Diabetes Care Volume 42, February 2019 331

Metabolic (Bariatric and Henry Buchwald1,2 and Jane N. Buchwald3 Nonbariatric) Surgery for Type 2 Diabetes: A Personal Perspective Review Diabetes Care 2019;42:331–340 | https://doi.org/10.2337/dc17-2654

Metabolic surgery can cause amelioration, resolution, and possible cure of type 2 diabetes. is metabolic surgery. In the future, there will be metabolic surgery operations to treat type 2 diabetes that are not focused on weight loss. These procedures will rely on neurohormonal modulation related to the gut as well as outside the peritoneal cavity. Metabolic procedures are and will always be in flux as surgeons seek the safest and most effective operative modality; there is no enduring gold standard operation. Metabolic bariatric surgery for type 2 diabetes is more than part of the clinical armamentarium, it is an invitation to perform basic research and to achieve fundamental scientific REVIEW knowledge.

And the Lord God caused a deep sleep to fall upon Adam, and he slept; and he took one of his ribs, and closed up the flesh instead thereof, and the rib which the Lord had taken from man, made he a woman....

dGenesis 2:21-22

METABOLIC SURGERY In 1978, in the foreword to the book Metabolic Surgery (1), by author H.B. and Richard L. Varco, we defined the discipline of metabolic surgery “as the operative manipu- 1Department of Surgery, University of Minne- sota, Minneapolis, MN lation of a normal organ or organ system to achieve a biological result for a potential 2 ” “ ” Department of Biomedical Engineering, Univer- health gain. The procedure described in Genesis was an operative manipulation sity of Minnesota, Minneapolis, MN under general anesthesia on a “normal organ” to achieve a “biological result”;itwas 3Division of Scientific Research Writing, Med- metabolic surgery. write Medical Communications, Maiden Rock, As early as 1896, bilateral oophorectomy was used to cause temporary regression of WI breast cancer metastases (2). The 100-year heyday of peptic, primarily duodenal, ulcer Corresponding author: Henry Buchwald, buchw001@ surgery, from the late 19th century to the discovery of Helicobacter pylori, involved umn.edu operating on normal stomachs and vagus nerves to cure the pathologic lesion, a distal Received 19 December 2017 and accepted 17 July ulcer left untouched by the surgeon. This was metabolic surgery, as was the partial ileal 2018 bypass (Fig. 1) for the treatment of hypercholesterolemia, introduced in 1962 and © 2019 by the American Diabetes Association. Readers may use this article as long as the work 1963 (3,4). The partial ileal bypass was used as the intervention modality in the is properly cited, the use is educational and not Program on the Surgical Control of the Hyperlipidemias (POSCH) (5–8), the first for profit, and the work is not altered. More infor- randomized controlled trial to use metabolic surgery. POSCH was the first study mation is available at http://www.diabetesjournals definitively to demonstrate the benefits of marked lowering in preventing .org/content/license. myocardial infarctions, peripheral vascular disease, and the need for coronary artery See accompanying article, p. 186. 332 Metabolic Surgery and Diabetes Diabetes Care Volume 42, February 2019

most of the in an obese malabsorptive, surgery. Thus, in 1973, patient, with bowel reconstruction by Printen and Mason (16) introduced an end-to-end jejunoileostomy and sep- gastroplasty. Their original procedure arate drainage of the bypassed bowel by consisted of a partial horizontal gastric an ileocecectomy (10). Varco never pub- transection, leaving a greater curvature lished this case. The first report of this conduit. In 1981, Laws and Piantadosi operation was published in 1954 by (17) made the restrictive pouch vertical Kremen et al. (11), also from the Uni- and narrowed the outlet with a Silastic versity of Minnesota. ring (Fig. 3). Mason (18) described his The JIB elicited excellent and lasting second-generation VBG in 1982, which Figure 1—Partial ileal bypass. A, division of weight loss but was associated with used a Marlex mesh band through a gas- , 200 cm from the ileocecal valve; B, extensive early and late complications. tric window in a vertical pouch for out- ileocecostomy above appendiceal stump; C, tacking proximal end bypassed ileum, clo- These included electrolyte imbalances, let restriction. The VBG rapidly gained sure mesenteric defects. vitamin and mineral deficiencies, diar- in popularity and soon rivaled the RYGB rhea, gas bloat syndrome, oxalate kidney for dominance in the field. Over time, stones, steatohepatitis and progressive however, VBG patients began to regain degeneration, cutaneous pustular weight, and the operation fell into disuse. eruptions, and mentation difficulties. To avoid the complications of the surgery or dilation and stenting, concur- Various causative mechanisms for these JIB and yet maintain the weight loss rently with coronary arteriographic ar- problems were hypothesized, with the achieved by that procedure, Nicola rest of disease progression and induction greatest credence given to short bowel Scopinaro introduced the BPD operation. of actual plaque regression, as well as syndrome and bacterial overgrowth in His procedure consists of a horizontal prolonging life expectancy over 25 years the bypassed small intestine causing the hemigastrectomy with gastric pouch of follow-up. Today bariatric surgery is elaboration of toxins and alcohol. Over drainage by a Roux limb, at least 250 the most used of metabolic surgery pro- time, most of these problems were an- cm in length, anastomosed to a long cedures and is performed worldwide as ticipated and prevented or treated. How- biliopancreatic limb to form the com- part of the treatment armamentarium to ever, with the emergence of the RYGB, mon channel of ;50 cm (19) (Fig. 4). The combat the epidemic of morbid . the JIB fell into disuse. Although there procedure avoids any stagnation of flow are JIB patients alive and doing well to- and, thereby, the potential for bacterial HISTORY OF BARIATRIC SURGERY day, 30–40 years after their operation, overgrowth, toxin formation, and alcohol To date, well over 50 operations have most of the JIB patients had their proce- production by fermentation. been suggested and tried for the man- dure reversed with the concurrent estab- The Scopinaro procedure was subse- agement of morbid obesity (9) (Table 1). lishment of another bariatric operation. quently transformed into the DS, first One might therefore conclude that the In 1966, Mason and Ito (12) introduced by Marceau et al. (20) of Canada, who most suitable or ideal operation has, as the gastric bypass. Their operation con- performed a vertical sleeve yet, not been conceived. This is true, as it sisted of a horizontal gastric division with cross-stapling of the duodenum is true in any area of surgery and certainly with a loop gastrojejunostomy. Alden and an ;100-cm common channel. Duo- in medicine in the prescription of drugs. (13) modified the Mason procedure by denal cross-staplingis, however,unstable, More importantly, it illustrates the vigor cross-stapling the upper and causing negation of the operative effect. and imagination of the proponents of draining the upper pouch by a loop Hess and Hess (21), in the U.S., conceived bariatric surgery. In the chronology of op- gastrojejunostomy. Within 1 year, Griffen the modern BPD/DS or DS, by dividing erative procedures, there are six histori- et al. (14) reported the first bypass with the duodenum and constructing a prox- cally dominant operations that have been a Roux-en-Y gastrojejunostomy, which imal duodenoileostomy (Fig. 5). successful in causing marked weight became the standard RYGB (Fig. 2). As The BPD and the BPD/DS are difficult, loss and that have had a major ef- cited (15), Pories and coworkers at the time-consuming operations that can tax fect on the field. Listed in chronologi- University of East Carolina should also the skill of many surgeons. They are also cal order of their introduction they are be credited for independently introduc- associated with long-term protein and jejunoileal bypass (JIB), Roux-en-Y gastric ing the Roux-en-Y drainage for the RYGB. other nutritional deficiencies and possi- bypass (RYGB), vertical banded gastro- The RYGB became the most widely ble . The surgeon and patient plasty (VBG), biliopancreatic diversion performed bariatric procedure worldwide committed to these procedures must, (BPD) or (DS), adjust- and has retained a position of prominence therefore, also be committed to metic- able gastric banding (AGB), and sleeve for more than 50 years. The complica- ulous lifelong follow-up. The salient ad- gastrectomy (SG). In addition, three oper- tion rate with the RYGB is low, patient vantages of these procedures are the ative innovations warrant mention: gas- satisfaction is high, and the weight-loss most marked and lasting weight loss tric stimulation, vagal blockade, and, most failure rate, although progressive over and the highest percentage of resolu- importantly, banded RYGB. time, is minimal to moderate. tion of obesity comorbidities of any of The first bariatric nonresectional sur- Mason was always eager to simplify the bariatric operations (22,23). gery procedure was performed in 1953 bariatric procedures and minimize their The simplest weight-loss operation by Richard L. Varco at the University of side effects and complications. He has, that has been routinely performed is Minnesota. It consisted of bypass of therefore, favored restrictive, rather than AGB, introduced by Kuzmak (24). The care.diabetesjournals.org Buchwald and Buchwald 333

