Several bariatric operations are currently used to produce sustained weight loss and treat obesity- related comorbidities. Currently considered the gold standard in bariatric surgical procedures, Roux-en-Y Gastric Bypass (RYGB) stimulates a considerable and sustained weight-loss in obese individuals. This reduced adiposity is often accompanied by profound improvement in glucose control of type 2 diabetic subjects. While some of the effects of RYGB on glucose control are secondary to reduced body weight, dramatic changes in gut nutrient sensing/presentation and hormone profile may contribute to the resolution of T2D in many individuals. Accumulating evidence indicates that duodenal nutrient exclusion (DNE) may be an important contributor to the metabolic benefits of RYGB. We can directly test such DNE without gastric restriction or altering the path of ingested nutrients using duodenal, barrier-endolumenal sleeves (DES) that prevent ingested nutrients from interacting with the upper intestine. Early pre-clinical experiments in rodents and clinical experiments in humans point to beneficial effects of DES in individuals with impaired glucose homeostasis. We have successfully established a rodent model of a DES that will allow for the careful mechanistic testing of DES that is not possible in humans. In our hands, we observe that DES results in a small in fat mass and a clear improvement in glucose tolerance, which is above and beyond the effect of the weight loss alone. This proposal will dissect components of glucose handling via hyperinsulinemic-euglycemic clamps. It will also investigate the role of the vagus and the central nervous system in the DES-enhancement of glucose metabolism. Together these studies will test the hypothesis that duodenal nutrient exclusion restores the ability of this nutrient-sensing circuitry to regulate glucose homeostasis.