Bariatric Surgery and Type 2 Diabetes (T2DM) Bariatric surgery is the most effective way to achieve significant, long-term weight loss. The most common bariatric procedure in the United States is Roux-en-Y gastric bypass, performed on more than 120,000 people in 2007. RYGB typically results in 50-80% loss of excess body weight, while purely restrictive procedures, such as gastric banding, result in 30-50% loss of excess body weight. In addition, bariatric surgery has shown to be an effective therapy for obese individuals with T2DM, with 71-100% of subjects experiencing complete resolution of diabetes after surgery. This resolution of diabetes is predominately caused by marked weight loss resulting in improved insulin sensitivity. However, the beneficial effects of bariatric surgery on glucose metabolism cannot be accounted for entirely by weight loss. This is best demonstrated by the observation that many bariatric surgery patients have resolution of T2DM within 1 week following bariatric surgery, before clinically significant weight loss has occurred. Role of Caloric Restriction Rapid resolution of hyperglycemia in bariatric surgery patients may be due in part to acute caloric restriction in the immediate post-operative period. Severe caloric restriction or fasting has long been known to improve glycemia control in patients with diabetes, and was used therapeutically for type 1 diabetes (T1DM) prior to the discovery of insulin. In 1971, Jackson and colleagues showed that fasting for 7-14 days can normalize fasting blood sugars in subjects with type 2 diabetes. Marked improvement in blood glucose with less severe caloric restriction (330 C 1800 kcal per day for 3-21 days) has been shown by multiple researchers since that time. Two studies in this group demonstrated an approximately 50% rise in insulin sensitivity, suggesting that improvements in insulin sensitivity may be a major mechanism underlying lower blood glucose levels following caloric restriction. It is worth noting, however, that in the majority of these studies, blood sugar concentrations did not completely normalize. For example, Henry et al. gave 30 obese subjects with T2DM 330 kcal/day for 10 days, which is roughly equivalent to the expected caloric intake during the first week after bariatric surgery. This degree of caloric restriction resulted in significant improvement in fasting blood glucose, from 297 13 mg/dL before the diet, to 158 10 mg/dL after the diet. However, fasting blood glucose did not return to the non-diabetic range of <126 mg/dL, suggesting that this degree of caloric restriction may be insufficient to explain complete reversal of T2DM within one week. Role of the Proximal Small Intestine Bariatric surgery appears to result in improvements in glucose metabolism and insulin sensitivity beyond that which would be expected on the basis of caloric restriction alone. This was well-demonstrated by Guidone et al., who studied 10 obese women with T2DM prior to and 7 days following RYGP. These patients all received parenteral nutrition (1800 kcal/day) for 6 days following surgery, and thus were not significantly calorically restricted. Despite the parenteral nutrition, which usually worsens diabetes control and causes insulin resistance, these patients exhibited complete resolution of diabetes, with 100% improvement in insulin sensitivity 7 days postoperatively. Several researchers have suggested that the rapid resolution of diabetes following malabsorptive bariatric surgical procedures is due to bypass of the proximal small intestine, through as-yet unclear mechanisms. This hypothesis is supported by data showing higher rates of rapid diabetes resolution in patients undergoing malabsorptive bariatric surgery (which involves bypass of the proximal small intestine) versus those undergoing purely restrictive procedures (e.g. gastric banding), in which the flow of nutrients through the small intestine remains intact. Animal data strongly suggest a unique role for the duodenum in glycemia control in rodents. In addition, there are recent reports of duodenal bypass (without the restrictive component of the surgery) curing T2DM in non-obese humans. Incretins, hormones secreted by the gastrointestinal tract that increase insulin secretion in response to oral, but not intravenous nutrients, are likely candidates mediating part of the improvement in glucose metabolism following bariatric surgery. Other gut hormones may play a role, as well. For example, ghrelin has been shown to decline and lose its prandial pattern after RYGP. Since ghrelin antagonizes insulin secretion and action, it was postulated to be one of the mechanisms explaining improved postoperative glucose metabolism. However, Thorner et al. have recently shown that the previously measured total ghrelin levels are made up by 2 main forms (acyl- and des-acyl-ghrelin), which have at times opposing physiologic effects. Thus, it may not be total ghrelin, but the ratio of acyl- to des-acyl ghrelin that determines the physiologic response. Presently, no data exist in patients who have undergone bariatric surgery. A very novel mechanism that may contribute to improved insulin sensitivity following bariatric surgery is enhanced intestinal gluconeogenesis leading to suppression of hepatic glucose production. The authors of this paper showed that, in mice, enterogastric anastamosis (EGA, an analog to RYGBP), but not gastric banding, enhanced intestinal gluconeogenesis. This glucose was secreted directly into the portal vein, resulting in decreased hepatic glucose production, as well as central nervous system signals to suppress food intake. Whether or not this mechanism plays a significant role in humans remains to be determined. Inclusion Criteria 1. Clinical diagnosis of Type 2 diabetes mellitus 2. Age 18-60 years 3. Body mass index 35 kg/m2 4. Either a. Patients scheduled for Roux-en-Y gastric bypass at Vanderbilt University Medical Center or University of Maryland OR b. Patients matched for race, sex, BMI ( 15%), and age ( 5 years) to RYGBP patients, above, but NOT scheduled for bariatric surgery. 5. Subjects must have an endocrinologist or primary care provider who manages their diabetes. Exclusion Criteria 1. Current use of insulin 2. Use of exenatide, sitagliptin (or other dipeptidyl peptidase inhibitor), thiazolidinediones, or experimental diabetes medication within the past 3 months 3. Medical condition that alters glucose metabolism (other than T2DM) or weight (e.g. chronic inflammatory diseases, monogenic obesity, etc) 4. Current use of medication that alters glucose metabolism (other than oral diabetes medications) or weight 5. Significant comorbidity that, in the opinion of the investigators, will increase risk to the subject, (e.g. current treatment for cancer, renal failure) 6. Positive urine pregnancy test or plans to become pregnant during clinical trial 7. Psychiatric or cognitive disorder that will, in the opinion of the investigators, limit the subject's ability to comply with study procedures 8. Body weight greater than 450 lbs 9. History of previous bariatric surgical procedure or other surgery altering the length or arrangement of the intestines Relevance of Study Results on Care If we confirm that bariatric surgery results in improvements in glucose metabolism beyond those of caloric restriction alone, this could support the increased use of surgical procedures in patients with T2DM (such as those with a BMI <35 kg/m2, who would not normally be eligible for bariatric surgery). In addition, identification of the underlying mechanisms may allow development of conservative (non-surgical) therapies mimicking the effects achieved with surgery.

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Rother, Kristina I; Brown, Rebecca J (2011) Selecting weight loss surgery based on HDL genotype--are we there yet? At the brink of ""personalized surgery"". J Clin Endocrinol Metab 96:1664-7
Laferrère, Blandine; Swerdlow, Nicholas; Bawa, Baani et al. (2010) Rise of oxyntomodulin in response to oral glucose after gastric bypass surgery in patients with type 2 diabetes. J Clin Endocrinol Metab 95:4072-6
Nandagopal, Radha; Brown, Rebecca J; Rother, Kristina I (2010) Resolution of type 2 diabetes following bariatric surgery: implications for adults and adolescents. Diabetes Technol Ther 12:671-7