Insights in Interventional Diabetology: Generations of Work Coming Together

An Interview with:

Dr. Walter Pories,Professor of Surgery, East Carolina University School of Medicine, Department of Surgery, Greenville, North Carolina, Past President, ASMBS

Dr. Neil Hutcher, Commonwealth Surgeons, Ltd., Richmond, Virginia; Past President, ASMBS

Dr. Ricardo Cohen, Director, The Center for the Surgical Treatment of Morbid Obesity and Metabolic Disorders, Hospital Oswaldo Cruz, and Baros Institute,
São Paulo, Brazil

Introduction by Joy C. Bunt, MD, PhD; and Robin Blackstone, MD, FACS

Introduction
As is often the case in medicine and science, some of the most important or promising findings are discovered by accident and/or met with initial skepticism. When Dr. Pories et al[1] first proposed the idea that diabetes could be “cured” with surgery, it was initially received with either disbelief or skepticism and was dismissed by many as nothing of significance. Diabetologists simply attributed the phenomenon to caloric restriction since it was known that blood glucose levels could quickly be normalized in patients with fasting or via very low-calorie diets.[2] Pories himself initially thought the rapid improvements in patients’ blood sugars after surgery were lab errors, but they kept occurring and persisted. He recognized that something important was happening and needed to be explored further. Once convinced that his findings were real, he published them knowing that he might risk his reputation. It was of greater importance to him, however, that others would also investigate this phenomenon and verify his results.

Confirmatory evidence did begin to accumulate as more reports of a remission of type 2 diabetes after bariatric surgery began to appear in the literature.[3,4] More importantly, follow-up studies indicated that many patients could maintain their improved blood sugars without medications for years.[5,6] 

Experiments using a variety of surgical revisions of the gastrointestinal tract in animals[8,9] indicated that something unique about gastric bypass surgery was responsible for the rather immediate, dramatic, and persistent “disappearance” of diabetes. Dr. Francesco Rubino’s work definitively demonstrated that bypassing the duodenum accounted for at least one mechanism of normoglycemia.[10] These experiments were pivotal in changing the paradigm of diabetes from focusing on the two accepted and required core defects of insulin action and insulin secretion[11] to asking the question of whether diabetes might be a disease of the foregut, as proposed early on by Pories.[12]

For the clinical scientist, bariatric surgery provides new research tools and new models to study the pathophysiology of diabetes. While much is known about how diabetes develops and progresses over time and there have been promising advancements in our ability to prevent, delay, or manage the disease, we still do not fully understand how the disease begins and what drives or determines its progression. Dr. Rubino’s “new paradigm” challenges us to think about the disease in a different way.[10] For the surgeon and clinician, bariatric surgery provides new treatment options to improve management and maybe even “cure” the disease.

Collectively, the work of both Dr. Pories and Dr. Hutcher and colleagues, as well as a new generation of surgeons, has lead to the emergence of a new field called “interventional diabetology.” Dr. Cohen is the first surgeon in the world to have performed an operation in a non-obese diabetic patient, as well as the first to report on Roux-en-Y gastric bypass in BMIs between 30 and 35. As such, he brings a singular and valuable perspective to this sharing of ideas and opinions based on history, research, surgical experience, and outcomes. Many others have contributed to the growth and development of this field, but it was the vision of Walter Pories that gave it life and it is the experimental work of Cohen and colleagues that has given it the direction for its future.

Do you support doing only a duodenum-rerouting metabolic procedure and not a stomach-reducing weight loss procedure for patients with diabetes who suffer from obesity to perhaps help them lose weight through diet and exercise?

Dr. Cohen: Morbidly obese patient with diabetes need to lose weight in order to keep their insulin resistance low and insulin sensitivity high, in spite of any incretin mechanism that lies behind any gastrointestinal anatomical rearrangement. We must not forget that massive overweight carries other comorbidities, such as sleep apnea, ostheoarthritis, gastroesophageal reflux disease (among others), and all those conditions, including type 2 diabetes mellitus (T2DM), will be addressed and mostly resolved through weight loss surgery. So, in this situation, today I support the RYGB for morbid obesity and T2DM.

