Diabetes Surgery: What Have We Learned?

| April 6, 2010

by Ricardo Cohen, MD

Dr. Cohen is from the Center of Excellence of Bariatric Surgery and Metabolic Disorders, Oswaldo Cruz Hospital, Sao Paulo, Brazil

Financial Disclosures:
Dr. Cohen has no financial disclosures relevant to the content of this article.

Bariatric Times. 2010;7(4):23–25

Abstract
There is a growing body of evidence that demonstrates gastrointestinal surgery may provide benefits in the control of type 2 diabetes and metabolic syndrome. This article provides a general overview of what the surgical community has learned that has become the foundation of a new discipline—metabolic surgery.

Introduction
A growing body of evidence demonstrates that weight loss surgery can provide remission of type 2 diabetes melitus (T2DM). Roux-en-Y gastric bypass (RYGB) and bileopancreatic diversions (BPD) can achieve 80 to 95 percent of long-term T2DM remission. Regarding excess weight loss (EWL), the numbers long term[1] are quite impressive, but EWL over time is less representative than T2DM resolution numbers.[2] And T2DM resolution in the patients who undergo RYGB and BPD occurs before any significant weight loss.[3]
Several animal and human studies[4,5] demonstrated that the anatomical rearrangement of the gastrointestinal (GI) anatomy may contribute to the amelioration of the components of metabolic syndrome. Those initial results, with return to euglycemia and normal insulin levels observed within days after surgery, suggest that weight loss alone cannot entirely explain why surgery improves diabetes. It is the foundation of a new discipline, GI surgery for T2DM, based on a provocative rationale, where rerouting food through the bowel may effectively contribute to those formidable results. The main goal of this article is to provide a general overview of what the surgical community has done to achieve the status of “diabetes/metabolic surgeons.” It is not intended to deeply discuss mechanisms of action, levels of incretins, or statistically significant decreases in A1c or any other metabolic parameter. It is a reflection of what is going on in the foundation of a new discipline—metabolic surgery.

What have we learned?
How the operations work. We learned the mechanisms of action, as the proximal and distal intestinal mechanisms,[6–8] intestinal gluconeogenesis,[9] and intestinal bowel glucose transportation secondary to duodenal exclusion.[10] Those important contributions started to build a strong basis to understand the mechanisms underlying the good results achieved.

Working as a team. T2DM is absolutely a medical disease and surgery will probably benefit only a very small fraction of this enormous universe. So, in order to understand a new idiom—“diabetolese”—we learned to work with basic scientists and endocrinologists/diabetoligists.

To reach the patients and the other professionals we started to learn some new vocabulary, e.g., incretin effect, insulin resistance, antidiabetics, and when and how to introduce/withdraw drugs and insulin. Without knowing that language, we would not be able to communicate with the endocrinologists. As stated by Mr. Al Gore, “If you want to go quickly, go alone. But if you want to go distant, go with a group.”

Learning “diabetolese” and patient behavior. After some time dealing with this devastating condition, we were taught that there may be several causes of diabetes, including autoimmune diabetes mellitus and latent autoimmune diabetes of adults (LADA). We also learned that in a considerable amount of patients, surgery is not magic. Drugs may have to continue being taken and titrated over time. We heard and understood the meaning of “gluco and lipotoxicity” and that one of the primary goals of controlling T2DM is to reduce long-term cardiovascular mortality.

And diving into the medical literature, we learned that we must aim at all three points of the metabolic syndrome—blood pressure, lipid control, and glycemia. After all, it is not only about sugars.11,12 And what did we demonstrate from our perspective? In 2007, two major papers reported decreased cardiovascular, diabetes-related, and overall mortality in a long-term follow up of surgical bariatric patients.[13,14] Sjostrom et al[14] showed a 24-percent decrease in mortality rate, mainly second to cardiovascular and cancer, and Adams et al[13] showed a 92-percent decrease in diabetes-related deaths in the surgical group. In 2003, Schauer et al[15] reported an efficient “three endpoints attack” after studying RYGB in patients with diabetes. Surgery can be a multifactorial approach to metabolic syndrome.