Table 1—Operations developed for the management of obesity JIB-related procedures RYGB-related procedures VBG-related procedures 1953: R.L. Varco (unpublished observations)d 1966: Mason and Ito (12)dhorizontal gastric 1973: Printen and Mason (16)dpartial end-to-end jejunoileostomy division with loop gastrojejunostomy horizontal gastric division with greater 1954: Kremen et al. (11)dend-to-end 1977: Alden (13)dhorizontal gastric cross- curvature conduit jejunoileostomy with ileocecostomy stapling with loop gastrojejunostomy 1979: Gomezdpartial horizontal gastric 1963: Payne and DeWinddend-to-side jejuno 1977: Griffen et al. (14)dhorizontal gastric stapling with suture reinforcement of (transverse colon) cross-stapling with Roux-en-Y gastric outlet 1965: Sherman et al.dend-to-side gastrojejunostomy 1979: Pace et al.dstapled gastric jejunoileostomy 1983: Torres et al.dvertical gastric cross- partitioning 1966: Lewis et al.dend-to-side jejunocecostomy stapling with Roux-en-Y gastrojejunostomy 1979: LaFave and Aldendtotal gastric d 1969: Payne and DeWindd14 in 3 4in 1986: Linner and Drew reinforced cross-stapling and gastrogastrostomy end-to-side jejunoileostomy gastrojejunostomy with fascial band 1981: Fabitodvertical gastric stapling with d 1971: Scott et al.dend-to-end jejunoileostomy 1987: Torres and Oca long-limb RYGB suture reinforcement of outlet 1988: Salmondcombined RYGB and VBG with ileo (transverse colon or sigmoid colon) 1981: Laws and Piatadosi (17)dvertical d colostomy 1989: Fobi et al. (33) Silastic ring VBG proximal gastric stapling, Silastic ring outlet d 1971: Salmon end-to-end jejunoileostomy with to RYGB restrictor 1994: Wittgrove et al.dfirst laparoscopic RYGB ileo (transverse colon) colostomy 1982: Mason (18)dvertical gastric d with end-to-end endoscopic stapling 1971: Buchwald and Varco 40 cm and 4 cm end- stapling, Marlex mesh band through to-end jejunoileostomy with ileocecostomy 1999: de la Torre and Scottdall intra- a gastric window outlet restrictor 1977: Forestieri et al.dend-to-side abdominal laparoscopic stapling 1983: Molina and Oriadgastric jejunoileostomy with proximal jejunal valve 1999: Higa et al.dhand-sewn laparoscopic segmentation construction gastrojejunostomy d 1978: Starkloff et al.dend-to-side 1986: Eckhout et al. vertical gastric AGB-related procedures jejunoileostomy with proximal jejunal valve stapling using a notched stapler, Silastic construction 1978: Wilkinson et al.dnonadjustable gastric ring outlet restrictor dfi 1980: Palmer and Marlissdend-to-side band 1994: Hess and Hess (21) rst jejunoileostomy with proximal jejunal valve 1983: Molina and Oriadnonadjustable gastric laparoscopic VBG construction band SG-related procedures 1988: Cleator and Gourlaydileogastrostomy to 1985: Bashour and Hilldgastro-clip drain bypassed intestine 1986: Kuzmak (24)dAGB 1976: Tretbar et al.dfundoplication 1989: Dorton and Kraldduodenoileal bypass 1993: Broadbent et al.dnonadjustable gastric 1980: Wilkinsondgastric wrapping with band laparoscopically mesh BPD/DS-related procedures 1993: Catona et al.dnonadjustable gastric 2003: Regan et al. (26)dfree-standing SG band laparoscopically as outgrowth of two-stage DS 1979: Scopinaro et al. (19)dsubtotal 1993: Belachew et al.dAGB laparoscopically 2007: Talebpour and Amolidfirst greater horizontal gastrectomy, 250 cm Roux d 1993: Forsell et al. AGB laparoscopically curvation gastric plication gastrojejunostomy, 50 cm common channel 1999: Cardiere et al.dAGB robotically 2017: Dolezalova-Kormanovaˇ et al.d 1993: Marceau et al. (20)dSG, pylorus greater curvature gastric plication preservation, cross-stapling of duodenum, duodenoileostomy, ;100 cm common channel 1994: Hess and Hess (21)dSG, pylorus preservation, duodenoileostomy, ∼100 cm common channel

Other innovative procedures 1974: Quaade et al.dhypothalamic stimulation and ablation 1996: Cigaina et al.dpaced gastric electrode stimulation 1999: Masondileal transposition 2008: Camilleri et al.dpaced vagal nerve blockade 2008: Rodriguez-Grunert et al.dduodenojejunal exclusion 2008: Rodriguez-Grunertdendoluminal sleeve Boldface type denotes historical landmark contributions.

peak of worldwide prominence in the use perforation, as well as by failure to main- by Gagner et al. (27) as the first stage in of this procedure can be credited to Paul tain weight loss. a laparoscopic DS. Gagner et al. soon E. O’Brien of Australia (25). In most other The last of the six dominant bariatric recognized that for some patients, the hands, the AGB proved to be unsuccess- procedures is the free-standing SG (Fig. 6). free-standing SG might achieve the weight- ful in the long term, plagued by compli- Theprocedurewasfirst advocated by loss objective without further surgery. cations such as band slippage and gastric Regan et al. (26) in 2005 and popularized The attraction of this procedure is that 334 Metabolic Surgery and Diabetes Diabetes Care Volume 42, February 2019