Dr. Pories: I strongly support the pursuit of controlled, clinical trials to address this question. The current data from the series by Arguelles, Ramos, and Lakdawalla are certainly promising, but we need more information.

Dr. Hutcher: I think that history is clear enough that people who are obese have been unable to lose and maintain weight loss over a significant period of time. Therefore, duodenal bypass alone—although it may help the diabetes—is not in their best interest. I believe if you are undertaking a surgical procedure, you should perform the one that has the best opportunity of addressing and improving the patient’s overall health situation.

How do you explain return of diabetes with weight gain after RYGB, if the mechanism is duodenal bypass?

Dr. Cohen: We must accept that diabetes is a complex, progressive disease and has several different pathogenic mechanisms. Knowing this, we can address this question. Diabetes recurrence after weight regain following a RYGB is fairly less common than weight regain and no diabetes. We have seen some patients regaining weight after 5 to 10 years followup with normal glycemic homeostasis, measured through fasting and postprandial glycemia and HbA1c.

But, there are a few patients who “regain” their T2DM along with their weight. It is possible that the pathophysiology of diabetes mellitus (DM) in those patients is not only related to beta cell dysfunction, but also to an increase of insulin resistance. So, although their beta cells are somehow stimulated, they do not produce enough insulin overcome the augmented peripheral resistance to it. If not managed appropriately, this metabolic scenario will produce a beta cell pancreatic failure and severe diabetes.

Dr. Pories: First, failure is not that common. Both in our series and the Swedish experience, most patients have an increase in weight during or after the second year and stabilize at about 10 percent above their maximum weight loss. This weight gain does not interfere with their remissions. There are several explanations for the return of the diabetes in the few cases that fail to achieve full and durable remission: 1) The return of the diabetes may be due to a technical failure such as a gastro-gastric fistula; 2) in some of our cases, the excluded intestinal segments were created to 100cm or less, now considered too short a limb, and in some of these patients the gut adapted; 3) in still others, the patients “out-eat” the pouch with almost continuous ingestion of sweets or high-density foods; and 4) there may be a fourth group where the bypass was performed too late in the disease process and full recovery could no longer be attained.

Dr. Hutcher: Even though there are beneficial metabolic effects that seem to be independent of weight loss, it is my feeling that significant weight regain can add enough stress through the usual mechanisms of insulin resistance and literally outpace the ability of the pancreas to keep up with insulin production and metabolism.

What length of follow-up in how many patients will be required for this to become standard practice?

Dr. Cohen: There is enough evidence today that bariatric surgery—mainly the procedures that involve anatomical rearrangement of the gastrointestinal tract—in patients with a BMI over 35 are excellent tools to induce long-term remission of T2DM. It is unquestionable, mainly for those who look at the literature with an unbiased view, that bariatric surgery leads to a high rate of diabetes remission and long-term mortality reduction of any cause, cardiovascular and cancer-related, with very low mortality (0.3%). Some new procedures, such as the sleeve gastrectomy, that without doubt have other mechanisms of action besides pure food restriction, need a bit more of follow-up to determine their use and long-term effectiveness. But the mid-term results so far are exciting.

In the 2004 American Society for Metabolic and Bariatric Surgery (ASMBS) Consensus, it is clearly stated that in patients with a BMI between 30 and 35, bariatric surgery can be performed if there are any severe comorbidities that will be resolved through surgery. Our group published in 2006 the first series of patients with BMIs from 30 to 35 with at least three comorbidities with excellent results. In this series, all were diabetic, and so far—with 4.5 years of follow-up—they are all (100%) diabetes free.
When addressing T2DM in patients with a BMI below 30, we are in a relatively unknown field for us surgeons and diabetologists. There are 400 described causes for type 2 diabetes. So we are dealing with a disease that is quite different than the one presented in obese subjects. Decreased incretin levels, fasting, and postprandial glucose levels probably play the same—or a more important—role than insulin sensitivity. Depending on the cause of diabetes, all clinical and surgical treatments may not be efficient.

