Metabolic (Bariatric and Nonbariatric) Surgery for Type 2 Diabetes: A Personal Perspective Review

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 manipulation of a normal organ or organ system to achieve a biological result for a potential health gain.” The procedure described in Genesis was an “operative manipulation” under general anesthesia on a “normal organ” to achieve a “biological result”; it was metabolic surgery.

As early as 1896, bilateral oophorectomy was used to cause temporary regression of breast cancer metastases (2). The 100-year heyday of peptic, primarily duodenal, ulcer surgery, from the late 19th century to the discovery of Helicobacter pylori, involved operating on normal stomachs and vagus nerves to cure the pathologic lesion, a distal ulcer left untouched by the surgeon. This was metabolic surgery, as was the partial ileal bypass (Fig. 1) for the treatment of hypercholesterolemia, introduced in 1962 and 1963 (3,4). The partial ileal bypass was used as the intervention modality in the Program on the Surgical Control of the Hyperlipidemias (POSCH) (5–8), the first randomized controlled trial to use metabolic surgery. POSCH was the first study definitively to demonstrate the benefits of marked cholesterol lowering in preventing myocardial infarctions, peripheral vascular disease, and the need for coronary artery surgery or dilation and stenting, concurrently with coronary arteriographic arrest of disease progression and induction of actual plaque regression, as well as prolonging life expectancy over 25 years of follow-up. Today bariatric surgery is the most used of metabolic surgery procedures and is performed worldwide as part of the treatment armamentarium to combat the epidemic of morbid obesity.

To date, well over 50 operations have been suggested and tried for the management of morbid obesity (9) (Table 1). One might therefore conclude that the most suitable or ideal operation has, as yet, not been conceived. This is true, as it is true in any area of surgery and certainly in medicine in the prescription of drugs. More importantly, it illustrates the vigor and imagination of the proponents of bariatric surgery. In the chronology of operative procedures, there are six historically dominant operations that have been successful in causing marked weight loss and that have had a major effect on the field. Listed in chronological order of their introduction they are jejunoileal bypass (JIB), Roux-en-Y gastric bypass (RYGB), vertical banded gastroplasty (VBG), biliopancreatic diversion (BPD) or duodenal switch (DS), adjustable gastric banding (AGB), and sleeve gastrectomy (SG). In addition, three operative innovations warrant mention: gastric stimulation, vagal blockade, and, most importantly, banded RYGB.

The first bariatric nonresectional surgery procedure was performed in 1953 by Richard L. Varco at the University of Minnesota. It consisted of bypass of most of the small intestine in an obese patient, with bowel reconstruction by an end-to-end jejunoileostomy and separate drainage of the bypassed bowel by an ileocecectomy (10). Varco never published this case. The first report of this operation was published in 1954 by Kremen et al. (11), also from the University of Minnesota.

The JIB elicited excellent and lasting weight loss but was associated with extensive early and late complications. These included electrolyte imbalances, vitamin and mineral deficiencies, diarrhea, gas bloat syndrome, oxalate kidney stones, steatohepatitis and progressive liver degeneration, cutaneous pustular eruptions, and mentation difficulties. Various causative mechanisms for these problems were hypothesized, with the greatest credence given to short bowel syndrome and bacterial overgrowth in the bypassed small intestine causing the elaboration of toxins and alcohol. Over time, most of these problems were anticipated and prevented or treated. However, with the emergence of the RYGB, the JIB fell into disuse. Although there are JIB patients alive and doing well today, 30–40 years after their operation, most of the JIB patients had their procedure reversed with the concurrent establishment of another bariatric operation.

In 1966, Mason and Ito (12) introduced the gastric bypass. Their operation consisted of a horizontal gastric division with a loop gastrojejunostomy. Alden (13) modified the Mason procedure by cross-stapling the upper stomach and draining the upper pouch by a loop gastrojejunostomy. Within 1 year, Griffen et al. (14) reported the first bypass with a Roux-en-Y gastrojejunostomy, which became the standard RYGB (Fig. 2). As cited (15), Pories and coworkers at the University of East Carolina should also be credited for independently introducing the Roux-en-Y drainage for the RYGB.

The RYGB became the most widely performed bariatric procedure worldwide and has retained a position of prominence for more than 50 years. The complication rate with the RYGB is low, patient satisfaction is high, and the weight-loss failure rate, although progressive over time, is minimal to moderate.

