REVIEW URRENT C OPINION Bariatric surgery in managing diabetes mellitus Mitchell S. Roslin and Courtney N. Cripps Purpose of review Obesity is a worldwide epidemic, having profound effects on Western populations. Bariatric surgery has long been employed to treat obesity and its related comorbidities. Over time, researchers have amassed significant data to support bariatric surgery in the pursuit of treating diabetes mellitus. This review serves to introduce the most recent findings and their relation to the various bariatric surgical options as bariatric surgery will continue to cement itself in the treatment paradigm of diabetes mellitus. Recent findings Numerous studies performed in the past 10 years have demonstrated the improvement or cessation of diabetes with bariatric surgical intervention. In comparing the vertical sleeve gastrectomy and Roux-en-Y gastric bypass, data demonstrate a more beneficial response of diabetes to the Roux-en-Y gastric bypass, and an even further exaggerated response with the biliopancreatic diversion/duodenal switch. The benefit has long been established, but what causes the improvement in diabetes mellitus after bariatric surgery? Recent data suggest a decrease in circulating bile salts as well as changes to inflammatory markers and circulating cytokines. Furthermore, tailoring of existing surgical procedures has led to the development of the SIPS procedure, and its benefit is demonstrated in bypassing a large portion of intestine while eliminating an enteroenterostomy, helping to reduce short gut syndrome and resultant diarrhea. Summary The surgical climate within the bariatric field is changing and will continue to do so in the future. As the understanding of the causes or mechanisms in which bariatric surgery improves metabolic disorders becomes more evident, the process of individualizing care for specific patients will become more prevalent. Keywords bariatric surgery, diabetes mellitus, gastric band, obesity, Roux-en-Y gastric bypass, sleeve gastrectomy INTRODUCTION It is estimated that one-third of Americans are obese, and the rate of obesity is increasing globally [1,2]. One of the major complications of obesity is type II diabetes mellitus, and the relationship between the two conditions is complex. Although the majority of diabetic patients are obese, the converse is not true, for only 30% of patients undergoing bariatric surgery for morbid obesity are diabetic [3,4]. In fact, the complexities are evident in epidemiology as Pima Indians, Aborigines, and those of Asian descent become insulin resistant at a lower basal metabolic index than those of European descent [5]. Whether obesity causes diabetes or the two are concurrent conditions remains unknown as does the sporadic or unpredictable incidence of diabetes in the obese patient. In years past, it would have been unfathomable to manage diabetes surgically. Although pancreatic or islet cell transplant might have been performed, gastrointestinal bariatric operations would have been readily dismissed. Today, bariatric surgery is increasingly being performed as a treatment for diabetes mellitus. Multiple randomized clinical trials demonstrate that surgical bariatric procedures (Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), and biliopancreatic diversion/ duodenal switch (BPD/DS)] offer improved control and a greater likelihood of remission compared with optimal medical therapy [6 ,7 ,8]. Weight loss alone is not the mechanism by which these surgeries improve diabetes mellitus. Changes in b cell responsiveness, incretin levels (e.g., glucagonlike peptides), and bile salt regulation also play a role [9 ,10 ,11–14,15 ]. Achieving an understanding of && & & & & Department of Surgery, Northwell Health-Lenox Hill Hospital, New York City, New York, USA Correspondence to Mitchell S. Roslin, MD, FACS, Department of Surgery, Northwell Health-Lenox Hill Hospital, 100 E 77th Street, New York, NY 10075, USA. Tel: +1 212 434 3285; fax: +1 212 434 3250; e-mail: mroslin@northwell.edu Curr Opin Gastroenterol 2016, 32:481–486 DOI:10.1097/MOG.0000000000000312 0267-1379 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-gastroenterology.com Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Stomach and duodenum KEY POINTS  It is estimated that one-third of Americans are obese, and the rate of obesity is increasing globally.  Multiple trials, like the STAMPEDE or STAMPEDE II, demonstrate a lasting benefit of bariatric surgery over medical management in the treatment of diabetes.  Surgical innovation has resulted in the formation of the SIPS procedure, one that improves surgical outcomes and reduces complications.  