Weight-loss surgery has been shown to reduce comorbidities

RESEARCH Review Obesity Surgery: Evidence for Diabetes Prevention/Management SUE CUMMINGS, MS, RD; CAROLINE M. APOVIAN, MD, FACP; LALITA KHAODHIAR, MD ABSTRACT Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. Development of type 2 diabetes can be delayed or sometimes prevented from manifestation in individuals with obesity that are able to lose weight. Weight loss can be achieved either medically with behavioral therapies that combine diet and exercise treatment or with behavioral therapies combined with weight-loss medications or weight-loss surgery. There is strong evidence of an amelioration or resolution of type 2 diabetes in patients undergoing gastric bypass surgery. A recently published retrospective cohort study indicated that long-term total mortality from diabetes, heart disease, and cancer after gastric bypass surgery was substantially reduced. In this review, we summarize the evidence of surgical interventions in the treatment of type 2 diabetes. J Am Diet Assoc. 2008;108:S40-S44. Weight-loss surgery has been shown to reduce comorbidities and mortality in patients with obesity and most significantly to ameliorate or resolve type 2 diabetes (1-3). Data from epidemiological studies have clearly shown the increased risk of type 2 diabetes as body weight increases. In the Nurses Health Study (4), a large prospective cohort study that involved over 121,000 female registered nurses age 30 to 55 years, increased risk for diabetes was observed with body mass indexes (BMI; calculated as kg/m 2 ) as low as 22. Women S. Cummings is clinical programs coordinator, MGH Weight Center, Massachusetts General Hospital, Boston, MA. C. M. Apovian is associate professor of Medicine and Pediatrics, Boston University School of Medicine and director, Nutrition and Weight Management Center, Boston Medical Center, Boston, MA. L. Khaodhiar is assistant professor of Medicine, Boston University School of Medicine and Nutrition and Weight Management Center, Boston Medical Center, Boston, MA. STATEMENT OF CONFLICT OF INTEREST: See page S43. Address correspondence to: Sue Cummings, MS, RD, MGH Weight Center, Massachusetts General Hospital, 50 Staniford St, 4th floor, Boston, MA 02114. Manuscript accepted: December 12, 2007. Copyright 2008 by the American Dietetic Association. 0002-8223/08/10804-1006$34.00/0 doi: 10.1016/j.jada.2008.01.017 with a healthy BMI of 24.0 to 24.9 had up to a fivefold elevated risk when compared with women with a BMI 22. In those with a BMI 31, risk of type 2 diabetes increased by more than 40-fold. The Professionals Health Study, which includes more than 51,000 US male health professionals 40 to 75 years of age, showed similar results (5). Relative risk of diabetes in men with a BMI of 35 was 42 times higher than that in men with a BMI 23. After controlling for BMI at age 21, family history, age and smoking habits, men who gained 15 kg after age 21 had a 8.9 times higher risk of diabetes than those who were within 2 kg of their weight at 21 years of age. OBESITY AND TYPE 2 DIABETES MELLITUS Obesity, particularly central obesity (abdominal adiposity) and type 2 diabetes independently and synergistically result in insulin resistance with hyperinsulinemia. This is believed to play a primary role in development of type 2 diabetes (6). Insulin resistance is also linked to other obesity-related comorbid conditions, including hypertension, dyslipidemia, atherosclerosis (ie, the metabolic syndrome) and polycystic ovary disease (7). Although many aspects of the mechanisms by which excess adipose tissue causes insulin resistance remain unknown, our understanding of the so called adipo-insulin axis has substantially increased during the past decade (8,9). Because insulin resistance is an adaptation of obesity, there is no question that any interventions that produce weight loss will improve insulin sensitivity. A reduction of fat mass that occurs with weight loss results in reduction of lipid oxidation and enhancement of glucose metabolism (10). Insulin secretion and plasma insulin concentrations have been shown to decrease substantially after weight loss. EFFECTS OF WEIGHT ON TYPE 2 DIABETES MELLITUS Weight-Loss Surgery Surgical procedures are characterized as purely restrictive (the laparoscopic adjustable gastric band (LAGB); gastric restriction with some malabsorption (the Rouxen-Y gastric bypass (RYGBP); or gastric restriction with substantial intestinal malabsorption (biliopancreatic diversion without or with duodenal switch). The two most common weight loss surgical procedures performed in the United States today are the RYGBP and LAGB procedures; fewer surgeons are performing the biliopancreatic diversion and biliopancreatic diversion with duodenal switch, which will not be discussed at length in this article. S40 Supplement to the Journal of the AMERICAN DIETETIC ASSOCIATION 2008 by the American Dietetic Association