Mason was always eager to simplify bariatric procedures and minimize their side effects and complications. He has, therefore, favored restrictive, rather than malabsorptive, surgery. Thus, in 1973, Printen and Mason (16) introduced gastroplasty. Their original procedure consisted of a partial horizontal gastric transection, leaving a greater curvature conduit. In 1981, Laws and Piantadosi (17) made the restrictive pouch vertical and narrowed the outlet with a Silastic ring (Fig. 3). Mason (18) described his second-generation VBG in 1982, which used a Marlex mesh band through a gastric window in a vertical pouch for outlet restriction. The VBG rapidly gained in popularity and soon rivaled the RYGB for dominance in the field. Over time, however, VBG patients began to regain weight, and the operation fell into disuse.

To avoid the complications of the JIB and yet maintain the weight loss achieved by that procedure, Nicola Scopinaro introduced the BPD operation. His procedure consists of a horizontal hemigastrectomy with gastric pouch drainage by a Roux limb, at least 250 cm in length, anastomosed to a long biliopancreatic limb to form the common channel of ∼50 cm (19) (Fig. 4). The procedure avoids any stagnation of flow and, thereby, the potential for bacterial overgrowth, toxin formation, and alcohol production by fermentation.

The Scopinaro procedure was subsequently transformed into the DS, first by Marceau et al. (20) of Canada, who performed a vertical sleeve gastrectomy with cross-stapling of the duodenum and an ∼100-cm common channel. Duodenal cross-stapling is, however, unstable, causing negation of the operative effect. Hess and Hess (21), in the U.S., conceived the modern BPD/DS or DS, by dividing the duodenum and constructing a proximal duodenoileostomy (Fig. 5).

The BPD and the BPD/DS are difficult, time-consuming operations that can tax the skill of many surgeons. They are also associated with long-term protein and other nutritional deficiencies and possible liver failure. The surgeon and patient committed to these procedures must, therefore, also be committed to meticulous lifelong follow-up. The salient advantages of these procedures are the most marked and lasting weight loss and the highest percentage of resolution of obesity comorbidities of any of the bariatric operations (22,23).

The simplest weight-loss operation that has been routinely performed is AGB, introduced by Kuzmak (24). The peak of worldwide prominence in the use of this procedure can be credited to Paul E. O’Brien of Australia (25). In most other hands, the AGB proved to be unsuccessful in the long term, plagued by complications such as band slippage and gastric perforation, as well as by failure to maintain weight loss.

The last of the six dominant bariatric procedures is the free-standing SG (Fig. 6). The procedure was first advocated by Regan et al. (26) in 2005 and popularized by Gagner et al. (27) as the first stage in a laparoscopic DS. Gagner et al. soon recognized that for some patients, the free-standing SG might achieve the weight-loss objective without further surgery. The attraction of this procedure is that it can be performed rapidly and requires no bowel anastomosis. By 2017, the SG had become the most frequently used bariatric procedure in the world (28). Unfortunately, there is a high incidence of staple-line leak, at least in the hands of many current practitioners. Further, the SG has not been evaluated for maintenance of weight loss for a prolonged period of time. A possibly safer alternative to SG being explored by Doležalova-Kormanova et al. (29), of the Czech Republic, is gastric plication, which avoids any gastric resection.

Of the three recent innovations, as yet unproven over the long term, the most intriguing is electrode stimulation of the stomach, which appears to be capable of inducing some weight loss as well as other metabolic outcomes. This approach, although not new (30), is in its intellectual infancy and has not found clinical applicability. Advocates have no solid knowledge of the number of electrodes to use, the location(s) in which these electrodes should be implanted, and the frequency and amplitude of the current to be applied. The most extensive work in efficacy assessment of this technique has been done by Lebovitz et al. (31). The converse to electrode stimulation is electrode blockage of neural transmission, best exemplified by vagal blockade (32). The success rate for this modality has been limited, however. Most studied and successful of these innovative procedures is the combination of an RYGB and a VBG advocated by Fobi et al. (33), the so-called banded RYGB (Fig. 7). The outcomes for this operation have seen favorable assessment in a systemic review and meta-analysis (34).