So, based on our recent experience in treating diabetics with BMIs from 25 to 30, we thus far—with an average of two years follow-up—have better glycemic control than the one presented in medical literature. But, to have this well  established as standard of practice in leaner patients, we should (and actually are today) conduct randomized, controlled trials comparing the surgical versus the best medical treatment and assess not only pure glycemic control, but cardiovascular benefits carotid artery intima thickness) and cardiovascular disease mortality with at least five years follow-up.

Dr. Pories: As in any other chronic disease, gastric bypass patients with diabetes and other comorbidities require lifelong follow-up. These patients are susceptible to serious nutritional deficiencies, internal hernias, and emotional challenges that they may not be able to handle without professional help.

Dr. Hutcher: We have now held two international meetings on the surgical treatment of T2DM, which have included endocrinologists and diabetologists from all over the world. There is tremendous resistance in the medical community to accepting surgery as a primary treatment for T2DM. After all these years of medical management, new classes of drugs, and new classes of insulin, I am sure they are frustrated with their inability to fully control diabetes through medical means. It almost seems unfair to some to suggest a surgical treatment even though the positive results have been shown beyond any reasonable doubt in those severely obese diabetics who have undergone bariatric surgery. In my own mind, although a direct relationship has not been fully worked out as far as duration of diabetes versus remission following bariatric surgery, it is certainly my feeling that the shorter the duration of the diabetes, the more likely the patient is to have a prolonged—if not permanent—remission of his or her disease process. The endocrinologists—at least at these two diabetic summits—seem to want randomized trials that last for 10 or more years. I am not sure that it would really take that long to prove the point or whether this is simply a tactic to delay the acceptance of surgery as a primary treatment for T2DM.

Do you foresee a role for prosthetic indwelling endoluminal sleeves in the proximal small bowel for the treatment of diabetes mellitus and/or weight loss?

Dr. Cohen: Yes. Results with endoluminal sleeves, so far, have demonstrated good glycemic control in diabetics. The caveat is that we do not yet have long-term follow-up.

Dr. Pories: I do not know enough about endoluminal sleeves, but the approach does not seem very promising to me. The sleeve is a foreign body that is likely to slip, leak, migrate, and, as a result, cause pain, obstruction, perforation, and bleeding. That is only an opinion. I am not familiar enough with the human data to make informed comments.

Dr. Hutcher: This is an intriguing concept that mirrors what Dr. Rubino was able to do in his diabetic rodents.  Historically, we know that the body does not like foreign objects. Whether the innovators of this prosthesis will be able to develop a sleeve that will reliably and permanently shield the duodenal mucosa from contact with food is a question that has yet to be answered. We also know historically that there are many innovative ideas that are very promising in animal studies that do not always work out when translated to the humans.

Do you believe gastric bypass is a viable alternative for diabetic patients who are not morbidly obese?

Dr. Cohen: This is a tricky question. Today, with the knowledge acquired from bariatric surgery for morbidly obese diabetic patients, the answer should be yes. In general, for obese patients with BMIs ranging from 30 to 35, it is a very viable option that carries excellent outcomes. For overweight patients with BMIs less than 30—as diabetes itself may have different aspects—we still need to clarify the importance of the glucose load into the bowel and its role in developing, worseninig, or simply not controlling T2DM. There are several reports in the literature that highlight the importance of the pylorus in controlling gastric emptying and subsequent glucose load to the intestine. This could potentially help achieve better outcomes in diabetics. To answer this, we are comparing through a randomized, controlled trial RYGB and a 52F sleeve gastrectomy plus duodenal jejunal bypass in nonobese patients and determining which is the best procedure for this subpopulation of diabetics that accounts for 45 percent of all diabetics in the world.