Diversion of biliary flow and the alteration of circulating inflammatory markers are predicted to be important in the improvement in obesity-related metabolic disorders, like diabetes. these procedures is imperative as they are now heavily employed in the management of diabetes, even supported as a primary therapy among antidiabetes interventions by the American Diabetes Association [16]. The purpose of this study is to discuss the changing climate regarding bariatric surgery as treatment for diabetes. MAKING A CASE FOR BARIATRIC SURGERY Bariatric surgery has existed for more than 60 years and involves restrictive and/or malabsorptive procedures. Restrictive procedures involve restriction and/or exclusion of a portion of the stomach as this reduces the reservoir for the food bolus and causes early satiety. Malabsorptive procedures involve removing or excluding a portion of the intestine as this decreases the surface area for absorption. Some operations, termed hybrid or mixed, incorporate both types of procedures. However, dividing the types of operations into restrictive and/or malaborptive is simplistic and inaccurate. Modifications made to the gastrointestinal tract by these operations are complex, the mechanisms not entirely understood, and cannot be simply reduced to two mechanisms. In the 1990s, bariatric surgery was somewhat experimental and not universally adopted. By 2000, bariatric surgery gained significant steam and became standard surgical practice [17–19]. The impetus was the worldwide obesity epidemic as well as the recognition of the medical risks associated with obesity. Currently, there are approximately 200 000 bariatric procedures performed annually in the United States [17]. The relationship between bariatric surgery and improvement in diabetes may be traced to a 1992 482 www.co-gastroenterology.com case report in the New England Journal of Medicine that described improvement in diabetes following a gastrojejunostomy. Following this report, Pories et al. [18] published an article in 1995 entitled, ‘Who would have thought it? A surgical treatment is the best treatment for diabetes’ in which he presented a cohort of patients that demonstrated lasting resolution of type II diabetes following RYGB. Despite advances in laparoscopic bariatric surgery and the data supporting improvement of diabetes after bariatric surgery, the medical community remained skeptic [19–22]. It has now been demonstrated that bariatric surgery offers improvement in diabetes when performed for patients who fail medical therapy but may offer remission in diabetes when performed earlier in the course when b cell function remains. In the last several years, multiple randomized controlled trials have compared surgical with medical therapy in the management of diabetes. The Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial, in which RYGB and VSG was compared with medical therapy showed that both surgical interventions were vastly superior to medical therapy [23 ]. The long-term follow-up of this study, the STAMPEDE II trial, shows a lasting advantage of surgery over medical therapy for controlling diabetes [24]. There was no statistical difference between the VSG and RYGB. Patients requiring insulin for longer periods of time prior to operative intervention were least likely to improve or enter into remission, supporting an earlier role for surgical intervention. Similar improved results of surgery compared with medical therapy have been reported for BPD and laparoscopic adjustable gastric banding (LAGB) [25–27]. && LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING LAGB involves the encirclement of a silicone ring with accompanying inner balloon at the upper aspect of the stomach to create a high-pressure zone adjacent to the gastroesophageal junction. The balloon is attached to a port that is located in the subcutaneous tissue, allowing for balloon adjustment via cutaneous injection or aspiration. The advantage to the band is ease at which it is placed thereby making it a low-risk operation in terms of operator dependency. Disadvantages include weight loss inferior to stapling procedures and device-related complications. The extraction rate is approximately 5% per year [25]. Although placement of the band has relatively no influence on the secretion of gastrointestinal hormones that impact hunger, satiety or glucose Volume 32  Number 6  November 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Bariatric surgery in managing diabetes mellitus Roslin and Cripps regulation, one meta-analysis of all bariatric procedures, and their impact on diabetes reported a 55% remission rate after LAGB [26]. In one randomized control trial comparing LAGB with medical therapy in terms of diabetes remission, the LAGB group demonstrated a higher likelihood of remission, yet the rate of remission dropped precipitously after further defining remission [27]. The use of LAGB is decreasing as its effects on weight loss are predominantly short term [18]. VERTICAL SLEEVE GASTRECTOMY As LAGB popularity has declined, VSG has become a prominent player in the arsenal of bariatric operations. By resecting the greater curvature of the stomach and leaving an intact, tubular structure along the lesser curvature, the volume of available stomach is significantly reduced. Having become the most popular international stapling procedure, weight loss is more significant than that of the LAGB, and nearly equal to the RYGB [28]. Advantages of VSG include the absence of foreign material in contact with the stomach as well as the maintenance of the native pathway for food passage thereby reducing