Introduction: For morbidly obese patients, insulin-resistant diabetes mellitus (type-2 DM) resolves within weeks following gastric bypass surgery, prior to any significant weight-loss. It has been proposed that diversion of nutrient flow away from the stomach may be responsible for this observation. This study prospectively evaluated the effects of roux-en-Y gastric bypass (RYGB) on insulin resistance and gene expression profiles of gut hormones related to glucose metabolism.Methods: Five women (mean age 35, mean BMI 44 kg/m2) were admitted to the General Clinical Research Center for intravenous glucose tolerance tests (IVGTT) prior to undergoing RYGB and again at postoperative follow-up within 2 months. Gastric pouch biopsies were obtained at the time of surgery and then again by endoscopy at follow-up. Specimens underwent mRNA extraction, labeling, and hybridization, and an Affymetrix microarray scanner was used to analyze the gene chips. mRNA quality was confirmed by Northern or spectrophotometry. Data were analyzed for fold-changes of metabolic hormones with known influence upon systemic insulin-glucose metabolism.Results: After surgery, all patients exhibited greater normalization of IVGTT compared with baseline. Significant alterations in expression were identified in 5 genes related to human insulin-glucose metabolism; pyruvate dehydrogenase kinase-4 (-8.7 folds, p < 0.01), fatty acid binding protein-4 (-6.0 folds, p < 0.5), insulin receptor substrate-2 (-2.4 folds, p < 0.02), leptin receptor (-2.0 folds, p < 0.05), preghrelin (-2.0 folds, p < 0.05).Conclusions: Systematic gene expression profiling may lend mechanistic insights into resolution of type-2 DM induced by RYGB, and may serve as biomarkers for predicting the efficacy of weight-reduction surgery.