Dr. Pories: Yes, I do; but again, the concept needs to be tested with prospective, controlled, clinical trials.

Dr. Hutcher: I believe that there are bariatric operations that are less weight loss-producing that will help address the metabolic problems seen in normal weight to slightly overweight people. These operations could include duodenal bypass, ileal interposition, or even forms of the biliopancreatic diversion with duodenal switch that have significantly longer absorptive surfaces and common channels resulting in less malabsorption.

Is your hypothesis related to mechanism of the sleeve or metabolic durability of weight loss surgery?

Dr. Cohen: There is a report from Lee[13] who compared the sleeve gastrectomy and RYGB and diabetes remission and he found at six months—with same excess weight loss—96 percent of T2DM remission for the bypass group and 46 percent remission for the sleeve group. Some other surgeons report greater T2DM remission rates after sleeves. I believe that sleeve gastrectomies are really more than pure restrictive procedures and there must be an endocrine mechanism involved that still remains unclear. When we think on endoluminal sleeves, the foregut mechanism is of course predominant.

Again, patients with diabetic obesity or morbid obesity who undergo weight loss surgery benefit from both intrinsic hormonal mechanisms and loss of fat mass to improve insulin sensitivity.

Dr. Pories: The explanation for the remission of diabetes in response to bariatric surgery is not “either/or.” We have evidence that weight loss and exclusion of gut from contact with food are both important factors.

Dr. Hutcher: Although we still have much to study and learn about all of this, sleeve gastrectomy or vertical gastric resection should act very much as any restrictive operation in the sense that there is no significant change in when the food reaches the ileum and there is no duodenal bypass. The mechanism and reliability of the vertical gastric resection and management of T2DM and the duration really will have to be worked out in continuing studies. We are just beginning to accumulate five-year data as to durability of weight loss with the vertical gastric resection. It remains to be seen what the long-term results on comorbidities will be.

What do you believe the role of ileal transposition versus duodenal exclusion will be?

Dr. Cohen: So far, there are good data from both procedures. It is unquestionable that ileal transposition is a very complex procedure with a lot of potential surgical complications. The only group performing that operation in the world adds the duodenal exclusion in more severe cases. So I have no doubt that both operations will have their place in different diabetic populations. And I ask all of the interested surgeons in this field to compare the so-called diverted ileal transposition (sleeve gastrectomy plus duodenal exclusion plus ileal transposition) to a duodenal switch: they are very similar, but the latter is already well established and less technically demanding.

Dr. Pories: The data regarding ileal transposition is promising but fragmentary. At this time, I see no role for the operations outside of prospective, controlled trials. Similarly, although we know quite a bit more about duodenal exclusion, and the data are indeed encouraging, it is still not ready for wide adoption. Further, well-controlled trials are needed.
It is important to remember that we already have tried several effective and safe procedures that provide durable, predictable remission of diabetes. The wise approach is to utilize these tested operations and await the collection of solid data before adopting other approaches. The basic principle remains, “Do no harm.”

Dr. Hutcher: I think that the role of these two operations will have to be tested in head-to-head competition, and that this question will take some time to answer. They are both intriguing concepts and not necessarily mutually exclusive. I think there is strong evidence that both could possibly play a role in the management of diabetes and other metabolic conditions in nonseverely obese patients. Dr. Rubino’s animal studies with duodenal bypass are fascinating, yet have failed to identify the factors that are involved. At least with the distal theory, one can look to the incretins as the possible explanation. This has been further elucidated by the pharmaceuticals that have GLP activity.

What will be the ideal diabetic? Resolution in the most difficult-to-control patients seems to be poor, especially those who require insulin or are more than 10 years with disease.