the risk for micronutrient deficiency. In addition to the mechanical impact of volume reduction, resection of the greater curvature alters gastrointestinal hormone levels. The secretion of ghrelin, a hunger hormone located in the resected portion of the stomach, is decreased, whereas the secretion of incretins that decrease blood glucose concentration such as PYY are increased [29 ,30]. Most studies report 70% resolution of diabetes after VSG (similar to that of RYGB) and a randomized controlled trial showed superiority of VSG over optimal medical therapy for diabetes resolution at 1 and 3 years [23 ,24,26]. whereas the bypass diminishes optimal mixing of digestive enzymes with the meal as well as the surface area available for nutrient absorption. Other physiologic changes include alteration of the enterohepatic circulation of bile salts and gut microbiome. RYGB induces resolution of diabetes, defined as the absence of medications to maintain glycemic control, in 75–85% [24,26]. Resolution of diabetes is somewhat independent of weight loss as it occurs early before hospital discharge. Unfortunately, not only does diabetes recur in 40% of patients several years after RYGB, even in those that maintain weight loss, but data from the Swedish Obese Subjects longitudinal data indicate a 20% incidence of new onset diabetes after the operation [31–33,34 ,35,36]. Fortunately, at 10 years, weight loss and control of diabetes are maintained in the majority of patients [22,37 ,38]. Although RYGB, overall, exerts beneficial effects on weight loss and glucose homeostasis, individual patient outcomes are variable. The early satiety induced by a small gastric pouch and jejunal distension from rapid gastric emptying may dissipate with time. Blood glucose concentrations may vary from euglycemia to hyperglycemia and hypoglycemia [39,40]. Medical weight loss relies upon the construct of insulin fluctuations, whereas RYGB relies upon glucose fluctuations, a limitation that will likely shift the bariatric surgery paradigm to other procedures [41]. && && & && ROUX-EN-Y GASTRIC BYPASS The RYGB involves creating a small pouch along the lesser curvature of the stomach in addition to the division of the proximal intestine 50–100 cm from the ligament of Trietz. The distal segment of that intestinal division is anastomosed to the gastric pouch, and intestinal continuity is restored by creating an anastamosis between the Roux limb and the biliopancreatic limb approximately 75–100 cm from the gastrojejunostomy. The food bolus and digestive enzymes are mixed downstream, bypassing a significant surface for absorption. Numerous changes occur anatomically and physiologically following this operation. The small gastric pouch reduces oral intake, BILIOPANCREATIC DIVERSION/ DUODENAL SWITCH The BPD/DS, in simplest terms, combines sleeve gastrectomy and intestinal bypass; however, the biliopancreatic limb is significantly longer and the biliary diversion far greater. The result is a more aggressive bypass with minimal complications. However, the BPD/DS is technically more difficult to perform and is more likely to cause long-term nutritional deficits. Compared with VSG and RYGB, BPD/DS achieves the greatest improvement in diabetes with resolution rates exceeding 90% [25,42–44]. All comorbidities, except gastroesophageal reflux disease, are improved to a greater extent with BDP/DS than RYGB [43]. When preoperative comorbidities are taken into consideration, there are no differences in the complication rates between BDP/DS and RYGB [26,33]. The Bariatric Outcomes Longitudinal Database (BOLD) demonstrates large and lasting weight loss, more pronounced with time, after BDP/DS [45 ]. 0267-1379 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved. & www.co-gastroenterology.com Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. 483 Stomach and duodenum MECHANISMS FOR GLUCOSE CONTROL FOLLOWING BARIATRIC SURGERY The impact of glucose tolerance testing was recently demonstrated in patients who had undergone VSG, RYGB, and DS. Following oral glucose, insulin concentrations at 1 h, 6 months, and 1 year were higher in the RYGB patient group compared with those having undergone BPD/DS, although insulin concentration increased significantly in both groups [46]. In the VSG patient group, the rise in insulin was more dramatic than the RYGB patients, but less dramatic than the BPD/DS patient group. BPD/DS results in more of a euglycemic state without wide fluctuations in insulin; the mechanism, however, is unknown. Some researchers speculate this is because of metabolism of glucose at the muscular level, the reduction of peripheral fat mass, or simply a peripheral process independent of central insulin production [47,48]. Patients undergoing RYGB produce more insulin when challenged with a food bolus, and also manifest less insulin resistance as a result of weight loss. Increased insulin production is likely because of increased secretion of incretins (glucagon-like peptides and PYY) that directly stimulate production and release of insulin. In patients with poorly functioning b cells, improvement in diabetes is less