Metabolic Surgery

First submitted by:
Shawn Tsuda
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Type 2 diabetes mellitus (T2DM) is a major cause of death in the world given its relation to kidney failure, blindness, amputations, heart attack and others as erectlie dysfunction, diarrhea and gastroparesis . Medical therapy for this disease has advanced considerably but still leaves a majority of patients susceptible to its severe effects. While new drug therapies continue to improve medical therapy for this disease, a majority never reach the defined targets for success .

Results following bariatric surgery

Clinical resolution of T2DM, usually defined as independence from all antidiabetic medications, was reported to occur in 48% of patients after adjustable gastric banding (AGB), 84% after Roux-en-Y gastric bypass(RYGB) and 98% after bilio pancreatic diversion (BPD) . T2DM resolution in AGB is proportional to weight loss. The remarkable resolution of diabetes after the 2 last mentioned procedures typically occurs too fast to be accounted for by weight loss alone, suggesting that there may have a direct and more profound impact on glucose homeostasis. The antidiabetic effect of bariatric surgery is long lasting. Long-term control of glycemia and normal levels of glycosylated hemoglobin after RYGB have been documented in large series with up to 14 years of follow up . While T2DM is often associated with obesity, this relationship is highly dependant on geographic location. The average BMI of a T2DM patient in the United States is 30 while in India, the average is 27 .Despite its efficacy with respect to weight loss and resolution of co-morbid health conditions, bariatric surgery is in theory, less desirable for normal/overweight patients. Bariatric operations have occasionally been performed in non-morbidly obese individuals. Cohen et al.,recently published the surgical treatment of 37 patients outside the standard 1991 NIH surgical indications, with BMIs varying from 32 to 35, all with T2DM among other comorbidities. These patients underwent laparoscopic RYGB and all had remission of their diabetes. The final common pathway of current and past surgical experience with regard to diabetes resolution seems to be duodenal bypass, although there is some degree of swifter food delivery to distal intestine in both RYGB and BPD. Eventually, amelioration of T2DM can be accounted for by the well-known effect of weight loss to increase insulin sensitivity, thereby decreasing glucotoxicity and lipotoxicity and improving ß-cell function, but again, T2DM remission usually occurs days or weeks after RYGB or BPD. So, if T2DM resolution happens long before considerable weight loss, it is long lasting, so why not offer it to lower BMI patients?

Potential mechanisms for glycemic control

Regardless of the molecular explanation, which still remains to be elucidated, it would be very important to understand which part of the typical anatomical rearrangement of RYGB/BPD is essential for the effect on diabetes. Two hypothesis have been proposed, based on some elegant animal studies. The ” foregut or upper intestinal hypothesis” holds that the exclusion of the duodenum and proximal jejunum from the transit of nutrients may prevent the secretion of a putative signal that promotes insulin resistance and leads to T2DM control. An alternative hypothesis the “hindgut or distal intestinal hypothesis”, justifies T2DM remission as resulting from the expedited delivery of nutrient chyme to the distal intestine, enhancing a physiologic signal that improves glucose metabolism .A potential candidate mediator of this effect is GLP-1 and/or other distal gut peptides. Although no obvious candidate molecules can be identified with current knowledge, if proven true, those theories might open new avenues in the search for the cause and cures of diabetes.

