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Roux-en-Y gastric bypass surgery (RYGB) is among the most effective therapies for obesity and type 2 diabetes, and intestinal adaptation is a proposed mechanism for these effects. It was hypothesized that intestinal adaptation precedes and relates to metabolic improvement in humans after RYGB.This was a prospective, longitudinal, first-in-human study of gene expression (GE) in the "Roux limb" (RL) collected surgically/endoscopically from 19 patients with and without diabetes. GE was determined by microarray across six postoperative months, including at an early postoperative (1 month ± 15 days) time point.RL GE demonstrated tissue remodeling and metabolic reprogramming, including increased glucose and amino acid use. RL GE signatures were established early, before maximal clinical response, and persisted. Distinct GE fingerprints predicted concurrent and future improvements in HbA1c and in weight. Human RL exhibited GE changes characterized by anabolic growth and shift in metabolic substrate use. Paradoxically, anabolic growth in RL appeared to contribute to the catabolic state elicited by RYGB.These data support a role for a direct effect of intestinal energy metabolism to contribute to the beneficial clinical effects of RYGB, suggesting that related pathways might be potential targets of therapeutic interest for patients with obesity with or without type 2 diabetes.

Background Postbariatric hypoglycemia (PBH) can be a devastating complication for which current therapies are often incompletely effective. More information is needed regarding frequency, incidence, and risk factors for PBH. Objectives To examine hypoglycemia symptoms following Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) and baseline and in-study risk factors. Setting Multicenter, at 10 US hospitals in 6 geographically diverse clinical centers. Methods A prospective, longitudinal cohort study of adults undergoing RYGB or LAGB as part of clinical care between 2006 and 2009 were recruited and followed until January 31, 2015, with baseline and annual postoperative research assessments. We analyzed baseline prevalence and post-operative incidence and frequency of self-reported hypoglycemia symptoms as well as potential preoperative risk factors. Results In all groups, postoperative prevalence of hypoglycemia symptoms was 38.5%. Symptom prevalence increased postoperatively from 2.8%–36.4% after RYGB in patients without preoperative diabetes (T2D), with similar patterns in prediabetes (4.9%–29.1%). Individuals with T2D had higher baseline hypoglycemia symptoms (28.9%), increasing after RYGB (57.9%). Hypoglycemia symptoms were lower after LAGB, with 39.1% reported hypoglycemia symptoms at only 1 postoperative visit with few (4.0%) having persistent symptoms at 6 or more annual visits. Timing of symptoms was not restricted to the postprandial state. Symptoms of severe hypoglycemia were reported in 2.6–3.6% after RYGB. The dominant risk factor for postoperative symptoms was preoperative symptoms; additionally, baseline selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor use was also associated with increased risk in multivariable analysis. Weight loss and regain were not related to hypoglycemia symptom reporting. Conclusion Hypoglycemia symptoms increase over time after RYGB, particularly in patients without diabetes. In a small percentage, symptoms can be persistent or severe and require hospitalization. Preoperative hypoglycemia symptoms and SSRI/SNRI use in RYGB patients without diabetes is associated with increased risk of symptoms.

BACKGROUND Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is the best treatment for severe obesity and its complications including type 2 diabetes mellitus (T2DM). Understanding the mechanisms responsible for the beneficial metabolic effects will help to engineer ways to improve the procedure or produce these effects without surgery. OBJECTIVE The aim is to present data on recruitment and feasibility of a translational study designed to collect intestinal samples before and after bariatric surgery. The goal of biobanking is to allow future studies to test the hypothesis that the mechanism of action of RYGB involves specific changes in the postsurgical short- and long-term metabolism and morphology of the jejunum (Roux limb). Specifically, to test whether the intestine enhances its metabolism and activity after RYGB and increases its fuel utilization, we designed a prospective, longitudinal study, which involved the recruitment of candidates for RYGB with and without T2DM. We describe the tissue bank that we have generated, and our experience, hoping to further facilitate the performance of longitudinal mechanistic studies in human patients undergoing bariatric surgery and especially those involving post-RYGB intestinal biology. METHODS We conducted a trial to characterize the effects of RYGB on intestinal metabolism. Intestinal tissue samples were collected from the jejunum at surgery, 1, 6, and 12 months postoperatively for the analysis of intestinal gene expression and metabolomic and morphologic changes. The target number of patients who completed at least the 6-month follow-up was 26, and we included a 20% attrition rate, increasing the total number to 32. RESULTS To enroll 26 patients, we had to approach 79 potential participants. A total of 37 agreed to participate and started the study; 33, 30, and 26 active participants completed their 1-month, 6-month, and 12-month studies, respectively. Three participants withdrew, and 30 participants are still active. Altruism and interest in research were the most common reasons for participation. Important factors for feasibility and successful retention included (1) large volume case flow, (2) inclusion and exclusion criteria broad enough to capture a large segment of the patient population but narrow enough to ensure the completion of study aims and protection of safety concerns, (3) accurate assessment of willingness and motivation to participate in a study, (4) seamless integration of the recruitment process into normal clinical flow, (5) financial reimbursement and nonfinancial rewards and gestures of appreciation, and (6) nonburdensome follow-up visits and measures and reasonable time allotted. CONCLUSIONS Human translational studies of the intestinal mechanisms of metabolic and weight changes after bariatric surgery are important and feasible. A tissue bank with unique samples has been established that could be used by investigators in many research fields, further enabling mechanistic studies on the effects of bariatric surgery. CLINICALTRIAL ClinicalTrials.gov NCT02710370; https://clinicaltrials.gov/ct2/show/NCT02710370 (Archived by WebCite at http://www.webcitation.org/75HrQT8Dl)