Figure 1. The Roux-en-Y gastric bypass procedure. Illustration courtesy of Janey Pratt, MD. This review will focus primarily on the RYGBP and the LAGB and the effects on type 2 diabetes. When reviewing the literature and comparing weight-loss outcomes, it is important to note that the surgical literature often refers to weight loss as a percentage of excess body weight, (excess weight loss [weight loss/excess weight] 100); excess weight is the total preoperative weight minus ideal weight. The medical literature more often describes weight loss as a percentage of initial body weight. When comparing studies, readers must be aware of the standard being used for weight-loss assessment. The beneficial effect of the bypass procedures on type 2 diabetes is one of the most important outcomes of weightloss surgery. Shorter duration of type 2 diabetes prior to surgery is one predictor of remission (1). Patients on insulin therapy who undergo these procedures, experience substantial decreases in insulin requirements, with the majority of type 2 diabetes patients able to completely discontinue insulin by 6 weeks postoperatively (11). Exact mechanisms for weight loss after RYGBP are not known; however, weight loss occurs most likely from a combination of restriction and changes in neural and hormonal pathways. The RYGBP procedure involves creating a small gastric pouch; the jejunum is divided 30 to 50 cm distal to the ligament of Treitze and the distal limb of the jejunum is then anastomosed to the small gastric pouch and a jejunojejunostomy is performed 50 to 150 cm distal from the gastrojejunostomy (Figure 1). Most gastric bypass studies report a weight loss of 60% to 70% of excess body weight (30% to 35% of total body weight). In a meta-analysis of 4,204 gastric bypass patients, mean excess body weight lost was reported as 68% (35% of initial weight) (12). There is evidence of resolution of type 2 diabetes in some individuals after the gastric bypass procedure, leaving some to suggest surgery as a cure (13). Two published studies by Schauer and colleagues (1) and Sugerman and colleagues (2) report resolution in 83% and 86% of patients, respectively. At 2-year follow-up, a 60% decrease in plasma insulin and a 20% decrease in plasma glucose were seen in the surgical weight-loss group in the Swedish Obesity Subjects study (14). Resolution of diabetes is more prevalent following gastric bypass than in gastric banding, 83.7% for gastric bypass and 47.9% for gastric banding (15). Buchwald and colleagues conducted a systematic review of the literature subjected to a meta-analysis with respect to comorbidity outcomes of bariatric surgery; they focused on the impact of bariatric surgery on four selected obesity comorbidities, including diabetes (12). In this meta-analysis of weight-loss surgeries, evidence of improvement in type 2 diabetes and impaired glucose tolerance was found across all bariatric surgeries. Diabetes was completely resolved in 76.8% of patients and resolved or improved in 86%. The meta-analysis data shows slower weight loss and less improvement in comorbidities, including diabetes, after the LAGB as compared to RYGBP. The LAGB procedure reduces the volume of the stomach. A band is placed round the upper part of the stomach, creating a small pouch that empties into the remaining lower stomach, the proximal foregut is not bypassed. A port is placed under the skin, which is tethered to the band by tubing that allows access for regular fills (adjustments) of the band (Figure 2). Placing the LAGB is a less-invasive procedure then the RYGBP procedure; it is adjustable and reversible, which makes it an attractive option for many patients. However, the reoperation rate is higher because of complications, such as band slippage or erosion. In a meta-analysis of 1,848 patients who had undergone gastric banding, the weighted mean weight loss was 50% of excess body weight (approximately 25% of initial weight loss) (12). In a randomized, prospective trial, the LAGB was associated with substantially less excess weight loss than the RYGB at 5 years postsurgery (16). MECHANISMS Although it has been a long-held belief that weight loss and decreased food intake are the mechanisms for remission of diabetes after weight-loss surgery, resolution of diabetes often occurs days after RYGBP surgery, before any substantial weight loss occurs (15). Resolution or improvement after bypass bariatric surgery may be related to metabolic changes that occur. Bypassing the fore- April 2008 Supplement to the Journal of the AMERICAN DIETETIC ASSOCIATION S41