of many current practitioners. Further, the hypertension, hyperlipidemia, etc., the SG has not been evaluated for mainte- field has come to recognize that bariatric nance of weight loss for a prolonged period surgery is a set of procedures within the of time. A possibly safer alternative to SG broader purview of metabolic surgery. being explored by Dolezalova-Kormanovaˇ Indeed, weight loss, the original and primary et al. (29), of the Czech Republic, is gastric goal of bariatric surgery, is, in itself, met- plication, which avoids any gastric resection. abolic in principle and in its mechanisms. Of the three recent innovations, as Based on their gross anatomical alter- yet unproven over the long term, the ations, it has been uniform practice to most intriguing is electrode stimulation describe bariatric procedures as being of the stomach, which appears to be restrictive or malabsorptive. However, capable of inducing some weight loss all restrictive procedures are actually as well as other metabolic outcomes. malabsorptive, and all malabsorptive This approach, although not new (30), is procedures are restrictive, making that in its intellectual infancy and has not distinction quite meaningless. The so- found clinical applicability. Advocates called restrictive operations (e.g., AGB, have no solid knowledge of the number SG) cause caloric malabsorption. The of electrodes to use, the location(s) in so-called malabsorptive operations (e.g., which these electrodes should be im- BPD/DS) limit the intestinal absorptive planted, and the frequency and ampli- surface, which, in turn, results in caloric tude of the current to be applied. The malabsorption. Thus, to understand the most extensive work in efficacy assess- true mechanisms and effects of the ment of this technique has been done metabolic/bariatric procedures, we must by Lebovitz et al. (31). The converse to analyze the complex metabolic effects electrode stimulation is electrode block- they induce. age of neural transmission, best exem- The intestinal tract is rich in parasym- plified by vagal blockade (32). The pathetic and sympathetic innervation. Figure 2—RYGB (reprinted with permission success rate for this modality has been Only ;10% of vagal nerve fibers, how- from the author and Elsevier Inc. H. Buchwald, limited, however. Most studied and suc- ever, are efferent; 90% are afferent Chapter 24. Buchwald’s Atlas of Metabolic & Bariatric Surgical Techniques and Procedures. cessful of these innovative procedures and carry messages from the gut to the Elsevier, New York, 2012, p. 351). is the combination of an RYGB and a brain, in particular, to the hypothalamus. VBG advocated by Fobi et al. (33), the The sympathetic nerve supply to the gut so-called banded RYGB (Fig. 7). The out- is primarily mediated via the celiac axis comes for this operation have seen fa- and is intimately involved in the func- it can be performed rapidly and requires vorable assessment in a systemic review tion of glucose production and release. no bowel anastomosis. By 2017, the SG and meta-analysis (34). In addition to these communicating net- had become the most frequently used Mention should be made of endoscop- works to and from cerebral centers, there bariatric procedure in the world (28). ically inserted gastric balloons, which is a dense intrinsic nerve syncytium in Unfortunately, there is a high incidence work as gastric bezoars to decrease ap- the submucosal layer of the intestine of staple-line leak, at least in the hands petite and induce satiety. These devices extending from the to the have not found acceptance as bariatric anus. Finally, a fundic gastric pacemaker procedures per se but can be useful for regulates gastric wave contractions and preoperative weight-loss preparation and synchronization of gastric function. remedial postbariatric surgery interven- These neural networks surely must be tion for weight regain or maintenance. involved in eating behavior, food selec- tion, and nutrient metabolism. By dividing, METABOLIC/BARIATRIC SURGERY excising, transposing, or stimulating, ev- MECHANISMS ery one of our metabolic/bariatric opera- The discipline of bariatric surgery has tions influences these, and very likely declared metabolic surgery to be an additional, regulating mechanisms. integral part of its scope, in particular The literature is saturated with, al- in the management of type 2 diabetes. though not clear about, the role of This recognition is appropriate but not hormones on the eating/satiety process accurate; it reverses the phylogenetic as well as on type 2 diabetes. There Figure 3—VBG (reprinted with permission order. Bariatric surgery has, and always are ;100 gut hormones, among which from the author and Elsevier Inc. H. Buchwald, will be, a species of the larger taxonomic glucagon-like peptide 1 (GLP-1), peptide Chapter 9. Buchwald’s Atlas of Metabolic & phylum of metabolic surgery. When YY (PYY), gastric inhibitory polypeptide Bariatric Surgical Techniques and Procedures. Elsevier, New York, 2011, p. 179). speaking of the advantageous meta- (GIP), and ghrelin have received the bolic consequences of bariatric surgery greatest attention, as has the adipocyte in the management of type 2 diabetes, and gut-derived hormone leptin. This care.diabetesjournals.org Buchwald and Buchwald 335

corrective effects of metabolic/bariatric In 1997, MacDonald et al. (38) followed- surgery. In turn, they interact with the up on their 1995 publication with a report neural mechanisms to form the gut neuro- of 232 morbidly obese patients with type 2 cerebral network. In time, the equations diabetes, 154 who had undergone RYGB that govern these elusive relationships and 28 who served as control subjects. will be ascertained and, thereby, offer The type 2 diabetes was mitigated in the medical science the ability to intervene in operated-on patients and progressed in a rational manner to mitigate pathology. the control subjects. Most startlingly, the acids have recently been cited mortality rate in the control subjects was to have, in addition to their digestive 31.8% (6.2 years of follow-up) compared functions, a role in metabolism and met- with 9% in the surgery group (9 years of abolic diseases, in particular obesity and follow-up), a reduction in annual mortality type 2 diabetes. Our metabolic/bariatric from 4.5% to 1%. operations interrupt the normal entero- By 2003, confirmatory papers of type hepatic bile acids cycles and, thereby, 2 diabetes resolution after bariatric sur- alter their particular oxidative biochem- gery had become common, among which ical structure. Hypotheses of causative were, notably, the papers of Sugerman mechanisms have also implicated the et al. (39), Polyzogopoulou et al. (40), and relationship of the human intestinal bac- Schauer et al. (41). The Schauer publi- Figure 4—BPD (reprinted with permission terial microbiome in obesity and type 2 cation reviewed the results of RYGB in from the author and Elsevier Inc. H. Buchwald, diabetes regulatory mechanisms. 240 patients with impaired fasting glu- Chapter 3. Buchwald’s Atlas of Metabolic & cose or with clinical type 2 diabetes. Bariatric Surgical Techniques and Procedures. METABOLIC BARIATRIC SURGERY Fasting blood glucose and glycosylated Elsevier, New York, 2011, p. 41). AND DIABETES hemoglobin concentrations returned to There were two cardinal literature re- normal levels (83%) or markedly im- ports by metabolic bariatric surgery pio- proved (17%), and an 80% resolution hormonal mosaic is integral to the mech- neers that focused the attention of the in the use of oral antidiabetes agents fi fi anisms that govern the origins of obe- eld on the bene ts of bariatric surgery and a 79% reduction in the need for sity and its metabolic comorbidities as in the management of type 2 diabetes. insulin therapy were demonstrated. Pa- well as to the modulating and often In 1995, Pories et al. (35) published a pa- tients with a preoperative duration of di- per with the intriguing title, “Who Would abetes of fewer than 5 years and those Have Thought It? An Operation Proves with the mildest form of the disease To Be the Most Effective Therapy for (diet controlled) and the greatest weight Adult-Onset Diabetes Mellitus.” They loss were most likely to achieve total demonstrated that blood glucose levels resolution of type 2 diabetes. normalized and the need for insulin There were several trials of medical therapy markedly diminished within versus surgical management. Serrot 24 h of an RYGB. Obviously, this outcome et al. (42) demonstrated that RYGB can occurred too rapidly to have been due to be performed in patients with type 2 weight loss and had to be the product diabetes with a BMI ,35 kg/m2 (n = 17) of a neurohormonal mechanism. In 1998, with better weight loss, glycemic con- Scopinaro et al. (36) published a series trol, and fewer hyperglycemic medications describing patients with type 2 diabetes compared with patients (n = 17) receiv- that dated back to 1984, wherein 100% ing standard medical therapy. Mingrone exhibited normalization of their fasting et al. (43) explored the other weight ex- blood glucose levels after BPD. A con- treme in a study of 60 severely obese pa- current report by Cowan and Buffington tients (BMI .35 kg/m2) who underwent (37) in 1998 also called attention to the RYGB or BPD or conventional medical lowering of fasting blood glucose levels therapy. At 2 years, diabetes remission after RYGB. had not occurred in any of the patients These papers initiated a confirmatory in the medical therapy group but was clinical cascade of case series and trial manifest in 75% of RYGB and 95% of reports. A PubMed search indicates that BPD patients. In patients with a BMI of 2 from 2000 to the present, 4,342 papers 30–42 kg/m and with an HbA1c $6.5%, Figure 5—DS (reprinted with permission have been referenced under bariatric Halperin et al. (44) compared the out- from the author and Elsevier Inc. H. Buchwald, surgery and diabetes, 2,219 for diabe- comes of RYGB (n = 19) versus intensive Chapter 4. Buchwald’s Atlas of Metabolic & tes plus RYGB, and for diabetes plus medical therapy (n = 19). RYGB produced Bariatric Surgical Techniques and Procedures. Elsevier, New York, 2011, p. 91). other bariatric procedures: SG, 804; greater weight loss and sustained im- BPD, 288; DS, 122; AGB, 145; and vagal provements in HbA1c and in cardiometa- blockade, 29. bolic risk factors within 1 year (P =0.03). 336 Metabolic Surgery and Diabetes Diabetes Care Volume 42, February 2019