Mention should be made of endoscopically inserted gastric balloons, which work as gastric bezoars to decrease appetite and induce satiety. These devices have not found acceptance as bariatric procedures per se but can be useful for preoperative weight-loss preparation and remedial postbariatric surgery intervention for weight regain or maintenance.

The discipline of bariatric surgery has declared metabolic surgery to be an integral part of its scope, in particular in the management of type 2 diabetes. This recognition is appropriate but not accurate; it reverses the phylogenetic order. Bariatric surgery has, and always will be, a species of the larger taxonomic phylum of metabolic surgery. When speaking of the advantageous metabolic consequences of bariatric surgery in the management of type 2 diabetes, hypertension, hyperlipidemia, etc., the field has come to recognize that bariatric surgery is a set of procedures within the broader purview of metabolic surgery. Indeed, weight loss, the original and primary goal of bariatric surgery, is, in itself, metabolic in principle and in its mechanisms.

Based on their gross anatomical alterations, it has been uniform practice to describe bariatric procedures as being restrictive or malabsorptive. However, all restrictive procedures are actually malabsorptive, and all malabsorptive procedures are restrictive, making that distinction quite meaningless. The so-called restrictive operations (e.g., AGB, SG) cause caloric malabsorption. The so-called malabsorptive operations (e.g., BPD/DS) limit the intestinal absorptive surface, which, in turn, results in caloric malabsorption. Thus, to understand the true mechanisms and effects of the metabolic/bariatric procedures, we must analyze the complex metabolic effects they induce.

The intestinal tract is rich in parasympathetic and sympathetic innervation. Only ∼10% of vagal nerve fibers, however, are efferent; 90% are afferent and carry messages from the gut to the brain, in particular, to the hypothalamus. The sympathetic nerve supply to the gut is primarily mediated via the celiac axis and is intimately involved in the function of glucose production and release. In addition to these communicating networks to and from cerebral centers, there is a dense intrinsic nerve syncytium in the submucosal layer of the intestine extending from the esophagus to the anus. Finally, a fundic gastric pacemaker regulates gastric wave contractions and synchronization of gastric function. These neural networks surely must be involved in eating behavior, food selection, and nutrient metabolism. By dividing, excising, transposing, or stimulating, every one of our metabolic/bariatric operations influences these, and very likely additional, regulating mechanisms.

The literature is saturated with, although not clear about, the role of hormones on the eating/satiety process as well as on type 2 diabetes. There are ∼100 gut hormones, among which glucagon-like peptide 1 (GLP-1), peptide YY (PYY), gastric inhibitory polypeptide (GIP), and ghrelin have received the greatest attention, as has the adipocyte and gut-derived hormone leptin. This hormonal mosaic is integral to the mechanisms that govern the origins of obesity and its metabolic comorbidities as well as to the modulating and often corrective effects of metabolic/bariatric surgery. In turn, they interact with the neural mechanisms to form the gut neurocerebral network. In time, the equations that govern these elusive relationships will be ascertained and, thereby, offer medical science the ability to intervene in a rational manner to mitigate pathology.

Bile acids have recently been cited to have, in addition to their digestive functions, a role in metabolism and metabolic diseases, in particular obesity and type 2 diabetes. Our metabolic/bariatric operations interrupt the normal enterohepatic bile acids cycles and, thereby, alter their particular oxidative biochemical structure. Hypotheses of causative mechanisms have also implicated the relationship of the human intestinal bacterial microbiome in obesity and type 2 diabetes regulatory mechanisms.

There were two cardinal literature reports by metabolic bariatric surgery pioneers that focused the attention of the field on the benefits of bariatric surgery in the management of type 2 diabetes. In 1995, Pories et al. (35) published a paper with the intriguing title, “Who Would Have Thought It? An Operation Proves To Be the Most Effective Therapy for Adult-Onset Diabetes Mellitus.” They demonstrated that blood glucose levels normalized and the need for insulin therapy markedly diminished within 24 h of an RYGB. Obviously, this outcome occurred too rapidly to have been due to weight loss and had to be the product of a neurohormonal mechanism. In 1998, Scopinaro et al. (36) published a series describing patients with type 2 diabetes that dated back to 1984, wherein 100% exhibited normalization of their fasting blood glucose levels after BPD. A concurrent report by Cowan and Buffington (37) in 1998 also called attention to the lowering of fasting blood glucose levels after RYGB.