Dr. Cohen: It is well known that patients with impaired glucose tolerance have 30-percent higher risk of cardiovascular mortality. It is becoming more and more clear that patients benefit of an early intervention. I am not advocating, of course, to operate all diabetic patients. There are some patients who still benefit from lifestyle modifications and drugs. But, there is a good amount of diabetics that fail to control their glucose homeostasis. This population must have a deadline to be referred to surgery. Forinstance, maybe after 24 months, they would be eligible for metabolic surgery. In our experience, in overweight, grade 1 obesity or even morbidly obese patients, we have not found any statistical significance that correlates long history of diabetes and poor outcomes, at least in the first two years of follow-up. Intuitively, when time elapses, there is a progressive beta cell dysfunction and an increased insulin resistance that precludes worst results.

Dr. Pories: I don’t know about the term ideal diabetic. Do you mean, “Which diabetic might be the ideal candidate?” It looks as if patients with a  history of diabetes less than 10 years and who are younger are more likely to reach full remission. However, older patients with longer histories still gain major benefits from bariatric surgery, i.e. they improve greatly even though the hyperglycemia may not resolve fully.

Dr. Hutcher: My personal feeling is that any patient with severe obesity with T2DM and other manifestations of the metabolic syndrome who demonstrates inability to lose enough weight when challenged with the facts about the natural history of his or her disease should then be offered the option of surgery. There is great frustration when I see patients who I should have seen 10 years before their actual surgery date. Tight control of diabetes with medications is certainly not without risk. We also know that, even under good control, the micro and macro of vascular changes continues. The effects of bariatric surgery are dramatic, not only as far as blood sugar and hemoglobin AlC are concerned, but even resolution and/or stabilization of some of the most devastating complications of diabetes have been observed. I was always taught in medical school and training that neuropathy, retinopathy, and nephropathy were all permanent injuries. Although I never promise my diabetic patients anything other than improved glucose control, I and others have certainly observed dramatic changes in the previously mentioned complications. It is very devastating to the patients, along with the fact that a type 2 diabetic-related lower extremity amputation occurs every 30 seconds around the clock in the US. Published studies, such as Dr. Adams’s in the New England Journal of Medicine, which showed a 92-percent reduction in the mortality of type 2 diabetes, in my mind call for earlier interventions.

Considering the foregut hypothesis, would you recommend the banding procedure over the Roux-en-Y procedure in a metabolically healthy obese patient who has normal glucose tolerance? What about sleeve?

Dr. Cohen: Adjustable gastric banding has no foregut mechanism behind it. It is a purely restrictive operation and its results are modest when compared to both RYGB and the sleeve gastrectomy. The sleeve has the advantage of an operation without any prosthesis, but is irreversible. There is a reasonable amount of opinions worldwide about the relative lower success in terms of weight loss when comparing the band to both aforementioned operations.

Dr. Pories: I am not sure that the foregut hypothesis has much to do with this choice. Overall, based on worldwide experience, it appears that the gastric bypass is more likely to produce durable success than the band, but both procedures have their place. It is always best to have several solutions when confronted with problems.

Dr. Hutcher: This is a difficult question that really requires a lot of interaction with a patient like this. In my practice of four bariatric surgeons, it is clear that overall, the bypass seems to have better, more reliable, and longer-lasting weight loss than the band. Our greatest difficulty with the band is patient selection. Having said that, there is no question that the band is an effective tool for many patients.  The sleeve is gaining strong support as a stand-alone primary bariatric operation. The popularity of this operation is growing. The recent acceptance of the sleeve as a procedure that counts toward volume requirements both by the ASMBS and the ACS Centers of Excellence will further enhance the frequency with which sleeves are performed.

Is it possible that both the foregut and hindgut mechanisms are involved in the postoperative responses of blood glucose regulation after the Roux-en-Y procedure? Have comparisons been made between patients receiving a duodenal sleeve versus a Roux-en-Y?