bariatric surgery patients compared definitively demonstrated the bene- with 16.4% and 72.3%, respectively, at fits of weight loss and the reduction 2 years (45). The relapse effect after of comorbidities induced by metabolic/ bariatric surgery has also been noted bariatric surgery: mean excess weight by others. Arterburn et al. (46) showed loss of 64.4%, complete resolution of that approximately one-third of patients type 2 diabetes in 76.8% and its resolu- with type 2 diabetes remission after tion or improvement in 86.0%, hyperlip- bariatric surgery experienced a relapse idemia improvement in 70% of patients, within 5 years. In this regard, it needs to and normalization of blood pressure be emphasized that every year of sus- in 61.7%, with resolution or improve- tained remission is an affirmative out- ment in 85.7% of hypertensive patients. come and may well represent a year All outcomes were highly statistically gained before the onset of the morbid significant (P , 0.01). and mortal complications of this disease. In 2009, we published a follow-up There have also been attempts to meta-analysis focused exclusively on the demonstrate the benefits of combination effect of metabolic/bariatric surgery of, rather than competition between, on type 2 diabetes (23). The data set in surgical and medical patient manage- this study included 135,246 patients. Our ment. Ikramuddin et al. (47) reported findings revealed a mean weight loss of that in patients with mild to moderate 38.5 kg or 55.9% of excess body weight type 2 diabetes, the addition of RYGB to in association with 78.1% complete reso- established lifestyle and medical man- lution and 86.6% resolution or improve- Figure 6—SG (reprinted with permission agement resulted in 28 of 60 patients ment of type 2 diabetes (P , 0.001). The from the author and Elsevier Inc. H. Buchwald, ’ (49%) with an RYGB compared with 11 effect on type 2 diabetes was a function Chapter 10. Buchwald s Atlas of Metabolic & . Bariatric Surgical Techniques and Procedures. of 60 patients (19%) without an RYGB of the weight loss achieved: BPD/DS Elsevier, New York, 2011, p. 219). achieving the American Heart Asso- RYGB . VBG . AGB. Further, insulin ciation triple end point of HbA1c ,7.0%, levels declined significantly postopera- LDL cholesterol ,100 mg/dL, and systolic tively, as did the HbA1c and the fasting blood pressure ,130 mmHg (P , blood glucose levels. The weight-loss ef- One of the most quoted prospective 0.05). Schauer et al. (48) published sim- fects were not diminished after 2 years studies in this field has been the Swedish ilar results in 150 patients randomized of follow-up. Obese Subjects (SOS) study, which re- to intensive medical therapy versus in- Encouraged by the demonstration that ported in 2014 that in 260 control pa- tensive medical therapy plus RYGB or SG metabolic/bariatric surgery in the obese tients and 343 bariatric surgery patients (P , 0.01). Even the operation with the resolves type 2 diabetes and that the with type 2 diabetes at 15 years, the least proven postoperative weight loss, likelihood that mechanisms other than diabetes remission rate was 6.5% in the AGB, when added to intensive med- weight loss were responsible for this the control patients and 30.4% in the ical therapy was shown by Dixon et al. benefit, metabolic/bariatric surgeons (49) to improve diabetes outcomes. were stimulated to explore the use of Courcoulas et al. (50) randomized 61 metabolic/bariatric surgery procedures patients to intensive lifestyle manage- for treatment of type 2 diabetes in over- ment or less intensive lifestyle manage- weight and essentially normal-weight ment with the addition of an RYGB or patients. In 2011, Scopinaro et al. (52) AGB and again found more favorable di- published another landmark paper dem- abetes outcomes and disease remission onstrating that the BPD resolved type 2 in the operative groups (P = 0.003). The diabetes in patients with a BMI of 25– recently completed STAMPEDE (Surgical 35 kg/m2 without engendering deleteri- Treatment and Medications Potentially ous weight loss. Because BPD causes the Eradicate Diabetes Efficiently) trial was most weight loss of the metabolic/ highly definitive in demonstrating that bariatric operations, this finding corrob- metabolic bariatric surgery plus medical orated the weight set-point hypothesis therapy was far more efficacious in low- and the metabolic basis for the outcomes ering the HbA1c in patients with type 2 of metabolic/bariatric surgery. Confir- diabetes at 5 years than intensive med- matory but cautious reports of type 2 ical therapy alone (51). diabetes resolution after metabolic/ Figure 7—Banded RYGB (reprinted with per- At the top of the evidence-based pyr- bariatric surgery in patients with a rel- mission from the author and Elsevier Inc. amid of data reliability is meta-analysis. atively low BMI followed (e.g., 53–55). H. Buchwald, Chapter 5. Buchwald’s Atlas of We published the first bariatric meta- Skepticism was essentially eliminated by Metabolic & Bariatric Surgical Techniques and Procedures. Elsevier, New York, 2011, analysis in 2004 (22). This study encom- the 2016 Cummings and Cohen (56) re- p. 113). passed 22,094 patients and included port to the second Diabetes Surgery five randomized controlled trials. It Summit. They proffered a meta-analysis care.diabetesjournals.org Buchwald and Buchwald 337