These papers initiated a confirmatory clinical cascade of case series and trial reports. A PubMed search indicates that from 2000 to the present, 4,342 papers have been referenced under bariatric surgery and diabetes, 2,219 for diabetes plus RYGB, and for diabetes plus other bariatric procedures: SG, 804; BPD, 288; DS, 122; AGB, 145; and vagal blockade, 29.

In 1997, MacDonald et al. (38) followed-up on their 1995 publication with a report of 232 morbidly obese patients with type 2 diabetes, 154 who had undergone RYGB and 28 who served as control subjects. The type 2 diabetes was mitigated in the operated-on patients and progressed in the control subjects. Most startlingly, the mortality rate in the control subjects was 31.8% (6.2 years of follow-up) compared with 9% in the surgery group (9 years of follow-up), a reduction in annual mortality from 4.5% to 1%.

By 2003, confirmatory papers of type 2 diabetes resolution after bariatric surgery had become common, among which were, notably, the papers of Sugerman et al. (39), Polyzogopoulou et al. (40), and Schauer et al. (41). The Schauer publication reviewed the results of RYGB in 240 patients with impaired fasting glucose or with clinical type 2 diabetes. Fasting blood glucose and glycosylated hemoglobin concentrations returned to normal levels (83%) or markedly improved (17%), and an 80% resolution in the use of oral antidiabetes agents and a 79% reduction in the need for insulin therapy were demonstrated. Patients with a preoperative duration of diabetes of fewer than 5 years and those with the mildest form of the disease (diet controlled) and the greatest weight loss were most likely to achieve total resolution of type 2 diabetes.

There were several trials of medical versus surgical management. Serrot et al. (42) demonstrated that RYGB can be performed in patients with type 2 diabetes with a BMI <35 kg/m² (n = 17) with better weight loss, glycemic control, and fewer hyperglycemic medications compared with patients (n = 17) receiving standard medical therapy. Mingrone et al. (43) explored the other weight extreme in a study of 60 severely obese patients (BMI >35 kg/m²) who underwent RYGB or BPD or conventional medical therapy. At 2 years, diabetes remission had not occurred in any of the patients in the medical therapy group but was manifest in 75% of RYGB and 95% of BPD patients. In patients with a BMI of 30–42 kg/m² and with an HbA_1c ≥6.5%, Halperin et al. (44) compared the outcomes of RYGB (n = 19) versus intensive medical therapy (n = 19). RYGB produced greater weight loss and sustained improvements in HbA_1c and in cardiometabolic risk factors within 1 year (P = 0.03).

One of the most quoted prospective studies in this field has been the Swedish Obese Subjects (SOS) study, which reported in 2014 that in 260 control patients and 343 bariatric surgery patients with type 2 diabetes at 15 years, the diabetes remission rate was 6.5% in the control patients and 30.4% in the bariatric surgery patients compared with 16.4% and 72.3%, respectively, at 2 years (45). The relapse effect after bariatric surgery has also been noted by others. Arterburn et al. (46) showed that approximately one-third of patients with type 2 diabetes remission after bariatric surgery experienced a relapse within 5 years. In this regard, it needs to be emphasized that every year of sustained remission is an affirmative outcome and may well represent a year gained before the onset of the morbid and mortal complications of this disease.

There have also been attempts to demonstrate the benefits of combination of, rather than competition between, surgical and medical patient management. Ikramuddin et al. (47) reported that in patients with mild to moderate type 2 diabetes, the addition of RYGB to established lifestyle and medical management resulted in 28 of 60 patients (49%) with an RYGB compared with 11 of 60 patients (19%) without an RYGB achieving the American Heart Association triple end point of HbA_1c <7.0%, LDL cholesterol <100 mg/dL, and systolic blood pressure <130 mmHg (P < 0.05). Schauer et al. (48) published similar results in 150 patients randomized to intensive medical therapy versus intensive medical therapy plus RYGB or SG (P < 0.01). Even the operation with the least proven postoperative weight loss, the AGB, when added to intensive medical therapy was shown by Dixon et al. (49) to improve diabetes outcomes. Courcoulas et al. (50) randomized 61 patients to intensive lifestyle management or less intensive lifestyle management with the addition of an RYGB or AGB and again found more favorable diabetes outcomes and disease remission in the operative groups (P = 0.003). The recently completed STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) trial was highly definitive in demonstrating that metabolic bariatric surgery plus medical therapy was far more efficacious in lowering the HbA_1c in patients with type 2 diabetes at 5 years than intensive medical therapy alone (51).

