Myths Associated with Obesity and Bariatric Surgery—Myth 4: “Diabetes improvement after bariatric surgery is dependent on weight loss.”

Exclusive Series: The Metabolic Applied Research Strategy initiative

Part 5: Myths Associated with Obesity and Bariatric Surgery—Myth 4: “Diabetes improvement
after bariatric surgery is dependent on weight loss.”

by Lee M. Kaplan, MD, PhD; Randy J. Seeley, PhD; and Jason L. Harris, PhDAbstract
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 fifth 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.

Bariatric Times. 2012;9(7):12–14

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.

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.

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Introduction

Strategies for addressing the obesity epidemic have reached the national and international stage with well-publicized efforts from local, state, and federal governments launched with increasing regularity. A particularly important driver of these efforts is the large and rapidly growing burden of type 2 diabetes mellitus (T2DM), arising as a direct result of the increasing prevalence and severity of overweight and obese individuals. At present, approximately 8.3 percent of the United States population, or 25.8 million children and adults, have diabetes, with 7 million individuals undiagnosed and unaware of their diabetes.1 A parallel concern is the estimated 79 million Americans with prediabetes.[1] In 2010 alone, 1.9 million new cases of diabetes were diagnosed in people aged 20 years and older.[1]

The cost of treating diabetes and it associated complications was estimated to be $218 billion in 2007, and diabetes contributed to more than 230,000 deaths.1 While many effective strategies exist for managing T2DM, success at controlling this disorder and its complications remains elusive in many patients.

Bariatric Surgery and its Effect on Diabetes
Over the past several years, there has been a growing recognition of the highly beneficial effects of bariatric surgery on T2DM, with a large number of patients exhibiting what appears to be a complete remission of this disorder.2 The high speed of the improvement in markers of diabetes, particularly after diversionary procedures, such as Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD) or duodenal switch (DS), suggest that these operations may exert beneficial effects on diabetes independent of the weight loss induced by the surgery. Such effects could best be explained by changes in the physiology of metabolic regulation, an observation that has given rise to the idea that these “bariatric” procedures exert direct physiological influences. The fact that bariatric surgery works by altering the physiology of energy balance and weight regulation is now clear,3,4 but the rapid effects of several such procedures on T2DM further underscores their direct metabolic effects, an observation that has given rise to the concept of “metabolic” surgery. Indeed, with the publication of two seminal, randomized, controlled trials earlier this year5,6 that demonstrate the powerful effects of RYGB, vertical sleeve gastrectomy (VSG), and BPD, there is increasing awareness and acceptance of the use of surgery for the treatment of T2DM.

The Science of Diabetes
So, how do the various gastrointestinal weight loss surgical (GIWLS) procedures cause improvement or remission of T2DM?  It turns out that the answer to this question is complex.

T2DM results from disorders of glucose and lipid metabolism, a complex web of nutritional and metabolic regulation that can be perturbed in many ways. Central to this regulatory process is insulin, a key regulator of carbohydrate and lipid metabolism that is made and secreted by pancreatic beta-cells. T2DM starts with the development of cellular resistance to the actions of insulin, which leads to a compensatory increase in the secretion of insulin to overcome the resistance. The increased requirement for beta-cell insulin secretion, combined with the toxic effects of chronically elevated concentrations of glucose and fatty acids on beta-cell function, cause progressively worse dysfunction of these pancreatic endocrine cells such that they can no longer meet the need for enhanced insulin secretion (Figure 1). The reduced insulin secretory capacity, combined with the increased need to overcome insulin resistance, causes an effective insulin deficiency state, or diabetes mellitus.

Mechanisms of Action in Diabetes Improvement
Several pharmacological approaches are available to treat T2DM. Some, such as insulin itself, or drugs that stimulate beta-cell insulin secretion (e.g., GLP-1 agonists and sulfonylureas) help overcome the beta-cell dysfunction that underlies T2DM. Others, such as thiazolidinediones (e.g., pioglitazone) and metformin, enhance effective insulin signaling so that less insulin is required to be secreted.
Metabolic surgery exerts effects that are in many ways similar to these drugs, causing improvement in both insulin secretion and insulin sensitivity (signaling); however, different operations appear to work through different mechanisms, as demonstrated by their differing clinical effects. For example, laparoscopic adjustable gastric banding (LAGB) has been shown to have substantial beneficial effects on T2DM, but these improvements occur over several weeks and months, in parallel with the associated weight loss. In contrast, the diversionary procedures (RYGB and BPD/DS) and VSG induce more rapid improvement in diabetes and appear to have effects above and beyond those caused by the associated weight loss alone.