of the 11 randomized controlled trials the intestinal microbiota (66). In a review of A recent interesting proposal has been providing class 1A evidence, as well as responsible mechanisms, Batterham and endoscopic hydrothermal duodenal mu- the meta-analysis of high-quality nonran- Cummings (67) stress that a constellation cosa ablation with secondary mucosal domized prospective studies, demon- of factors, rather than a single overarch- regeneration (80,81). The authors of this strating that benefits of metabolic/ ing mechanism, with these factors vary- procedure have shown promising results bariatric surgery for type 2 diabetes re- ing by surgical procedure, is responsible up to 6 months with a 1.8% reduction in mission, glycemic control, and HbA1c for the observed reduced glucose pro- the HbA1c. lowering were equally true for patients duction, increased tissue glucose up- Turning to the opposing hindgut hypoth- with a baseline BMI below or above take, improved insulin sensitivity, and esis, several investigators have focused 35 kg/m2. enhanced b-cell function. In a recent on the ileum in their attempt to treat The overwhelming import of these report, Sista et al. (68) postulated that type 2 diabetes with no or minimal weight data were responsible for prompting a SG affects glucose homeostasis by two se- loss. This orientation is based on the knowl- joint statement by several international quential mechanisms: initially hormonal edge that the ileum is a primary site for diabetes organizations composed of sur- and subsequently weight loss itself. the elaboration of GLP-1 and PYY in re- geons and nonsurgeons advocating that sponse to an intraluminal stimulus. These NONBARIATRIC METABOLIC b metabolic surgery be included in the treat- incretin hormones increase -cell mass, SURGERY FOR DIABETES ment algorithm for type 2 diabetes (57). stimulate glucose-independent insulin The revelation that metabolic/bariatric With the knowledge that the type 2 secretion, and inhibit glucagon release. surgery can cause resolution of type 2 diabetes resolution effect of gut surgery Some believe that moving a segment of diabetes markedly increased the impetus is partly independent of weight loss, ileum higher in the intestinal tract will surgeons started to explore the possi- promote type 2 diabetes resolution and to elucidate the metabolic mechanisms bility of an operation dedicated to treat- that ileal transposition should therefore responsible not only for postoperative ing type 2 diabetes with minimal or no be added to a standard or diverted (du- weight loss but also for the seemingly weight lossdtrue diabetes surgery. odenal exclusion) independent resolution of type 2 diabe- Many such operations have been per- (82,83). tes. As early as 1998, Hickey et al. (58) formed: some have failed, some have Considering the focus on the terminal wrote, partially succeeded, and some may come ileum and its incretin hormones, we Weight loss is not the reason why GB to be successful. measured GLP-1, PYY, and leptin blood [gastric bypass] controls diabetes mellitus. Because visceral adiposity is a risk levels after stimulation of the terminal Instead, bypassing the foregut and reduc- factor for the metabolic complications ileum or cecum by a static infusion of a ing food intake produce the profound long- associated with obesity, omentectomy food hydrolysate in markedly obese pa- term alterations in glucose metabolism and was an early proposed surgical inter- tients undergoing a DS procedure (84). fi insulin action. These ndings suggest that vention to influence type 2 diabetes. We found elevations of GLP-1 and PYY our current paradigms of type 2 diabetes Study reports of omentectomy alone, or with a decrease in leptin levels peaking mellitus deserve review. The critical lesion in addition to a standard bariatric oper- at 90–120 min by both ileal and cecal may lie in abnormal signals from the gut. ation, varied as to no benefit (69,70), stimulation. We concluded that the Pories and Albrecht (59) expanded this possible benefit (71,72), and demonstra- transposition of the ileum higher in concept in 2001 by stating that the rapid ble benefit (73,74). the intestinal tract, with the 2-h delay correction to euglycemia after RYGB “is The electrode stimulation operations, in the peak hormonal response, would not the loss of weight (i.e., reduction which have not been highly successful not enhance its immediate response to in fat mass) but, rather, the result of for weight loss, appeared to cause im- a food stimulus. Next, we reversed the the exclusion of food and a secondary provement in diabetic parameters. Such conceptof ileal enhancement byperform- alteration in incretin signals from the an- reports have been made for the Entro- ing a partial ileal bypass or ileal excision trum, duodenum, and proximal Medics VBLOC device (75). In addition, in Goto-Kakizaki rats, thereby limiting to the islets.” Rubino and Marescaux Khawaled et al. (76) have shown, albeit the ileal mucosal exposure to intestinal (60) provided confirmatory evidence in in rats, that duodenal electrode stimu- flow; we found a five- to sixfold increase an interesting Goto-Kakizaki rat exper- lation will normalize diabetic blood glu- (not a decrease) in plasma GLP-1 (85). iment wherein duodenal exclusion sig- cose levels. In a subsequent retrospective analysis nificantly improved glucose tolerance The foregut hypothesis, popularized of the POSCH study data, we found that and the restoration of the duodenal pas- by Rubino et al. (77), is based on the the diet control group had a 2.7-fold sage reestablished impaired glucose assumption that the hormone GIP is in- higher incidence of type 2 diabetes com- tolerance. tegral to the etiology of type 2 diabetes pared with the partial ileal bypass inter- Thought soon turned to the role of and that type 2 diabetes can be resolved vention group during 35 years of follow-up gastrointestinal hormones (61), in par- by neutralizing the duodenum, the pri- (86). We have currently initiated a clinical ticular the postprandial release of in- mary site of GIP secretion. This concept is trial to ascertain the effect of the essentially cretin hormones and the recovery of the basis for the proposed duodenal- nonweight loss–inducing, cholesterol- the incretin effect on insulin secretion jejunal bypass, which has demonstrated lowering partial ileal bypass operation (62,63), improvement in insulin sensitiv- reductions in fasting blood glucose and on established type 2 diabetes. ity and b-cell function (HOMA) (64), as HbA1c without significant weight loss Interestingly, several extragastric/ well as the function of bile acids (65) and (78,79). intestinal procedures qualify as metabolic 338 Metabolic Surgery and Diabetes Diabetes Care Volume 42, February 2019