At the top of the evidence-based pyramid of data reliability is meta-analysis. We published the first bariatric meta-analysis in 2004 (22). This study encompassed 22,094 patients and included five randomized controlled trials. It definitively demonstrated the benefits of weight loss and the reduction of comorbidities induced by metabolic/bariatric surgery: mean excess weight loss of 64.4%, complete resolution of type 2 diabetes in 76.8% and its resolution or improvement in 86.0%, hyperlipidemia improvement in 70% of patients, and normalization of blood pressure in 61.7%, with resolution or improvement in 85.7% of hypertensive patients. All outcomes were highly statistically significant (P < 0.01).

In 2009, we published a follow-up meta-analysis focused exclusively on the effect of metabolic/bariatric surgery on type 2 diabetes (23). The data set in this study included 135,246 patients. Our findings revealed a mean weight loss of 38.5 kg or 55.9% of excess body weight in association with 78.1% complete resolution and 86.6% resolution or improvement of type 2 diabetes (P < 0.001). The effect on type 2 diabetes was a function of the weight loss achieved: BPD/DS > RYGB > VBG > AGB. Further, insulin levels declined significantly postoperatively, as did the HbA_1c and the fasting blood glucose levels. The weight-loss effects were not diminished after 2 years of follow-up.

Encouraged by the demonstration that metabolic/bariatric surgery in the obese resolves type 2 diabetes and that the likelihood that mechanisms other than weight loss were responsible for this benefit, metabolic/bariatric surgeons were stimulated to explore the use of metabolic/bariatric surgery procedures for treatment of type 2 diabetes in overweight and essentially normal-weight patients. In 2011, Scopinaro et al. (52) published another landmark paper demonstrating that the BPD resolved type 2 diabetes in patients with a BMI of 25–35 kg/m² without engendering deleterious weight loss. Because BPD causes the most weight loss of the metabolic/bariatric operations, this finding corroborated the weight set-point hypothesis and the metabolic basis for the outcomes of metabolic/bariatric surgery. Confirmatory but cautious reports of type 2 diabetes resolution after metabolic/bariatric surgery in patients with a relatively low BMI followed (e.g., 53–55). Skepticism was essentially eliminated by the 2016 Cummings and Cohen (56) report to the second Diabetes Surgery Summit. They proffered a meta-analysis of the 11 randomized controlled trials providing class 1A evidence, as well as the meta-analysis of high-quality nonrandomized prospective studies, demonstrating that benefits of metabolic/bariatric surgery for type 2 diabetes remission, glycemic control, and HbA_1c lowering were equally true for patients with a baseline BMI below or above 35 kg/m².

The overwhelming import of these data were responsible for prompting a joint statement by several international diabetes organizations composed of surgeons and nonsurgeons advocating that metabolic surgery be included in the treatment algorithm for type 2 diabetes (57).

The revelation that metabolic/bariatric surgery can cause resolution of type 2 diabetes markedly increased the impetus to elucidate the metabolic mechanisms responsible not only for postoperative weight loss but also for the seemingly independent resolution of type 2 diabetes. As early as 1998, Hickey et al. (58) wrote,

Pories and Albrecht (59) expanded this concept in 2001 by stating that the rapid correction to euglycemia after RYGB “is not the loss of weight (i.e., reduction in fat mass) but, rather, the result of the exclusion of food and a secondary alteration in incretin signals from the antrum, duodenum, and proximal jejunum to the islets.” Rubino and Marescaux (60) provided confirmatory evidence in an interesting Goto-Kakizaki rat experiment wherein duodenal exclusion significantly improved glucose tolerance and the restoration of the duodenal passage reestablished impaired glucose tolerance.

