Myths Associated with Obesity and Bariatric Surgery—Myth 3: “Vertical sleeve gastrectomy is not a metabolic procedure.”
Exclusive Series: The Metabolic Applied Research Strategy Initiative
Part 4
Myths Associated with Obesity and Bariatric Surgery—Myth 3: “Vertical sleeve gastrectomy is not a metabolic procedure.”
by Randy J. Seeley, PhD; Jason L. Harris, PhD; and Lee M. Kaplan, MD, PhD
Abstract
The Metabolic Applied Research Strategy is a multi-year, multi-generational collaborative research program between the Massachusetts General Hospital, the University of Cincinnati, and Ethicon Endo-Surgery. Its focus is to interrogate and understand the physiologic and metabolic changes that occur after bariatric surgery (i.e., how bariatric surgery works to resolve conditions such as type 2 diabetes) with the goal of inventing new, less invasive, and less expensive treatments for patients suffering from obesity and its related health issues. In this article, which is the fourth in a series of articles published in Bariatric Times dedicated to the Metabolic Applied Research Strategy initiative, the authors discuss past and present understanding on why bariatric surgery works, its mechanism of action, and how these findings might help researchers, surgeons, and industry harness the remarkable effectiveness of bariatric surgery.
RANDY J. SEELEY, PhD
Dr. Randy J. Seeley is Professor of Medicine and holds the Donald C. Harrison Endowed Chair at the University of Cincinnati College of Medicine. In 2009, Dr. Seeley was appointed as the Director of the Cincinnati Diabetes and Obesity Center (CDOC). His scientific work has focused on the actions of various peripheral hormones in the central nervous system that serve to regulate food intake, body weight, and the regulation of circulating fuels. In particular, he focuses upon the numerous hypothalamic and gastrointestinal peptides and their associated receptors that influence both energy intake as well as peripheral metabolic processes with the aim of developing new treatment strategies for both obesity and diabetes.
JASON L. HARRIS, PhD
Dr. Jason L. Harris is a Principal Engineer leading Metabolic Applied Research Strategy co-invention and product development efforts at Ethicon Endo-Surgery, a Johnson and Johnson company. Since 2006, he has been exploring novel treatment approaches for patients suffering from the effects of metabolic disease. His primary focus is applying insights from basic and applied research efforts to develop improved therapies and predictive tools for the treatment of this disease.
LEE M. KAPLAN, MD, PhD
Lee M. Kaplan, MD, PhD, is Director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital (MGH) and Associate Professor of Medicine at Harvard Medical School. He is the Director of the subspecialty Fellowship Program in Obesity Medicine and Nutrition at MGH; Associate Director of the NIH-sponsored Boston-area Obesity and Nutrition Research Center; a member of the NIH Clinical Obesity Research Panel; and past chairman of the Board of the Campaign to End Obesity. Dr. Kaplan’s clinical expertise is in the areas of obesity medicine, gastroenterology, and liver disease. His research program is focused on understanding the mechanisms by which the gastrointestinal tract regulates metabolic function and using physiological and genetic approaches to identify therapeutically relevant subtypes of obesity and its complications.
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Introduction
The term metabolic surgery has been used to describe the important effects of at least some bariatric procedures on a variety of metabolic control systems. In particular, attention has been focused on the resolution of type 2 diabetes mellitus (T2DM) in patients after bariatric surgery. While it is difficult to underestimate the beneficial effects of weight loss alone to improve glucose regulation, metabolic surgery refers to the ability to improve such metabolic systems beyond those that are accrued from the weight loss itself. The two procedures that have received the most attention in terms of their ability to produce weight-independent effects on glucose regulation are biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass (RYGB).
Vertical sleeve gastrectomy: mechanisms of action
A key question becomes whether other procedures share the ability of these two procedures of inducing metabolic effects beyond their effect on body weight. Vertical sleeve gastrectomy (VSG) is often termed a “restrictive” procedure and does not involve the rerouting of nutrients in the small intestine that is presumably an important aspect of both BPD and RYGB. A wide range of data for VSG points to the notion that much of the effect of VSG cannot be explained by its gastric restrictive component.[1]
Evidence
It seems that reduction in food intake is not directly related to the restrictive elements of VSG. This can be seen in studies of rodent models where it is easier to make accurate measurements of food intake. While food intake suppression is a hallmark of VSG immediately following surgery, Wilson-Perez et al[2] have recently shown that after three weeks rats increased their intake such that it was back to the levels seen before surgery even though the stomach itself had not increased in volume.
