström L, Narbro K, Sjöström CD, et al; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007; 357(8): Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357(8): Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17): Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17): Mechanisms Mediating Weight Loss and Diabetes Remission After Bariatric/Metabolic Surgery 81