Thought soon turned to the role of gastrointestinal hormones (61), in particular the postprandial release of incretin hormones and the recovery of the incretin effect on insulin secretion (62,63), improvement in insulin sensitivity and β-cell function (HOMA) (64), as well as the function of bile acids (65) and the intestinal microbiota (66). In a review of responsible mechanisms, Batterham and Cummings (67) stress that a constellation of factors, rather than a single overarching mechanism, with these factors varying by surgical procedure, is responsible for the observed reduced glucose production, increased tissue glucose uptake, improved insulin sensitivity, and enhanced β-cell function. In a recent report, Sista et al. (68) postulated that SG affects glucose homeostasis by two sequential mechanisms: initially hormonal and subsequently weight loss itself.

With the knowledge that the type 2 diabetes resolution effect of gut surgery is partly independent of weight loss, surgeons started to explore the possibility of an operation dedicated to treating type 2 diabetes with minimal or no weight loss—true diabetes surgery. Many such operations have been performed: some have failed, some have partially succeeded, and some may come to be successful.

Because visceral adiposity is a risk factor for the metabolic complications associated with obesity, omentectomy was an early proposed surgical intervention to influence type 2 diabetes. Study reports of omentectomy alone, or in addition to a standard bariatric operation, varied as to no benefit (69,70), possible benefit (71,72), and demonstrable benefit (73,74).

The electrode stimulation operations, which have not been highly successful for weight loss, appeared to cause improvement in diabetic parameters. Such reports have been made for the EntroMedics VBLOC device (75). In addition, Khawaled et al. (76) have shown, albeit in rats, that duodenal electrode stimulation will normalize diabetic blood glucose levels.

The foregut hypothesis, popularized by Rubino et al. (77), is based on the assumption that the hormone GIP is integral to the etiology of type 2 diabetes and that type 2 diabetes can be resolved by neutralizing the duodenum, the primary site of GIP secretion. This concept is the basis for the proposed duodenal-jejunal bypass, which has demonstrated reductions in fasting blood glucose and HbA_1c without significant weight loss (78,79).

A recent interesting proposal has been endoscopic hydrothermal duodenal mucosa ablation with secondary mucosal regeneration (80,81). The authors of this procedure have shown promising results up to 6 months with a 1.8% reduction in the HbA_1c.

Turning to the opposing hindgut hypothesis, several investigators have focused on the ileum in their attempt to treat type 2 diabetes with no or minimal weight loss. This orientation is based on the knowledge that the ileum is a primary site for the elaboration of GLP-1 and PYY in response to an intraluminal stimulus. These incretin hormones increase β-cell mass, stimulate glucose-independent insulin secretion, and inhibit glucagon release. Some believe that moving a segment of ileum higher in the intestinal tract will promote type 2 diabetes resolution and that ileal transposition should therefore be added to a standard or diverted (duodenal exclusion) sleeve gastrectomy (82,83).

Considering the focus on the terminal ileum and its incretin hormones, we measured GLP-1, PYY, and leptin blood levels after stimulation of the terminal ileum or cecum by a static infusion of a food hydrolysate in markedly obese patients undergoing a DS procedure (84). We found elevations of GLP-1 and PYY with a decrease in leptin levels peaking at 90–120 min by both ileal and cecal stimulation. We concluded that the transposition of the ileum higher in the intestinal tract, with the 2-h delay in the peak hormonal response, would not enhance its immediate response to a food stimulus. Next, we reversed the concept of ileal enhancement by performing a partial ileal bypass or ileal excision in Goto-Kakizaki rats, thereby limiting the ileal mucosal exposure to intestinal flow; we found a five- to sixfold increase (not a decrease) in plasma GLP-1 (85).

In a subsequent retrospective analysis of the POSCH study data, we found that the diet control group had a 2.7-fold higher incidence of type 2 diabetes compared with the partial ileal bypass intervention group during 35 years of follow-up (86). We have currently initiated a clinical trial to ascertain the effect of the essentially nonweight loss–inducing, cholesterol-lowering partial ileal bypass operation on established type 2 diabetes.

Interestingly, several extragastric/intestinal procedures qualify as metabolic surgery to alleviate type 2 diabetes. Pancreas transplantation (87) and islet cell transplantation (88) in patients with type 2 diabetes have been shown to be beneficial, as has insulin infusion by an implantable pump (89,90). Most fascinating is the work of Mahfoud et al. (91), who found that after arterial catheter perirenal neuroablation for the treatment of hypertension in patients with type 2 diabetes, there was normalization of the fasting blood glucose, fasting insulin levels, C-peptide, and insulin resistance (HOMA), all indicative of type 2 diabetes resolution.