As described previously, numerous studies have demonstrated that weight loss leads to improvement in T2DM, an unsurprising observation given the close association between obesity and the development of diabetes. Importantly, however, diet-induced weight loss causes a dramatic improvement in T2DM that begins well before significant weight loss. A similar improvement has been shown to result from the acute decrease in food intake that is an intrinsic component of most diets. Since food intake is severely limited immediately after bariatric surgery, the early postoperative improvement in T2DM certainly results in part from the acute drop in food intake. This important effect cannot be the whole story, however, since the rate of improvement varies among different bariatric procedures, and many other operations that require decreased postoperative food intake do not lead to the same degree of acute improvement in glucose regulation. Thus, we have to consider: 1) that some of the early effects of surgery occur independently of the decreased postoperative food intake (and thus enhance those effects), and 2) that different operations affect these early mechanisms differently.

From the available clinical data RYGB and BPD/DS appear to cause the most rapid postoperative improvement in glucose regulation, with an intermediate effect of VSG and a more gradual improvement after LAGB.[7]

Studies in animal models of RYGB and VSG[8–10] have clearly demonstrated an improvement in glucose homeostasis that is greater than that observed by a similar degree of food restriction alone, providing strong evidence for a direct and immediate metabolic effect of these procedures and differentiating them from LAGB in this regard.

A similar effect has been shown after implantation of an endoluminal duodenal-jejunal liner in rats,[9] suggesting that the duodenal bypass component of RYGB and BPD/DS (rather than the gastric manipulation) is the primary mediator of this metabolic effect in the diversionary procedures. If this is true, however, how can we explain the direct metabolic effect of VSG, since it does not include duodenal exclusion? The answer to this question is still unknown and is an important focus of ongoing investigation.

Late after each of these operations, the acute decrease in food intake is less profound, but of course, weight loss is nearly universal. Since weight loss, and particularly the substantial weight loss induced by these procedures, is unquestionably associated with improvement in T2DM, it is reasonable to conclude that the weight loss is the primary driver of the long-term improvement in T2DM. There is no doubt that weight loss makes a crucial contribution. However, the differences in outcomes from different bariatric procedures provide strong evidence for another, weight loss independent mechanism, at least for RYGB, BPD/DS, and VSG (See Table 1 for a summary of recent comparative studies).

Weight Loss Independent Mechanisms of Action
In the past few years, both human and animal studies[8–10] have demonstrated that the improvement in glucose tolerance (the response to ingestion or intravenous administration of a large dose of glucose) after these procedures is greater than that produced with an equivalent amount of weight loss induced by food restriction alone. Glucose tolerance testing is an assessment of the overall glucose regulatory system, reflecting both insulin secretory activity and the effectiveness of insulin action (i.e., insulin sensitivity). While glucose regulation and insulin sensitivity are improved after all forms of bariatric surgery, RYGB, BPD/DS, and VSG improve insulin secretion to a far greater extent than seen after weight loss alone.

Conclusion
So, why is this important? First, it helps us differentiate among different procedures. All bariatric surgery causes decreased food intake and weight loss, both of which lead to improvements in T2DM. VSG and diversionary procedures appear to exert an additional effect above and beyond decreased food intake and weight loss. This direct physiological effect provides a means of differentiating bariatric surgery from true metabolic surgery, and the metabolic effects of these operations may explain the high rates of full remission and the durability of improvement in T2DM.

Second, the direct metabolic effects of surgery could be particularly valuable in the treatment of patients with T2DM without severe obesity. Many patients with T2DM, particularly those of south or east Asian origin, have a much lower body mass index (BMI) than typical T2DM patients of European or African descent. The weight loss independent effects of these metabolic procedures may be essential to maximizing the benefit in these lower weight populations.