surgery to alleviate type 2 diabetes. Pan- and prophylactic low-grade antico- mechanisms is dependent on our per- creas transplantation (87) and islet cell agulation, mechanical precautions, and ceptivity of phenomena and the inter- transplantation (88) in patients with early ambulation are recommended. pretation of outcomes using simple type 2 diabetes have been shown to be The most effective procedures for investigative tools, which, for the most beneficial, as has insulin infusion by an weight and type 2 diabetes reduction, part, are noninvasive. Knowledge of eti- implantable pump (89,90). Most fasci- the BPD and the DS, necessitate skilled ology should lead to the formulation nating is the work of Mahfoud et al. (91), surgeons who regard gentleness in of evidence-based therapy. We accept who found that after arterial catheter the handling of tissues of greater im- the dictum that basic research is the perirenal neuroablation for the treat- portance than speed. BPD/DS patients, foundation for translational clinical ther- ment of hypertension in patients with more so than any other bariatric pa- apy and must also adopt the concept that type 2 diabetes, there was normalization tients, require a lifetime of follow-up empiric clinical therapy can lead to basic of the fasting blood glucose, fasting in- and are prone to nutritional, mineral, and scientifictruths. sulin levels, C-peptide, and insulin re- vitamin deficiencies. In so far as the SG Metabolic bariatric surgeons, in and sistance (HOMA), all indicative of type 2 portion of the DS is concerned, caution is out of academic institutions, have warmed, diabetes resolution. required in patients with gastroesoph- or are warming to the concept that ageal reflux disease (GERD). they are not only technicians and clini- PERSPECTIVE The RYGB, however, essentially cures cians but that they also have a role Metabolic surgery for type 2 diabetes is GERD and is recommended for individ- as researchers in the emerging field of a work in progress. We have yet to learn uals with this affliction. It is the procedure ascertaining knowledge of the neuro- the precise nature of the mechanisms of with the longest history of patient and hormonal mechanisms of metabolic dis- action the metabolic perturbations our surgeon acceptance. RYGB was the first eases subject to metabolic surgery. In surgical interventions elicit and, indeed, procedure definitively to demonstrate this endeavor, progress will be hastened their implications regarding the disease resolution of type 2 diabetes before if diabetologists, endocrinologists, inter- process of type 2 diabetes itself. We any weight loss is achieved. nists, cardiologists, and basic scientists cannot operate on the one-third of the The SG, in the hands of current practi- join surgeons in this quest. Together, U.S. population who are obese, the more tioners, has a high leak rate in the upper wemaybeabletoeradicatetype2 than ;30 million people with type 2 di- retained stomach. This is unacceptable diabetes. abetes, or the fraction with both. We can and should be remedied by reinforcing only take on a limited percentage of the the resection staple line. The SG is the needy.Wecan,however, learn from these most commonly performed operation in Duality of Interest. No potential conflicts of patients lessons for the benefitofthe the world today and mitigates type 2 interest relevant to this article were reported. majority. diabetes with corresponding favorable Author Contributions. H.B. and J.N.B. re- searched the data in the literature. H.B. provided The three currently popular meta- changes in the incretin hormones. In insights from 50 years’ experience in metabolic bolic/bariatric procedures elicit resolu- association with its rapidly increasing bariatric surgery. H.B. and J.N.B. wrote and tion or remission of type 2 diabetes in the popularity, there is accumulating evi- edited the manuscript. same rank order that they demonstrate dence that the SG can accentuate ex- weight loss, namely, BPD/DS . RYGB . isting, or cause de novo, GERD. References SG. The recurrence rate of type 2 diabe- The multitude of procedures for curing 1. Buchwald H, Varco RL. Metabolic Surgery. New York, Grune & Stratton, 1978 tes is reciprocally progressive with an type 2 diabetes under current trial, and 2. Boyd S. On oophorectomy¨ in the treatment average of 2–6% per year; we have no those newly proposed in the process of of cancer. BMJ 1897;2:890–896 knowledge of when the nadir is reached. translational research, cannot be criti- 3. Buchwald H. Lowering of cholesterol absorp- Overall operative mortality for bariat- cally assessed at this time. They all have tion and blood levels by ileal exclusion. Exper- ric surgery today is ;0.1%, equivalent to in common the goal of mitigating the imental basis and preliminary report. Circulation 1964;29:713–720 that of a routine laparoscopic cholecys- neurohormonal network gone wrong in 4. Buchwald H, Moore RB, Lee GB, et al. Five tectomy. If a reoperation becomes nec- the promulgation of type 2 diabetes by years experience with the use of partial ileal essary for a failed procedure, the safety stimulating an affirmative therapeutic bypass in the treatment of hypercholesterole- risk is, of course, cumulative, a fact that metabolic response. mia and atherosclerosis. Isr J Med Sci 1969;5: – is often not stated in describing the 760 765 ; THE FUTURE 5. Buchwald H, Varco RL, Matts JP, et al. Effect SG with a reoperation rate of 50%. If of partial ileal bypass surgery on mortality and bowel is opened during the procedure, We have available to us a human labo- morbidity from coronary heart disease in patients the minimal wound infection rate is in- ratory with hundreds of thousands withhypercholesterolemia.ReportoftheProgram creased. If the size of the stomach is of subjects who have had their type 2 on the Surgical Control of the Hyperlipidemias – markedly reduced, 30-day postoperative diabetes ameliorated, possibly even (POSCH). N Engl J Med 1990;323:946 955 6. Buchwald H, Matts JP, Fitch LL, et al. Changes nausea, vomiting, and dehydration ad- cured, by metabolic/bariatric surgery. in sequential coronary arteriograms and sub- verse side effects are more common. If These individuals, our patients, hold sequent coronary events. Surgical Control of the the small intestine is cut, anastomosed, the secret of the etiology of type 2 Hyperlipidemias (POSCH) Group. JAMA 1992; and translocated, the long-term risk of diabetes, its relationship to obesity, 268:1429–1433 7. Buchwald H, Campos C, Varco RL, et al. an internal is increased. Deep and the neurohormonal response we Effective modification by partial ileal bypass vein thrombophlebitis and pulmonary elicit by our surgical procedures. Our reduced long-term coronary heart disease mor- emboli occurrences are unpredictable, success in the elucidation of causative tality and morbidity: five-year posttrial follow-up care.diabetesjournals.org Buchwald and Buchwald 339