Figure 2. The laparoscopic adjustable gastric band procedure. Illustration courtesy of Janey Pratt, MD. gut leads to improvement in the physiological responses of gut hormones involved in glucose regulation and appetite control, including ghrelin, glucagon-like peptide-1, and peptide YY (17,18). Insulin resistance and loss of glucose-stimulated acute insulin response are the two major and earliest defects in the course of type 2 diabetes. Polyzogopoulou and colleagues investigated whether weight loss after bariatric surgery in patients with obesity and type 2 diabetes could restore euglycemia and normal acute insulin response to an intravenous glucose tolerance test (19). Euglycemia was restored in parallel with the normalization of insulin sensitivity, the reappearance of a normal acute insulin response to glucose and restoration of a normal relationship of acute insulin response to insulin sensitivity in their subjects (19). The patients in this study underwent a biliopancreatic diversion with RYGBP, which not only normalized insulin sensitivity early after surgery when the patients still had obesity, but also restored a normal acute insulin response appropriate to the degree of insulin sensitivity. The detailed mechanisms that led to normalization of glucose tolerance and insulin secretion in this study are not entirely known. The researchers concluded that their findings support the concept that the diminished acute insulin response for the degree of insulin resistance is important for development of impaired glucose tolerance and diabetes. Their results show that loss of glucose-induced acute insulin response in patients with obesity and type 2 diabetes of mild or moderate severity is not permanent, but reversible (19). Faraj and colleagues examined the hypothesis that the change in adipose tissue hormones, acylation-stimulating protein, leptin, and adiponectin, may predict amelioration of the metabolic and cardiovascular risk factors after weight-loss surgery (20). They looked at fasting plasma insulin, acylation-stimulating protein, and metabolic/cardiovascular risk profile before and 15 months after RYGBP surgery in 50 subjects. The concentration of acylation-stimulating protein is elevated in obesity, type 2 diabetes mellitus, and coronary artery disease. Acylationstimulating protein increases both glucose uptake and fatty acid esterification in a manner that is independent of, but additive to, insulin. Eighty-six percent of the patients had elevated preoperative plasma acylation-stimulating protein concentrations, which decreased postoperatively. However, because most subjects met the criteria for obesity (BMI 30) even after substantial weight loss, the average concentrations remained higher than normal. Adiponectin is one of the most abundant adipose tissue specific factors and data suggests that it is a mediator of insulin sensitivity and an enhancer of fatty acid oxidation (21). Low levels of adiponectin are associated with risk factors for coronary artery disease. In this study, adiponectin increased in response to weight loss after RYGBP surgery in almost all subjects, and mean adiponectin levels were normal in all postoperative subjects. Overall findings from this study suggest that preoperative fasting adiponectin concentrations are predictive of the extent of weight loss; and, changes in acylation-stimulating protein and adiponectin improve insulin action. Kellum and colleagues examined the gastrointestinal hormone responses to meals in patients before and after RYGBP and vertical banded gastroplasty (22). Vertical banded gastroplasty was the most common procedure done in the United States in the early 1980s. Vertical banded gastroplasty is a purely restrictive procedure and is rarely performed today, having been replaced by the LAGB. Substantial glucose intolerance was noted in study subjects before weight-loss surgery. Vertical banded gastroplasty patients had lesser reductions of hyperglycemia and hyperinsulinemia postsurgery. However, after RYGBP surgery, there was a substantial reduction of fasting and postprandial glucose levels after meals high in glucose or carbohydrate. Patients who underwent RYGBP surgery had a substantial