Recent human reports

a) Duodenal jejunal bypass (DJB) – Cohen et al. published in early 2007, a step toward extending animal studies’ findings into the clinical arena, reporting 2 cases of persons with diabetes who underwent a DJB. The patients were overweight or mildly obese, with BMIs of 29 and 30.3 kg/m2. Their diabetes was not particularly longstanding (2 and 7 years, respectively), and it was treated before surgery with insulin plus metformin in one case, and with rosiglitazone in the other. Although no preoperative laboratory data were shown, evaluations at one week, one month, and thereafter at monthly intervals for 9 months, demonstrated rapid and unequivocal improvements in several simple measures of glucose control. Fasting blood sugars were initially in the diabetic range (148 and 178 mg/dL), but they decreased steadily after surgery, reaching nondiabetic values by 1 month and remaining at 100 mg/dL throughout postoperative months 3 through 9. Similarly, fasting insulin levels started high (27 and 29 mmol/L) but declined quickly and progressively after surgery, remaining at levels typical of persons without diabetes (approximately 5 mmol/L) throughout postoperative months 3 through 9. Reflecting the improvement in glycemia, hemoglobin A1c values fell from diabetic (8%–9%) to normal (5%–6%) values by 3 months, and they remained equally low thereafter during the remaining 6 months of observation. One patient was discharged a few days after surgery without any diabetes medications, and the other had discontinued diabetes medications by 5 weeks after surgery. In short, both patients converted from having poorly controlled diabetes, despite being on medications, to having normoglycemia off of all such medications. A key finding was that this salutary transformation occurred with no weight loss in either patient. b) Ileal Interposition (IL) – De Paula in 2006 described the initial experience performing laparoscopic ileal interposition combined with gastric restriction (“neuroendocrine brake” operation) in severely obese adults. Nineteen patients underwent laparoscopic sleeve gastrectomy and were followed up a mean of 11.6 months (range 1–17) and among them, 5 were diabetic. After 3 weeks, all 5 patients with T2DM preoperatively (3 taking oral hypoglycemic agents and 2 receiving insulin) had normal blood glucose levels without medication. The authors hypothesize that this operation might have significant advantages compared with simple, purely gastric restrictive operations by diminishing the gastroesophageal reflux of proximal gastric stenosis with its side effects and long-term sequelae and by eliminating the need for cognitive control of eating behavior , owing to the appetitive effects of the nutrient-stimulated ileal segment . Furthermore, in the absence of the small intestinal bypass, characteristic of all combined bariatric surgical procedures to date, this operation avoids the risk of significant malabsorption and the attendant requirement for supplementation.

Proposed guidelines

On late March 2007, a group of around 53 professionals involved with T2DM, reunited in Rome for a consensus conference on the further steps that should be followed to achieve success in the exciting field of metabolic surgery. Among the experts, there were basic scientists, endocrinologists, diabetologists and surgeons. This meeting was called the 2007 Diabetes Surgery Summit. Several presentations were given in 2 days and in the third, after an electronic voting panel among the experts some statements regarding the future of metabolic surgery were released. To validate any statement, e.g, to call it “consensus’,they should be voted by at least 70% of the experts involved. The main consensus statements were: – All bariatric operations improve T2DM, however, only some of them match the criteria for the definition of antidiabetic operations (100%); – Anatomic modification of various regions of the GI tract likely contribute to the amelioration of T2DM trough distinct physiological mechanisms. (83%); – Gastrointestinal bypass procedures can improve diabetes by mechanisms beyond changes in food intake and body weight. (98%); – Gastrointestinal surgery may be appropriate for the treatment of T2DM in patients who are appropriate surgical candidates with BMI of 30 to 35 who are inadequately controlled by lifestyle and medical therapy. (82%) – Collaboration among endocrinologists, surgeons and basic investigators should be encouraged to facilitate the understanding of GI mechanisms of metabolic regulation and to allow use of these mechanisms for improved treatment of T2DM. (100%) Hopefully, such guidelines can be established, so that proper clinical trials of “diabetes surgery” can move forward, in association with basic animal experiments designed to elucidate the fascinating mechanisms by which various rearrangements of gastrointestinal anatomy can control T2DM.

References

1) 1.King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care1998; 21:1414-31.
2) Pories WJ, MacDonald KG, Morgan EJ, e cols.. Surgical treatment of obesity and its effect on diabetes: 10-y follow-up. Am J Clin Nutr 1992; 55 (2 Suppl): 582S–585S.
3) Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724 –37.
4) Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995;222:339 –52
5) Cohen R, Pinheiro JS, Correa JL, Schiavon CA. Laparoscopic Roux-en-Y gastric bypass for BMI <35 kg/m2: a tailored approach Surgery for Obesity and Related Diseases 2006; 2 : 401-404
6) Cummings DE, Overduin J, Foster-Shubert KE, Carlson M – Role of the bypassed proximal intestine in the antidiabetic effects of bariatric surgery. Surgery for Obesity and Related Diseases 3 (2007) 109–115
7) Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal 97 small intestine in the pathophysiology of type 2 diabetes. Ann Surg 2006;244:741–9.
8) Strader AD, Vahl TP, Jandacek RJ, Woods SC, D’Alessio DA, Seeley RJ. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab 2005;288:E447–53.
9) Cohen R, Schiavon CA, Pinheiro JC, Correa JL, Rubino F. Duodenaljejunal bypass for the treatment of type 2 diabetes in patients with body mass index of 22–34 kg/m2: a report of 2 cases. Surg ObesRelat Dis 2007;3: 195-197.
10)de Paula AL, Macedo AL, Prudente AS, Queiroz L, Schraibman V,Pinus J. Laparoscopic sleeve gastrectomy with ileal interposition (“neuroendocrine brake”) – pilot study of a new operation. Surg ObesRelat Dis 2006;2:464- 467