report from the POSCH. Program on the Surgical 28. Angrisani L, Santonicola A, Iovino A, et al arandomizedclinicaltrial. JAMA Surg 2014; Control of the Hyperlipidemias. Arch Intern Med Bariatric surgery and endoluminal procedures: 149:716–726 1998;158:1253–1261 IFSO worldwide survey 2014. Obes Surg 2017; 45. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. 8. Buchwald H, Rudser KD, Williams SE, Michalek 27:2279–2289 Association of bariatric surgery with long-term VN, Vagasky J, Connett JE. Overall mortality, 29. Dolezalova-Kormanovaˇ K, Buchwald JN, remission of type 2 diabetes and with microvas- incremental life expectancy, and cause of death Skochova D, Pichlerova D, McGlennon TW, Fried cular and macrovascular complications. JAMA at 25 years in the Program on the Surgical Con- M. Five-year outcomes: laparoscopic greater cur- 2014;311:2297–2304 trol of the Hyperlipidemias. Ann Surg 2010;251: vature plication for treatment of morbid obesity. 46. Arterburn DE, Bogart A, Sherwood NE, et al. 1034–1040 Obes Surg 2017;27:2818–2828 A multisite study of long-term remission and 9. Buchwald H. The evolution of metabolic/ 30. Cigaina V. Gastric pacing as therapy for relapse of type 2 diabetes mellitus following bariatric surgery. Obes Surg 2014;24:1126–1135 morbid obesity: preliminary results. Obes Surg gastric bypass. Obes Surg 2013;23:93–102 10. Buchwald H, Buchwald JN. Evolution of oper- 2002;12(Suppl. 1):12S–16S 47. Ikramuddin S, Korner J, Lee WJ, et al. Roux- ative procedures for the management of morbid 31. Lebovitz HE, Ludvik B, Kozakowski J, et al. en-Y gastric bypass vs intensive medical man- obesity 1950-2000. Obes Surg 2002;12:705–717 Gastric electrical stimulation treatment of type 2 agement for the control of type 2 diabetes, 11. Kremen AJ, Linner JH, Nelson CH. An exper- diabetes: effects of implantation versus meal- hypertension, and hyperlipidemia: the Diabetes imental evaluation of the nutritional importance mediated stimulation. A randomized blinded Surgery Study randomized clinical trial. JAMA of proximal and distal small intestine. Ann Surg cross-over trial. Physiol Rep 2015;3:e12456 2013;309:2240–2249 1954;140:439–448 32. Shikora SA, Wolfe BM, Apovian CM, et al. 48. Schauer PR, Bhatt DL, Kirwan JP, et al. 12. Mason EE, Ito C. Gastric bypass in obesity. Sustained weight loss with vagal nerve blockade Bariatric surgery versus intensive medical ther- Surg Clin North Am 1967;47:1345–1351 but not with sham: 18-month results of the apy for diabetesd3-year outcomes.N Engl J Med 13. Alden JF. Gastric and jejunoileal bypass. A ReCharge Trial. J Obes 2015;2015:365604 2014;370:2002–2013 comparison in the treatment of morbid obesity. 33. Fobi M, Lee H, Flemming A. The surgical 49. Dixon JB, O’Brien PE, Playfair J, et al. Adjust- Arch Surg 1977;112:799–806 technique of the banded R-Y gastric bypass. J able gastric banding and conventional therapy 14. Griffen WO Jr, Young VL, Stevenson CC. A Obes Wt Reduc 1989;8:99–102 for type 2 diabetes: a randomized controlled prospective comparison of gastric and jejunoileal 34. Buchwald H, Buchwald JN, McGlennon TW. trial. JAMA 2008;299:316–323 bypass procedures for morbid obesity. Ann Surg Systematic review and meta-analysis of medium- 50. Courcoulas AP, Belle SH, Neiberg RH, et al. 1977;186:500–509 term outcomes after banded Roux-en-Y gastric Three-year outcomes of bariatric surgery vs 15. Liscia G, Scaringi S, Facchiano E, Quartararo G, bypass. Obes Surg 2014;24:1536–1551 lifestyle intervention for type 2 diabetes melli- Lucchese M. The role of drainage after Roux-en-Y 35. Pories WJ, Swanson MS, MacDonald KG, tus treatment: a randomized clinical trial. JAMA gastric bypass for morbid obesity: a systematic et al. Who would have thought it? An opera- Surg 2015;150:931–940 review. Surg Obes Relat Dis 2014;10:171–176 tion proves to be the most effective therapy for 51. Schauer PR, Bhatt DL, Kirwan JP, et al.; 16. Printen KJ,MasonEE. Gastric surgery for relief adult-onset diabetes mellitus. Ann Surg 1995; STAMPEDE Investigators. Bariatric surgery versus of morbid obesity. Arch Surg 1973;106:428–431 222:339–350; discussion 350–352 intensive medical therapy for diabetesd5-year 17. Laws HL, Piantadosi S. Superior gastric re- 36. Scopinaro N, Adami GF, Marinari GM, et al. outcomes. N Engl J Med 2017;376:641–651 duction procedure for morbid obesity: a prospec- Biliopancreatic diversion. World J Surg 1998;22: 52. Scopinaro N, Adami GF, Papadia FS, et al. tive, randomized trial. Ann Surg 1981;193:334–340 936–946 Effects of biliopancreatic diversion on type 2 18. Mason EE. Vertical banded gastroplasty 37. Cowan GS Jr., Buffington CK. Significant diabetes in patients with BMI 25 to 35. Ann Surg for obesity. Arch Surg 1982;117:701–706 changes in blood pressure, glucose, and 2011;253:699–703 19. Scopinaro N, Gianetta E, Civalleri D, Bonalumi with . World J Surg 1998; 53. Reis CE, Alvarez-Leite JI, Bressan J, Alfenas U, Bachi V. Bilio-pancreatic bypass for obesity: 22:987–992 RC. Role of bariatric-metabolic surgery in the II. Initial experience in man. Br J Surg 1979;66: 38. MacDonald KG Jr., Long SD, Swanson MS, treatment of obese type 2 diabetes with body 618–620 et al. The gastric bypass operation reduces the mass index ,35 kg/m2: a literature review. 20. Marceau P, Biron S, Bourque R-A, Potvin M, progression and mortality of non-insulin-depen- Diabetes Technol Ther 2012;14:365–372 Hould FS, Simard S. Biliopancreatic diversion with a dent diabetes mellitus. J Gastrointest Surg 1997; 54. Maggard-Gibbons M, Maglione M, Livhits new type of gastrectomy. Obes Surg 1993;3:29–35 1:213–220; discussion 220 M, et al. Bariatric surgery for weight loss and 21. Hess DW, Hess DS. Laparoscopic vertical 39. Sugerman HJ, Wolfe LG, Sica DA, Clore JN. glycemic control in nonmorbidly obese adults banded gastroplasty with complete transection Diabetes and hypertension in severe obesity and with diabetes: a systematic review. JAMA 2013; of the staple-line. Obes Surg 1994;4:44–46 effects of gastric bypass-induced weight loss. 309:2250–2261 22. Buchwald H, Avidor Y, Braunwald E, et al. Ann Surg 2003;237:751–756 55. Hsu CC, Almulaifi A, Chen JC, et al. Effect of Bariatric surgery: a systematic review and meta- 40. Polyzogopoulou EV, Kalfarentzos F, bariatric surgery vs medical treatment on type 2 analysis. JAMA 2004;292:1724–1737 Vagenakis AG, Alexandrides TK. Restoration of diabetes in patients with body mass index lower 23. Buchwald H, Estok R, Fahrbach K, et al. euglycemia and normal acute insulin response than 35: five-year outcomes. JAMA Surg 2015; Weight and type 2 diabetes after bariatric sur- to glucose in obese subjects with type 2 diabe- 150:1117–1124 gery: systematic review and meta-analysis. Am J tes following bariatric surgery. Diabetes 2003; 56. Cummings DE, Cohen RV. Bariatric/meta- Med 2009;122:248–256.e5 52:1098–1103 bolic surgery to treat type 2 diabetes in patients 24. Kuzmak LI. Silicone gastric banding: a sim- 41. Schauer PR, Burguera B, Ikramuddin S, et al. with a BMI ,35 kg/m2. Diabetes Care 2016;39: ple and effective operation for morbid obesity. Effect of laparoscopic Roux-en Y gastric bypass 924–933 Contemp Surg 1986;28:13–18 on type 2 diabetes mellitus. Ann Surg 2003;238: 57. Rubino F, Nathan DM, Eckel RH, et al.; 25. O’Brien PE, MacDonald L, Anderson M, 467–484; discussion 84–85 Delegates of the 2nd Diabetes Surgery Summit. Brennan L, Brown WA. Long-term outcomes 42. Serrot FJ, Dorman RB, Miller CJ, et al. Com- Metabolic surgery in the treatment algorithm after bariatric surgery: fifteen-year follow-up parative effectiveness of bariatric surgery and for type 2 diabetes: a joint statement by in- of adjustable gastric banding and a systematic nonsurgical therapy in adults with type 2 di- ternational diabetes organizations. Diabetes review of the bariatric surgical literature. Ann abetes mellitus and body mass index ,35 kg/m2. Care 2016;39:861–877 Surg 2013;257:87–94 Surgery 2011;150:684–691 58. HickeyMS,PoriesWJ,MacDonaldKGJr.,etal. 26. Regan JP, Inabnet WB, Gagner M, Pomp A. Early 43. Mingrone G, Panunzi S, De Gaetano A, et al. A new paradigm for type 2 diabetes mellitus: experience with two-stage laparoscopic Roux-en-Y Bariatric surgery versus conventional medical could it be a disease of the foregut? Ann Surg gastric bypass as an alternative in the super-super therapy for type 2 diabetes. N Engl J Med 2012; 1998;227:637–643; discussion 643–644 obese patient. Obes Surg 2003;13:861–864 366:1577–1585 59. Pories WJ, Albrecht RJ. Etiology of type II 27. Gagner M, DeitelM, KalbererTL, Erickson AL, 44. Halperin F, Ding SA, Simonson DC, et al. diabetes mellitus: role of the foregut. World J Crosby RD. The Second International Consensus Roux-en-Y gastric bypass surgery or lifestyle with Surg 2001;25:527–531 Summit for Sleeve Gastrectomy, March 19-21, intensive medical management in patients with 60. Rubino F, Marescaux J. Effect of duodenal- 2009. Surg Obes Relat Dis 2009;5:476–485 type 2 diabetes: feasibility and 1-year results of jejunal exclusion in a non-obese animal model of 340 Metabolic Surgery and Diabetes Diabetes Care Volume 42, February 2019