lowering of glucose levels while fasting and at all times after a protein meal. In addition, the 3-hour integrated glucose response to a carbohydrate meal decreased substantially in these patients. They concluded that RYGBP surgery results in amelioration of glucose intolerance and hyperinsulinemia (22). Hanusch-Enserer and colleagues tested the hypothesis that LAGB decreases plasma ghrelin concentration and that this effect precedes changes in body weight (23). However, in their observations, the mean fasting plasma ghrelin concentrations before and after LAGB surgery did not differ substantially, At 12 months post-lagb surgery, there was a trend toward a higher plasma ghrelin concentration. They also report decreases in plasma glucose and plasma C-peptide concentrations at 12 months postbanding, and an increase in insulin sensitivity. These improvements were more likely related to the total amount of weight lost. These researchers conclude that the success of RYGBP surgery cannot be explained sim- S42 April 2008 Suppl 1 Volume 108 Number 4

ply by the reduction of the gastric volume, but also must involve other metabolic mechanisms. Bariatric Surgery: Morbidity and Mortality in Patients with Type 2 Diabetes MacDonald and colleagues compared a group of patients with type 2 diabetes who underwent gastric bypass with a nonsurgical control group. The two groups were compared retrospectively to determine differences in survival and need for medical management of their diabetes (24). Mean glucose levels in the surgical group fell from 187 mg/dl preoperatively and remained 140 mg/dl for up to 10 years of follow-up. The percentage of control subjects being treated with oral hypoglycemics or insulin increased from 56.4% at initial contact to 86.5% at last contact (mean length of follow-up for the control group was 6.2 years). The percent of surgical patients requiring medical management fell from 31.8% preoperatively to 8.6% at last contact (mean follow-up for surgical patients was 9 years). Mortality rate in the control group was 28% compared to 9% in the surgical group. Researchers reported that for every year of follow-up, patients in the control group had a 4.5% chance of dying vs a 1% chance for those in the surgical group (24). The improvement in mortality rates was primarily a result of the decrease in the number of cardiovascular deaths. Kopp and colleagues report that elevated levels of C- reactive protein (CRP) and interleukin-6 (IL-6) have been associated with features of insulin-resistance syndrome and incidence of cardiovascular disease (25). They studied the cross-sectional and longitudinal relation of CRP, IL-6 and tumor necrosis factor- with features of the insulin-resistance syndrome in patients at different stages of glucose tolerance before and 14 months after banded gastroplasty surgery. Their analysis revealed that the decrease in insulin resistance remained independently and substantially correlated with a decrease in IL-6 concentrations and the decrease in body mass index correlated with the decrease in CRP. These researchers demonstrated a substantial reduction in the levels of CRP and IL-6 by as much as 81% and 23%, respectively, compared with baseline levels. A doubling of CRP or IL-6 levels has been found to be associated with a doubling in the risk of myocardial infarction in apparently healthy men. They conclude that it is likely that a substantial reduction in CRP and IL-6 levels associated with weight loss could also reduce cardiovascular risk in patients with severe obesity. Bariatric Surgery and Type 2 Diabetes: Looking to the Future In the spring of 2007, the first International Consensus Conference on the role of bariatric and gastrointestinal operations in treating type 2 diabetes convened in Rome, Italy. The intent of the conference was to gather world authorities with expertise in type 2 diabetes, obesity, bariatric surgery, and evidence-based medicine to collectively review evidence regarding the effect of bariatric and gastrointestinal operations on diabetes remission, as well as possible mechanisms of action. The goal of this panel was to develop consensus statements regarding the role of surgery and type 2 diabetes and set forth priorities, guidelines, and opportunities for further research. Preliminary recommendations were reported at the 2007 Practical Approaches for the Treatment of Obesity Conference in Cambridge, MA (26). The panel recommended collaboration among endocrinologists, surgeons, and basic investigators to facilitate greater understanding of the gastrointestinal mechanisms