Dr. Cohen: I will add more than a simple yes. Both mechanisms complement each other. Last year, a French group demonstrated in animals a new role for the gut—its capability to produce glucose, regulated through a portal-sensoring mechanism, the so-called intestinal gluconeogenesis. I have no doubts that all mechanisms are involved in diabetes resolution after any gastrointestinal operation.

There are no studies yet that  compare the RYGB and the endoluminal sleeve. As I mentioned earlier, we are conducting a randomized, controlled trial comparing the sleeved duodenal jejunal bypass (surgical) and the traditional RYGB.

Dr. Pories: I am convinced that both the foregut and hindgut play a role in T2DM and other comorbidities. The gut is one organ with gentle gradations of cell distributions along its course.

Dr. Hutcher: I believe that the role of the small intestinal peptides still has many chapters to be written. Both duodenal bypass and ileal transposition have been shown both experimentally and clinically to have beneficial effects on glucose metabolism. It is my feeling that both areas are extremely important metabolically and it is not an “either/or” situation. The study of these mechanisms will ultimately lead to better understanding of the pharmacologic and medical management of type 2 diabetes. I do not know how many years it will take, but I am convinced that surgery as the primary and most effective treatment of type 2 diabetes will be a bridge to more effective, less invasive, and/or pharmacologic measures for this disease. It is imperative that type 2 diabetes be brought under control. We cannot sustain the devastating medical and economic results of the seemingly epidemic proportions of the disease.

While it is established that the major defects responsible for type 2 diabetes are impaired insulin action and insulin secretion, there appears to be a multitude of potential underlying mechanisms involved with these two required defects. This would explain the clinically apparent heterogeneity and progressive nature of this disease. What do you think are some of the major questions that need to be answered so that guidelines can be developed to determine when and which type of bariatric surgery would be the most effective and appropriate for a given degree and/or type of metabolic disorder and disease?

Dr. Cohen: Although a complex matter, there are still the following unanswered points:
• Mechanism of action of the operations, as there are controversial data on its action over the insulin secretion and peripheral sensitivity and the real role of the incretin effect.
• Longer follow-up that can determine the role of surgery in preventing diabetes complications and decreased cardiovascular mortality.
• The role of any surgical technique and its indications. Is any operation prone to treat prediabetes, which we know carries a 30-percent risk of mortality? Is there any operation more efficient in diabetics with longer history?
• Although in surgical literature there is evidence of decreased mortality after bariatric surgery secondary to cancer, cardiovascular diseases, and diabetes, some endocrinologists/diabetologists demand Level 1 evidence. In my opinion, the surgical bariatric community has already demonstrated excellent long-term outcomes in diabetes resolution. Further validation may be necessary and enriching, but not mandatory. It is well known that diabetes complications such as blindness, limb amputations, and dyalisis, among others, have not decreased over time, and mortality secondary to diabetes still varies from 3 to 10 percent per year. Is it ethical now to randomize a patient with obesity who is taking high doses of insulin and 3 or 4 oral drugs to a medical arm in a trial comparing “surgery x” medical management, knowing the long-term benefit of surgery over drugs (old or new regimens)/insulin? Flipping to patients with BMIs below 30, I have no doubts that those trials need to be performed.

Dr. Pories: While there are many questions that need to be addressed, we must not deny patients the chance for relief from diabetes, asthma, heart failure, crippling arthritis, infertility, stress, incontinence, and the many other comorbidities while we seek explanations for mechanisms of action. We demand this of no other treatment. Do we demand a full explanation of aspirin or insulin or digoxin before prescribing these useful drugs?

The tragedy is that 99 percent of the 24 million Americans with diabetes are denied not only access, but even information about the effects of bariatric surgery on their disease. Would this occur if there was a pill that reversed diabetes fully and longterm in 4 out of 5 patients? I doubt it.