type 2 diabetes: a new perspective for an old diabetes remission at 1 month after Roux-en-Y resurfacing: role in the treatment of metabolic disease. Ann Surg 2004;239:1–11 gastric bypass surgery in patients randomized to disease. Gastrointest Endosc Clin N Am 2017; 61. Kellum JM, Kuemmerle JF, O’Dorisio TM, omentectomy. Diabetes Care 2012;35:137–142 27:299–311 et al. Gastrointestinal hormone responses to 72. Lima MM, Pareja JC, Alegre SM, et al. Vis- 82. Celik A, Pouwels S, Cagiltay E, Karaca FC, meals before and after gastric bypass and ver- ceral fat resection in humans: effect on insulin Buy¨ ukbozk¨ ırlı D. Time to glycemic control - an tical banded gastroplasty. Ann Surg 1990;211: sensitivity, beta-cell function, adipokines, and observational study of 3 different operations. 763–770; discussion 770–771 inflammatory markers. Obesity (Silver Spring) Obes Surg 2017;27:694–702 62. Vilsbøll T, Holst JJ. Incretins, insulin secretion 2013;21:E182–E189 83. Oh TJ, Ahn CH, Cho YM. Contribution of the and type 2 diabetes mellitus. Diabetologia 2004; 73. Milleo FQ, Campos AC, Santoro S, et al. distal small intestine to metabolic improvement 47:357–366 Metabolic effects of an entero-omentectomy after bariatric/metabolic surgery: lessons from 63. Laferrere` B, Heshka S, Wang K, et al. Incretin in mildly obese type 2 diabetes mellitus patients ileal transposition surgery. J Diabetes Investig levels and effect are markedly enhanced 1 month after three years. Clinics (São Paulo) 2011;66: 2016;7(Suppl. 1):94–101 after Roux-en-Y gastric bypass surgery in obese 1227–1233 84. Buchwald H, Dorman RB, Rasmus NF, patients with type 2 diabetes. Diabetes Care 74. Dillard TH, Purnell JQ, Smith MD, et al. Michalek VN, Landvik NM, Ikramuddin S. Effects 2007;30:1709–1716 Omentectomy added to Roux-en-Y gastric bypass on GLP-1, PYY, and leptin by direct stimulation of 64. Dixon JB, Dixon AF, O’Brien PE. Improve- surgery: a randomized, controlled trial. Surg terminal ileum and cecum in humans: implica- ments in insulin sensitivity and beta-cell func- Obes Relat Dis 2013;9:269–275 tions for ileal transposition. Surg Obes Relat Dis tion (HOMA) with weight loss in the severely 75. Herrera MF, Toouli J, Kulseng B, et al. Vagal 2014;10:780–786 obese. Homeostatic model assessment. Diabet nerve block for improvements in glycemic con- 85. Buchwald H, Menchaca HJ, Michalek VN, Med 2003;20:127–134 trol in obese patients with type 2 diabetes Bertin NT. Ileal effect on blood glucose, HbA1c, 65. Argyropoulos G. Bariatric surgery: preva- mellitus: three-year results of the VBLOC DM2 and GLP-1 in Goto-Kakizaki rats. Obes Surg 2014; lence, predictors, and mechanisms of diabetes study. J Diab Obes 2017;4:1–6 24:1954–1960 remission. Curr Diab Rep 2015;15:15 76. Khawaled R, Blumen G, Fabricant G, Ben-Arie 86. Buchwald H, Oien DM, Schieber DJ, Bantle 66. Aron-Wisnewsky J, Dore´ J, Clement K. The J, Shikora S. Intestinal electrical stimulation JP, Connett JE. Partial ileal bypass affords protec- importance of the gut microbiota after bariatric decreases postprandial blood glucose levels in tion from onset of type 2 diabetes. Surg Obes surgery. Nat Rev Gastroenterol Hepatol 2012;9: rats. Surg Obes Relat Dis 2009;5:692–697 Relat Dis 2017;13:45–51 590–598 77. Rubino F, Forgione A, Cummings DE, et al. 87. Orlando G, Stratta RJ, Light J. 67. Batterham RL, Cummings DE. Mechanisms The mechanism of diabetes control after gas- transplantation for type 2 diabetes mellitus. of diabetes improvement following bariatric/ trointestinal bypass surgery reveals a role of the Curr Opin Organ Transplant 2011;16:110–115 metabolic surgery. Diabetes Care 2016;39: proximal small intestine in the pathophysiology 88. Echeverri GJ. Type 2 diabetes mellitus: met- 893–901 of type 2 diabetes. Ann Surg 2006;244:741–749 abolic surgery and gastric submucosal islet trans- 68. Sista F, Abruzzese V, Clementi M, Guadagni 78. Lee HC, Kim MK, Kwon HS, Kim E, Song KH. plantation, is there a connection? Transplantation S, Montana L, Carandina S. Resolution of type 2 Early changes in incretin secretion after lapa- 2010;90:1036 diabetes after sleeve gastrectomy: a 2-step hy- roscopic duodenal-jejunal bypass surgery in 89. Buchwald H, Rohde TD, Dorman FD, et al. A pothesis. Surg Obes Relat Dis 2018;14:284–290 type 2 diabetic patients. Obes Surg 2010;20: totally implantable drug infusion device: labo- 69. Fabbrini E, Tamboli RA, Magkos F, et al. 1530–1535 ratory and clinical experience using a model Surgical removal of omental fat does not improve 79. Petry TZ, Fabbrini E, Otoch JP, et al. Effect of with single flow rate and new design for mod- insulin sensitivity and cardiovascular risk factors in duodenal-jejunal bypass surgery on glycemic con- ulated insulin infusion. Diabetes Care 1980;3: obese adults. Gastroenterology 2010;139:448–455 trol in type 2 diabetes: a randomized controlled 351–358 70. Herrera MF, Pantoja JP, Velazquez-Fern´ andez´ trial. Obesity (Silver Spring) 2015;23:1973–1979 90. Rupp WM, Barbosa JJ, Blackshear PJ, et al. D, et al. Potential additional effect of omentec- 80. Rajagopalan H, Cherrington AD, Thompson The use of an implantable insulin pump in the tomy on metabolic syndrome, acute-phase reac- CC, et al. Endoscopic duodenal mucosal resur- treatment of type II diabetes. N Engl J Med 1982; tants, and inflammatory mediators in grade III facing for the treatment of type 2 diabetes: 307:265–270 obese patients undergoing laparoscopic Roux-en-Y 6-month interim analysis from the first-in-human 91. Mahfoud F, Schlaich M, Kindermann I, et al. gastric bypass: a randomized trial. Diabetes Care proof-of-concept study. Diabetes Care 2016;39: Effect of renal sympathetic denervation on glu- 2010;33:1413–1418 2254–2261 cose metabolism in patients with resistant hy- 71. Dunn JP, Abumrad NN, Breitman I, et al. 81. Cherrington AD, Rajagopalan H, Maggs D, pertension: a pilot study. Circulation 2011;123: Hepatic and peripheral insulin sensitivity and Deviere` J. Hydrothermal duodenal mucosal 1940–1946