of metabolic regulation. There was consensus that gastrointestinal surgery be considered for treatment of type 2 diabetes in patients who are appropriate surgical candidates with BMI 35 and who are inadequately controlled by lifestyle and medical therapy. The study of gastrointestinal metabolic surgery provides valuable opportunities for investigating gastrointestinal contributions to glucose homeostasis and the pathophysiological mechanisms of type 2 diabetes. An article that includes consensus statements and a summary of the evidence and methodology of the consensus conference is in progress. CONCLUSION It is important to note the progressive nature of type 2 diabetes when obesity is not treated. In an earlier study reported by Pories and colleagues (15) older patients who had diabetes 3 years longer on average, failed to become euglycemic after gastric bypass; again, perhaps suggesting that type 2 diabetes is a progressive disease that becomes more irreversible with time. Gastric bypass can prevent progression of this disease in the majority of patients if it is performed in a timely fashion, before irreversible destruction of the function of the islet cells (27). In conclusion, health care providers should continue to evaluate for risks and/or presence of type 2 diabetes and to offer behavioral treatment, including diet and physical activity therapies. However, when these therapies alone are not enough, for patients meeting the criteria for weight-loss surgery, behavioral programs in conjunction with weight-loss surgery should be considered. Because of the strong data showing resolution or, at the very least, substantial improvements in type 2 diabetes after weight-loss surgery; bariatric surgery is being considered as appropriate therapy for patients with type 2 diabetes and with lower BMIs. Research is ongoing to elucidate the link between gut hormones and amelioration of type 2 diabetes after bariatric surgery. This research will most likely lead to development of effective, safe, and longterm pharmacotherapies. Because medical nutrition therapy is the foundation of all weight-loss interventions, dietitians play an important role in the evaluation, assessment, and treatment of all patients who are overweight or have obesity. It is imperative that dietitians stay informed about current bariatric surgical procedures, the mechanisms of action, and the impact on nutritional status. STATEMENT OF CONFLICT OF INTEREST: The authors have no conflict of interest to report with the sponsor of this supplement article or products discussed in this article. References 1. Schauer PR, Burguera B, Ikramuddin S, Cottam D, Gourash W, Hamad G, Eid G, Mattar S, Ramanathan R, Barinas-Mitchel E, Har- April 2008 Supplement to the Journal of the AMERICAN DIETETIC ASSOCIATION S43

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Cummings DE, Overduin J, Foster-Shubert MD, Carlson MJ. Roles of the bypassed proximal intestine in the anti-diabetic effects of bariatric surgery. Surg Obes Relat Dis. 2007;3:109-115. 19. Polyzogopouou EV, Kalfarentzos F, Vagenakis AG, Alexandrides TK. Restoration of euglycemia and normal acute insulin response in obese subjects with type 2 diabetes following bariatric surgery. Diabetes. 2003;52:1098-1103. 20. Faraj M, Havel PJ, Phelis S, Blank D, Sniderman AD, Cianflone K. Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2003;88:1594-1602. 21. Berg AH, Combs TP, Scherer PE. ACRPeo/adiponectin: An adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002;13:84-89. 22. Kellum JM, Kuemmerle JF, O Dorisio TM, Rayford P, Martin D, Engle K, Wolf L, Sugerman H. Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Ann Surg. 1990;211:763-770. 23. Hanusch-Enserer U, Brabant G. Ghrelin concentrations in morbidly obese patients after adjustable gastric banding. N Engl J Med. 2003; 348:2159-2160. 24. MacDonald KG, Long SD, Swanson MS, Brown BM, Morris P, Dohm GL, Pories WJ. The gastric bypass operation reduces the progression and mortality of non-insulin-dependent diabetes mellitus. J Gastrointest Surg. 1998;1:213-220. 25. Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler Thromb Vasc Biol. 2003;23: 1042-1047. 26. Schauer P. Metabolic surgery, The Rome Diabetes Surgery Summit and our future. Presented at the International Conference on Practical Approaches to the Treatment of Obesity, Cambridge, MA, 2007. 27. Christou NV, Sampalis JS, Liberman M, Look D, Auger S, McLean A, MacLean LD. Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients. Ann Surg. 2004;240:416-423. S44 April 2008 Suppl 1 Volume 108 Number 4