Finally, the ability of these procedures to induce direct metabolic effects provides a unique and valuable opportunity. The physiological mechanisms that mediate these effects, once better understood, could be harnessed to develop new therapies for T2DM, such as specialized surgery, medical devices, and drugs that complement and enhance our current approaches. Elucidating those mechanisms and using that understanding to develop novel therapies are primary goals of MARS and similar efforts to address the growing worldwide epidemic of diabetes. In the meantime, we still have surgery itself, a regulator of metabolic function, that is likely to have an increasing role in the long-term management of T2DM and its often devastating consequences.

References
1.     American Diabetes Association, Diabetes Statistics, 2011 National Diabetes Fact Sheet . http://www.diabetes.org/diabetes-basics/diabetes-statistics/
2.    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(3):339–350; discussion 350–352.
3.    Kaplan LM, Seeley RJ, Harris J. Myths associated with obesity and bariatric surgery. Myth 2: “Bariatric surgery induces weight loss primarily by mechanical restriction and nutrient malabsorption.” Bariatric Times. 2012;9(5):12–13
4.    Seeley RJ, Kaplan LM, Harris J. Myths associated with obesity and bariatric surgery. Myth 3: “Vertical sleeve gastrectomy is not a metabolic procedure.” Bariatric Times. 2012;9(6):16–17
5.    Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–1576.
6.    Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577–1585.
7.    Rubino F, R’bibo SL, del Genio F, et al. Metabolic surgery: the role of the gastrointestinal tract in diabetes mellitus. Nat Rev Endocrinol. 2010;6(2):102–109.
8.    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.
9.    Muñoz R, Stylopoulos N, Davis P, Kaplan LM. Isolated duodenal exclusion improves glucose homeostasis by both weight loss-dependent andindependent mechanisms in diet-induced obese rats. Obesity. 2010;18 (Supp 2): S5.
10.    Muñoz R, Stylopoulos N, Yin H, Kaplan LM. 2011. GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in diet-induced obese (DIO) mice. Presented at: American Diabetes Association 71st Scientific Sessions, 2011.
11.    Gan SS, Talbot ML, Jorgensen JO. Efficacy of surgery in the management of obesity-related type 2 diabetes mellitus. ANZ J Surg. 2007;77(11):958–962.
12.    Lee WJ, Chong K, Ser KH, et al. Gastric bypass vs sleeve gastrectomy for type 2 diabetes mellitus: a randomized controlled trial. Arch Surg. 2011;146(2):143–148.
13.    Chouillard EK, Karaa A, Elkhoury M, et al. Laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy for morbid obesity: case-control study. Surg Obes Relat Dis. 2011;7(4):500–505.
14.    Vidal J, Ibarzabal A, Nicolau J, et al. Short-term effects of sleeve gastrectomy on type 2 diabetes mellitus in severely obese subjects. Obes Surg. 2007;17(8):1069–1074.
15.    Vidal J, Ibarzabal A, Romero F, et al.  Type 2 diabetes mellitus and the metabolic syndrome following sleeve gastrectomy in severely obese subjects. Obes Surg. 2008;18(9):1077–1082.
16.    Lakdawala MA, Bhasker A, Mulchandani D, Goel S, Jain S. Comparison between the results of laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass in the Indian population: a retrospective 1 year study. Obes Surg. 2010;20(1):1-6.
17.    Abbatini F, Rizzello M, Casella G, et al. Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes. Surg Endosc. 2010;24(5):1005–1010.
18.    Benaiges D, Goday A, Ramon JM, et al. Laparoscopic sleeve gastrectomy and laparoscopic gastric bypass are equally effective for reduction of cardiovascular risk in severely obese patients at one year of follow-up. Surg Obes Relat Dis. 2011;7(5):575–580.
19.    Nocca D, Guillaume F, Noel P, et al. Impact of laparoscopic sleeve gastrectomy and laparoscopic gatric bypass on HbA1c blood level and pharmacological treatment of type 2 diabetes mellitus in severe or morbidly obese patients. Results of a multicenter prospective study at 1 year. Obes Surg. 2011;21(6):738–743.
20.    Ruiz de Gordejuela AG, Pujol Gebelli J, García NV, et al. Is sleeve gastrectomy as effective as gastric bypass for remission of type 2 diabetes in morbidly obese patients? Surg Obes Relat Dis. 2011;7(4):506–509.

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