More dramatically, this study also showed that rats that have been forced to lose more weight after surgery via direct food restriction returned to their post-VSG weight in a manner that was identical to that of animals who had not had surgery; they did so by increasing their food intake.[2] Consequently, they were not only capable of eating the normal amount of food for a rat, they could eat even more when called upon to do so.
Finally, when VSG rats were given a choice in their food consumption, they showed a profound shift in food choice toward less calorically dense foods.3 This stands in stark contrast to what would be expected if the physical restriction was a primary driver of the change in ingestive behavior since the animal should prefer more calorically dense substances.
Such behavioral results highlight that VSG must have an important impact on key signals that come from the gastrointestinal (GI) tract. It is possible that these altered physiological signals also affect glucose regulation in a weight-independent way. Again, a wide range of evidence would indicate that there is a potent effect of VSG to improve multiple aspects of glucose regulation.
Vertical Sleeve Gastrectomy and Glucose Regulation
First, in both rat and human models, VSG results in improvement in post-prandial glucose levels, an effect that is associated with a potent increase in the early insulin secretory response to nutrients in the GI tract.[4] Circulating GI hormone levels are also affected by VSG. In both rats and humans, dramatic increases in the secretion of glucagon-like peptide-1 (GLP-1) occurs after meals. Another key question is whether any of these important effects are “weight-independent.” Preliminary work in rodents would indicate that it is. In particular, when rats were evaluated at 14 days after VSG, RYGB, or dietary restriction, both VSG and RYGB had larger reductions in hepatic glucose production than the food-restricted controls. In addition to glucose regulation, rodent data indicate a potent and weight-independent effect of VSG to improve plasma triglycerides.[5] Such work points to an important effect of VSG to alter the liver in a manner that would reduce glucose levels in patients with T2DM.
Discussion
While there remains controversy about whether RYGB is substantially superior to VSG in inducing diabetes remission, recent data have shown that both operations result in diabetes remission that is substantially superior to medical management.[6] It is important to note that these results do not directly address the clinical question of which procedure should be the preferred metabolic surgery for an individual with T2DM or at elevated risk for T2DM. Further work is needed to help patients and surgeons match the best procedure for each individual. Nevertheless, the available data point to key metabolic effects of VSG that appear to be far greater than what would be expected from a purely restrictive procedure.
References
1. Stefater M a, Wilson-Pérez HE, Chambers AP, et al. All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr Rev. 2012;33:1–28.
2. Stefater MA, Pérez-Tilve D, Chambers AP, et al. Sleeve gastrectomy induces loss of weight and fat mass in obese rats, but does not affect leptin sensitivity. Gastroenterology. 2010;138(7):2426–2436, 2436.e1–3.
3. Wilson-Pérez HE, Chambers AP, Sandoval DA, et al. The effect of vertical sleeve gastrectomy on food choice in rats. Int J Obes (Lond). 2012 Feb 14. [Epub ahead of print]
4. Chambers AP, Jessen L, Ryan KK, et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology. 2011;141(3):950–958.
5. Stefater MA, Sandoval DA, Chambers AP, et al. Sleeve gastrectomy in rats improves postprandial lipid clearance by reducing intestinal triglyceride secretion. Gastroenterology. 2011;141(3):939–949:e1–4.
6. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–1576.
FUNDING: No funding was provided.
DISCLOSURES: Dr. Kaplan has received research support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIH), Ethicon Endo-Surgery, Merck Research Laboratories, and GI Dynamics. He has done consulting for C.R. Bard, Gelesis, Rhythm Pharmaceuticals, Medtronic, Sanofi-Aventis, Amylin Pharmaceuticals, Allergan, Merck, GI Dynamics, and Johnson & Johnson. Dr. Seeley has received research support, has done speaking or consulting for the following companies: Amylin Pharmaceuticals, Eli Lilly, Ethicon Endo-Surgery, Novo Nordisk, Zafgen Inc., Merck, Roche, Alkermes, and Pfizer. Dr. Harris is an employee of Ethicon Endo-Surgery.
Category: MARS Initiative Series, Past Articles
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