Metabolic surgery for type 2 diabetes is a work in progress. We have yet to learn the precise nature of the mechanisms of action the metabolic perturbations our surgical interventions elicit and, indeed, their implications regarding the disease process of type 2 diabetes itself. We cannot operate on the one-third of the U.S. population who are obese, the more than ∼30 million people with type 2 diabetes, or the fraction with both. We can only take on a limited percentage of the needy. We can, however, learn from these patients lessons for the benefit of the majority.

The three currently popular metabolic/bariatric procedures elicit resolution or remission of type 2 diabetes in the same rank order that they demonstrate weight loss, namely, BPD/DS > RYGB > SG. The recurrence rate of type 2 diabetes is reciprocally progressive with an average of 2–6% per year; we have no knowledge of when the nadir is reached.

Overall operative mortality for bariatric surgery today is ∼0.1%, equivalent to that of a routine laparoscopic cholecystectomy. If a reoperation becomes necessary for a failed procedure, the safety risk is, of course, cumulative, a fact that is often not stated in describing the SG with a reoperation rate of∼50%. If bowel is opened during the procedure, the minimal wound infection rate is increased. If the size of the stomach is markedly reduced, 30-day postoperative nausea, vomiting, and dehydration adverse side effects are more common. If the small intestine is cut, anastomosed, and translocated, the long-term risk of an internal hernia is increased. Deep vein thrombophlebitis and pulmonary emboli occurrences are unpredictable, and prophylactic low-grade anticoagulation, mechanical precautions, and early ambulation are recommended.

The most effective procedures for weight and type 2 diabetes reduction, the BPD and the DS, necessitate skilled surgeons who regard gentleness in the handling of tissues of greater importance than speed. BPD/DS patients, more so than any other bariatric patients, require a lifetime of follow-up and are prone to nutritional, mineral, and vitamin deficiencies. In so far as the SG portion of the DS is concerned, caution is required in patients with gastroesophageal reflux disease (GERD).

The RYGB, however, essentially cures GERD and is recommended for individuals with this affliction. It is the procedure with the longest history of patient and surgeon acceptance. RYGB was the first procedure definitively to demonstrate resolution of type 2 diabetes before any weight loss is achieved.

The SG, in the hands of current practitioners, has a high leak rate in the upper retained stomach. This is unacceptable and should be remedied by reinforcing the resection staple line. The SG is the most commonly performed operation in the world today and mitigates type 2 diabetes with corresponding favorable changes in the incretin hormones. In association with its rapidly increasing popularity, there is accumulating evidence that the SG can accentuate existing, or cause de novo, GERD.

The multitude of procedures for curing type 2 diabetes under current trial, and those newly proposed in the process of translational research, cannot be critically assessed at this time. They all have in common the goal of mitigating the neurohormonal network gone wrong in the promulgation of type 2 diabetes by stimulating an affirmative therapeutic metabolic response.

We have available to us a human laboratory with hundreds of thousands of subjects who have had their type 2 diabetes ameliorated, possibly even cured, by metabolic/bariatric surgery. These individuals, our patients, hold the secret of the etiology of type 2 diabetes, its relationship to obesity, and the neurohormonal response we elicit by our surgical procedures. Our success in the elucidation of causative mechanisms is dependent on our perceptivity of phenomena and the interpretation of outcomes using simple investigative tools, which, for the most part, are noninvasive. Knowledge of etiology should lead to the formulation of evidence-based therapy. We accept the dictum that basic research is the foundation for translational clinical therapy and must also adopt the concept that empiric clinical therapy can lead to basic scientific truths.

Metabolic bariatric surgeons, in and out of academic institutions, have warmed, or are warming to the concept that they are not only technicians and clinicians but that they also have a role as researchers in the emerging field of ascertaining knowledge of the neurohormonal mechanisms of metabolic diseases subject to metabolic surgery. In this endeavor, progress will be hastened if diabetologists, endocrinologists, internists, cardiologists, and basic scientists join surgeons in this quest. Together, we may be able to eradicate type 2 diabetes.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. H.B. and J.N.B. researched the data in the literature. H.B. provided insights from 50 years’ experience in metabolic bariatric surgery. H.B. and J.N.B. wrote and edited the manuscript.