Sometimes the inequity is explained by the reluctance of our endocrinology colleagues to accept the efficacy of bariatric surgery. I doubt that explanation. They are just as eager to treat their diabetic patients successfully. It is much more likely that they have not been well informed. We need to share our data with our co-specialists and let them know that we need their help in patient evaluation, in judgment regarding surgical therapies, and in follow-up. Just as cardiac surgeons cannot function well without cardiologists, we cannot serve our patients ideally without the help of endocrinologists.
In terms of the major questions:
• What are the long-term outcomes, i.e. in terms of decades, from the various bariatric procedures?
• How do the bariatric operations compare in terms of efficacy, efficiency, and safety when applied to the different metabolic syndromes?
• What are the biologic mechanisms that account for the remission of each of the comorbidities?
• Why is the prevalence of cancer reduced after bariatric surgery?

Dr. Hutcher: This is a difficult and complex question as it is becoming more apparent that every facet of the metabolic syndrome and the related effects seem to be inter-related. This is very much like learning about the global nature of the banking system. Its role in diabetes, liver disease, hyperlipidemia, organic heart disease, hypertension, and even cancer seems to be intertwined. I believe many people will be working many hours over many years to identify these complex relationships. Having said that, I have stated many times that this issue has the simplest solution—eat less, eat better, exercise more. It is reasonably clear that the vast majority of metabolic issues are lifestyle-related. We have now “medicalized” lifestyle issues and are expending between 80 and 90 percent of our total healthcare budget on these issues. There is no question that many of these conditions are genetically based. We, however, are now seeing a perfect storm-like event as our genetic information is being acted upon by the current changes over the last 30 years of the availability of food, the switch to higher-density foods, and the almost complete reversal of the need for physical activity. I have always felt over the past 30 years that there was some mysterious activity going on in the duodenum and proximal small bowel that played a major role in expression of these serious comorbidities. Although much work remains to be done to identify, classify, and explain the activity and relationships of these substances, we do have enough information to confirm the importance of this area of the intestinal tract. My personal prejudice is that until we have a better understanding of these complex intestinal relationships, the single most important anatomic part of the bariatric operation will be to continue to bypass the duodenum and proximal small bowel.

REFERENCES
1.    Pories W, Caro JF, Flickinger EG, et al. The control of diabetes mellitus (NIDDM) in the morbidly obese with the Greenville gastric bypass. Ann Surg. 1987;206(3):316–323.
2.    Kelley DE, Wing R, Buonocore C, et al. Relative effects of calorie restriction and weight loss on noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1993;77:1287–1293.
3.    Sugerman HJ, Wolfe LG, Sica DA, Clore JN. Diabetes and hypertension in severe obesity and effects of gastric bypass-induced weight loss. Ann Surg. 2003;237:751–758.
4.    Shauer PR, Burguera B, Ikramuddin S, et al. Effect of laparoscopic Roux-en-Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003;238:467–485.
5.    Sjöström L, Narbro K, Sjöström CD. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 007;357(8):741–752.
6.    Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357(8):753–761.
7.    Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004;292(14):1724–1737.
8.    Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg. 2004;239:1–11.
9.    Strader AD, Vahl TP, Jandacek RJ, et al. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab. 2005;288:E447–E453.
10.    Rubino F. Is type 2 diabetes an operable intestinal disease? A provocative and reasonable hypothesis. Diabetes Care. 2008;31 (Suppl 2):S290–S296.
11.    Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes. J Clin Invest. 1999;104:787–794.
12.    Pories WJ, Albrecht RJ. Etiology of type 2 diabetes mellitus: role of the foregut. World J Surg. 2001;25:527–531.
13.    Lee W, Lee Y, Chen J, et al. A randomized trial comparing laparoscopic sleeve gastrectomy versus gastric bypass for the treatment of type 2 diabetes melitus: Preliminary report. SOARD. 2008;4(3);290.

Category: Interviews, Past Articles