Intestinal Metabolic Reprogramming as a Key Mechanism of Gastric Bypass in Humans

The purpose of this research study is to determine how gastric bypass surgery effects metabolism in obesity and Type 2 Diabetes. One mechanism that has been investigated in animal models is change to the biology of the small intestine (Roux limb) and how glucose and other fuels are metabolized (or how the body digests and uses sugar and other fuels). This study will evaluate the role of the intestine in the beneficial metabolic effects of gastric bypass surgery. It specifically will examine whether the intestine increases its metabolism and its activity, and whether this results in an increase in fuel utilization. Thirty two (32) subjects will be recruited (18 with and 14 without Type 2 Diabetes). At the time of gastric bypass surgery, a small piece of intestine that is usually discarded will be collected. At three time points over the first year after surgery, intestinal samples will be obtained by endoscopy or insertion of a lighted flexible tube through the mouth. Blood samples will be taken at all time points, as well. All samples will undergo comprehensive metabolic analyses. Comparisons will be made between the two groups to understand the metabolic changes over time and if there are differences between the two groups.

Several studies have concluded that Roux-en-Y gastric bypass surgery (RYGBS) is the best current treatment option for obesity-related Type 2 Diabetes Mellitus (T2DM). The mechanisms underlying RYGBS-induced improvement in glycemic control remain unclear. Many investigators have advocated that this effect does not depend upon body weight loss, based on clinical observations that improvement in glucose homeostasis occurs early in the postoperative period, often prior to hospital discharge. Understanding the mechanisms underlying the metabolic effects of RYGBS will help to engineer ways to improve RYGB or to produce these effects without surgery. This study will examine the concept of intestinal metabolic reprogramming as one of the key mechanisms of action for diabetes improvement following Roux-en-Y gastric bypass surgery (RYGBS) in humans. It is hypothesized that the reconfigured intestine is characterized by an increase in energetically expensive processes, such as structural remodeling, cytoskeletal reorganization, and cellular proliferation. To accommodate the increased bioenergetics demands, the intestinal epithelium increases its metabolic activity and reprograms its fuel utilization. Specifically, glucose, cholesterol and amino acid metabolism are all dramatically altered to increase anabolic pathways and generate building blocks for cellular growth and maintenance. It has not previously been possible to test this hypothesis in humans as: A) the adaptive processes of the intestine in patients undergoing RYGBS have not been thoroughly characterized, B) it is not known whether the intestinal reprogramming appears early enough to explain the prompt improvement in glucose metabolism observed after RYGBS in humans, and C) the variability of the degree of intestinal metabolic adaptation, which could account for the variability in remission of T2DM, has not been studied. This study will perform a longitudinal, comprehensive metabolic analysis of the Roux limb in human subjects with and without T2DM undergoing RYGBS and determine the time course of the adaptive metabolic changes. Eighteen (18) subjects with and fourteen (14) subjects without T2DM (total 32 subjects), who have been scheduled to undergo RYGBS as standard of care, will be recruited. For each enrolled subject, data collection will include an intestinal tissue sample (Roux limb tissue sampling from discarded tissue) at the time of RYGBS, from the mucosa of the jejunum, within 40 cm from the gastrojejunal anastomosis. Postoperatively, tissue sampling from the same area will be performed by an Upper GI endoscopy, at 1 month (±15 days), 6 months (±1 month) and 12 months (±2 months) after RYGBS. Tissue samples will be processed for histo-morphological examination and for RNA, protein and metabolomics analyses. A blood sample will be obtained at all time points and analyzed for metabolic biomarkers. Data analysis will include description and comparison of the morphological, gene protein and metabolite signatures of the intestinal (Roux limb) tissue and the blood biomarkers from each time point. Additionally, these outcome measures will be compared between the two groups (T2DM and Non-T2DM). Finally, a correlation of the intestinal adaptive changes with metabolic status, some eating behaviors, adverse symptomatology, and quality of life will be undertaken.