In the first papers and reports of GI surgery in patients with body mass indices (BMIs) below 30kg/m2,[5,16–18] we learned that these patients have a different pathophysiology compared to patients with BMIs greater than 30kg/m[2] and diabetes. In later papers and reports, we learned that insulin resistance plays a major role in patients with BMIs less than 30kg/m[2]. Insulin resistance has a secondary participation, indicating that these patients have an intense beta cell dysfunction as a major component of their disease. This means that theese patients are harder to manage and good results are achieved over time where there is indirect evidence of an improved beta cell function.

Is it all about weight?
Indications for surgical treatment of T2DM should not be solely based on BMI. In general terms, BMI has been adopted worldwide as the predominant measure to guide classification of obesity and to determine risk of morbidity and mortality due to obesity. While BMI does represent one conveniently calculated parameter of obesity, it is  far from a fully inclusive measure of all risk. For instance, ethnicity plays a large role in obesity risk. For example, Asians do not correlate their BMI with their metabolic risk profile.[19] Several other parameters should be taken into account to properly assess the patient’s risk and selectively indicate the more suitable treatment. Waist circumference, fat distribution, and body composition are parameters that play a role in defining who bears “malignant obesity,” meaning that BMI alone is not an accurate predictor of the  risk to develop diabetes and/or metabolic syndrome. BMI is even less adequate as a measure to define the overall risk of morbidity and mortality in patients with established diabetes.[20] Fabbrini et al[21] recently proved that there other parameters that should be taken into account to stratify metabolic risk in individuals. Fabbrini et al found that the intrahepatic fat and insulin resistance are more important than the body fat distribution itself. In fact, using the current arbitrary BMI cutoff may delay a potentially life-saving option for patients with lower BMI who are at similar risk from diabetes. Cohen et al[22] in 2006 and Chiellini et al[23] in 2009 reported excellent results in treating patients with T2DM with RYGB and BPD, respectively, in a group of patients with BMIs below 35kg/m[2]. It is unquestionable that the discriminatory BMI criteria must be revised soon.

What was achieved?
So far, it has not been an inglorious enterprise. For the first time, bariatric surgery is mentioned in the American Diabetes Association  Guidelines (ADA) for T2DM control.[24] By December 2009, a consensus statement of the ADA was published defining T2DM cure,[25] based on decrease of A1c over time without any antidiabetic drug. In 2007, in Rome, Italy, a group of diabetologists, basic scientists, and surgeons met to define some guidelines to the approach of GI surgery for T2DM. The position statement that came from that meeting was recently published in the Annals of Surgery[.26]

Where are we going?
Although the preliminary data from studies on the efficacy of surgery on diabetes in patients with BMI less than 35kg/m[2] are encouraging, it would still be premature to consider a surgical approach generally indicated in these patients. In fact, due to the lack of well-controlled studies, it is not clear if a surgical approach would have satisfactory long-term efficacy and safety in patients with lesser degrees of obesity.
A large multicentered, randomized, clinical trial comparing surgery versus conventional medical treatment on patients with overweight or mild obesity and T2DM would help clinicians select the best approach and assist healthcare payers in their decision to cover specific treatment options. Clearly, a large-scale, randomized, controlled trial, as well as investigations aimed at identifying new parameters other than BMI to select appropriate candidates for surgical treatment of diabetes have become important research priorities.
In fact, the current BMI-centric paradigm of bariatric surgery is clearly obsolete and should be replaced by criteria based on metrics of diabetes and metabolic disease rather than BMI alone, consistent with the modern concept of “metabolic surgery.”