likely to occur. In contrast, BPD/DS patients require less insulin to maintain euglycemia. The effect is largely extrapancreatic as patients who are challenged with a food bolus do not produce a hyperinsulinemic response [21,26]. BILE SALTS AND INFLAMMATION, MEDIATORS OF DIABETES? New bariatric procedures are being developed [Scopinaro procedure, mini-gastric bypass, and SADI (SIPS)] that promise greater weight loss and/or improved management of diabetes [49,50,51 ,52]. What these procedures share is a separation of bile from ingested food [53 ,54 ]. It is suggested that patients with higher levels of circulating bile salts are likely to achieve remission of diabetes and that greater separation of bile salts from food results in decreased gastrointestinal inflammation. As previously stated, resolution of diabetes often occurs significantly sooner than weight loss. It is speculated that the driving force behind this process is inflammation and this can be assessed by measuring cytokines and acute phase proteins [55 ]. Although poorly understood at this time, the use of biomarkers may become valuable in the future as a means to predict who will respond to bariatric surgery, both temporarily and permanently [55 ]. & & & Various T cell subsets, like Th17, have recently been implicated as major contributors to inflammation and hyperglycemia, creating another target for intervention or marker to identify changes following operative intervention [56 ]. Postoperative changes in inflammatory markers are expected as surgery offers some insult to tissue, and the true utility of using these markers remains to be seen [57 ]. To further elucidate this notion, a recent study demonstrated the persistent, unchanged levels of IL6 following RYGB thus revealing the minimal effect of this marker on the diabetes disease process [58 ]. & & & CONCLUSION The purpose of this review is to provide a framework to improve understanding of the metabolic effects of bariatric surgery beyond weight loss alone. With a broader understanding of expected results, one can refer patients in need to the appropriate physicians, including surgeons, to achieve maximal benefit. What should we be offering our obese patients with diabetes? Should bariatric surgery be offered sooner? The answers are not clear cut and no specific algorithms have been adopted. Patients and their diseases should be stratified and their treatments individualized depending upon comorbidities. In early diabetes, VSG may be adequate. In intermediate diabetes, a two-stage procedure may be contemplated. VSG could be first attempted and if the patient fails to lose sufficient weight and improve diabetes BPD/DS could be offered. In advanced diabetes, BDP/DS, and perhaps SADI, offers the best chance for control of diabetes. As more research surfaces purporting the beneficial effect of bariatric surgery not only on diabetes but also on cancer reduction, cardiovascular-related mortality, and nonalcoholic steatohepatitis, it is anticipated that bariatric surgeries will become more prevalent and performed earlier. Innovation and a combined effort of internists, endocrinologists, cardiologists, gastroenterologists, and surgeons can and will change the lives of those suffering from obesity and obesity-related diseases. Acknowledgements None. Financial support and sponsorship None. & & 484 www.co-gastroenterology.com Conflicts of interest M.S.R. is an educational consultant for compensation at Johnson & Johnson Incorporated, Covidien Limited and W.L. Gore & Associates. He acts on the scientific Volume 32  Number 6  November 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Bariatric surgery in managing diabetes mellitus Roslin and Cripps advisory board at SurgiQuest and ValenTx, and also has stock options with each. C.N.C. has no conflicts of interest to declare. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2008. JAMA 2010; 303:235–241. 2. Mendis S, Davis S, Norrving B. 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An additional study reflecting the role of inflammation in the formation of the diabetic disease process in obese patients. 56. Ortega FJ, Vilallonga R, Xifra G, et al. Bariatric surgery acutely changes the & expression of inflammatory and lipogenic genes in obese adipose tissue. Surg Obes Relat Dis 2016; 12:357–362. An additional study reflecting the role of inflammation in the formation of the diabetic disease process in obese patients. 57. Kratz M, Hagman DK, Kuzma JN, et al. Acute improvements in glycemic & control after gastric bypass occur despite persistent adipose tissue inflammation. Obesity 2016; 24:1438–1445. An additional study reflecting the role of inflammation in the formation of the diabetic disease process in obese patients. 58. Fouse T, Brethauer S. Resolution of comorbidities and impact on longevity & following bariatric and metabolic surgery. Surg Clin North Am 2016; 96:717– 732. A large review suggesting bariatric surgery decreases all-cause mortality as a result of decreases in cancer, diabetes, and cardiovascular comorbidities. Volume 32  Number 6  November 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.