Despite the remarkable, early remission of T2D after RYGB, the surgery’s key mechanisms have yet to be defined in a way that can be translated to less invasive therapies. Recently, we demonstrated that improved glucose homeostasis after RYGB in rodents is associated with intestinal metabolic reprogramming: the Roux Limb (RL) exhibits dramatic morphologic and metabolic remodeling, leading to augmented utilization of metabolic fuels to support the increased bioenergetic demand. To address whether this phenomenon is important for T2D remission in human patients after RYGB, RL biopsies were obtained at the time of surgery and at 1 and 6 months postoperatively. Differentially expressed genes (DEG) were determined using Affymetrix HTA 2.0 microarrays; morphology was examined via electron microscopy, revealing a significant increase in microvillus length over time (P Disclosure M.A. Stefater: None. C. Panciotti: None. H.A. Feldman: None. W.F. Gourash: Research Support; Self; Coviden, Ethicon US, LLC., National Institute of Diabetes and Digestive and Kidney Diseases. E. Shirley: None. A. Courcoulas: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Patient-Centered Outcomes Research Institute, National Institutes of Health, Coviden. N. Stylopoulos: None.

Background: Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is the best treatment for severe obesity and its complications including type 2 diabetes mellitus (T2DM). Understanding the mechanisms responsible for the beneficial metabolic effects will help to engineer ways to improve the procedure or produce these effects without surgery. Objective: The aim is to present data on recruitment and feasibility of a translational study designed to collect intestinal samples before and after bariatric surgery. The goal of biobanking is to allow future studies to test the hypothesis that the mechanism of action of RYGB involves specific changes in the postsurgical short- and long-term metabolism and morphology of the jejunum (Roux limb). Specifically, to test whether the intestine enhances its metabolism and activity after RYGB and increases its fuel utilization, we designed a prospective, longitudinal study, which involved the recruitment of candidates for RYGB with and without T2DM. We describe the tissue bank that we have generated, and our experience, hoping to further facilitate the performance of longitudinal mechanistic studies in human patients undergoing bariatric surgery and especially those involving post-RYGB intestinal biology. Methods: We conducted a trial to characterize the effects of RYGB on intestinal metabolism. Intestinal tissue samples were collected from the jejunum at surgery, 1, 6, and 12 months postoperatively for the analysis of intestinal gene expression and metabolomic and morphologic changes. The target number of patients who completed at least the 6-month follow-up was 26, and we included a 20% attrition rate, increasing the total number to 32. Results: To enroll 26 patients, we had to approach 79 potential participants. A total of 37 agreed to participate and started the study; 33, 30, and 26 active participants completed their 1-month, 6-month, and 12-month studies, respectively. Three participants withdrew, and 30 participants are still active. Altruism and interest in research were the most common reasons for participation. Important factors for feasibility and successful retention included (1) large volume case flow, (2) inclusion and exclusion criteria broad enough to capture a large segment of the patient population but narrow enough to ensure the completion of study aims and protection of safety concerns, (3) accurate assessment of willingness and motivation to participate in a study, (4) seamless integration of the recruitment process into normal clinical flow, (5) financial reimbursement and nonfinancial rewards and gestures of appreciation, and (6) nonburdensome follow-up visits and measures and reasonable time allotted. Conclusions: Human translational studies of the intestinal mechanisms of metabolic and weight changes after bariatric surgery are important and feasible. A tissue bank with unique samples has been established that could be used by investigators in many research fields, further enabling mechanistic studies on the effects of bariatric surgery. Trial Registration: ClinicalTrials.gov NCT02710370; https://clinicaltrials.gov/ct2/show/NCT02710370 (Archived by WebCite at http://www.webcitation.org/75HrQT8Dl)

The effectiveness of Roux-en-Y gastric bypass (RYGB) against obesity and its comorbidities has generated excitement about developing new, less invasive treatments that use the same molecular mechanisms. Although controversial, RYGB-induced improvement of metabolic function may not depend entirely upon weight loss. To elucidate the differences between RYGB and dieting, we studied several individual organ molecular responses and generated an integrative, interorgan view of organismal physiology. We also compared murine and human molecular signatures. We show that, although dieting and RYGB can bring about the same degree of weight loss, post-RYGB physiology is very different. RYGB induces distinct, organ-specific adaptations in a temporal pattern that is characterized by energetically demanding processes, which may be coordinated by HIF1a activation and the systemic repression of growth hormone receptor signaling. Many of these responses are conserved in rodents and humans and may contribute to the remarkable ability of surgery to induce and sustain metabolic improvement.