References
1.    Pories WJ, Dohm GL. Full and durable remission of type 2 diabetes? Through surgery? Surg Obes Relat Dis. 2009;5(2):285–288.
2.    Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122(3):248–256. e5.
3.    Bikman BT, Zheng D, Pories WJ. Mechanism for improved insulin sensitivity after gastric bypass surgery. J Clin Endocrinol Metab. 2008;93(12):4656–4663.
4.    Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741–749.
5.    Cohen RV, Schiavon CA, Pinheiro JS, et al. Duodenal-jejunal 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 Obes Relat Dis. 2007;3(2):195–197.
6.    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):1–11.
7.    Patriti A, Facchiano E, Sanna A, et al. The enteroinsular axis and the recovery from type 2 diabetes after bariatric surgery. Obes Surg. 2004;14(6):840–848.
8.    Strader AD, Clausen TR, Goodin SZ, Wendt D. Ileal interposition improves glucose tolerance in low dose streptozotocin-treated diabetic and euglycemic rats. Obes Surg. 2009;19(1):96–104.
9.    Troy S, Soty M, Ribeiro L, et al. Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap-band in mice. Cell Metab. 2008;8(3):201–211.
10.    Stearns AT, Balakrishnan A, Tavakkolizadeh A. Impact of Roux-en-Y gastric bypass surgery on rat intestinal glucose transport. Am J Physiol Gastrointest Liver Physiol. 2009 Sep 3. [Epub ahead of print]
11.    Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med. 2008;358(24):2630–2633.
12.    Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med, 2008;358(6):580–591.
13.    Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357(8):753–761.
14.    Sjöström L, Gummesson A, Sjöström CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357(8):741–752.
15.    Schauer PR, Burguera B, Ikramuddin S, et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003;238(4):467–484; discussion 84–85.
16.    DePaula AL, Macedo AL, Rassi N, et al. Laparoscopic treatment of type 2 diabetes mellitus for patients with a body mass index less than 35. Surg Endosc. 2008;22(3):706–716.
17.    Geloneze B, Geloneze SR, Fiori C, et al. Surgery for nonobese type 2 diabetic patients: an interventional study with duodenal-jejunal exclusion. Obes Surg. 2009;19(8):1077–1083.
18.    Ramos AC, Galvão Neto MP, de Souza YM, et al., Laparoscopic duodenal-jejunal exclusion in the treatment of type 2 diabetes mellitus in patients with BMI<30kg/m2 (LBMI). Obes Surg. 2009;19(3):307–312.
19.    Deurenberg P, Yap M, van Staveren WA. Body mass index and percent body fat: a meta analysis among different ethnic groups. Int J Obes Relat Metab Disord. 1998;22(12):1164–1171.
20.    Schulman AP, del Genio F, Sinha N, Rubino F. “Metabolic” surgery for treatment of type 2 diabetes mellitus. Endocr Pract. 2009;15(6):624–631.
21.    Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A, 2009;106(36):15430–15435.
22.    Cohen R, Pinheiro JS, Correa JL, Schiavon CA. Laparoscopic Roux-en-Y gastric bypass for BMI < 35 kg/m(2): a tailored approach. Surg Obes Relat Dis. 2006;2(3):401–404, discussion 404.
23.    Chiellini C, Rubino F, Castagneto M, et al. The effect of bilio-pancreatic diversion on type 2 diabetes in patients with BMI <35 kg/m2. Diabetologia. 2009;52(6):1027–1030.
24.    The American Diabetes Association (ADA) has been actively involved in the development and dissemination of diabetes care standards, guidelines, and related documents for many years. Introduction. Diabetes Care. 2009;32 Suppl 1:S1–S2.
25.    Buse JB, Caprio S, Cefalu WT, et al. How do we define cure of diabetes? Diabetes Care. 2009;32(11):2133–2135.
26.    Rubino F, Kaplan LM, Schauer PR, Cummings DE; Diabetes Surgery Summit Delegates. The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus. Ann Surg. 2010;251(3):399–405.

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