Roux-en-Y gastric bypass surgery causes complete, durable remission of type 2 diabetes (T2DM) in 84% of cases, typically within a few days to weeks after surgery. Mounting evidence indicates that this dramatic phenomenon results from effects beyond those related to weight loss and reduced caloric intake alone. The mechanisms mediating the weight-independent anti-diabetes impact of RYGB are unknown, and elucidating them could lead to new diabetes medicines. Human subjects will undergo frequently sampled I.V. glucose tolerance tests (FS-IVGTT) and tracer-enhanced hyperinsulinemic/euglycemic clamps (to measure insulin secretion and sensitivity) before RYBG and 3 times in the first six weeks afterward, during which the proximal small bowel will either be excluded from nutrient contact or exposed to nutrients delivered through an indwelling gastric cannula. We hypothesize that nutrient delivery to the proximal GI tract will reverse RYGB-mediated improvements in glucose homeostasis, possibly in association with changes in nutrient-regulated gut peptides involved in glucose control. Our study will allow us to test the upper intestinal hypothesis rigorously in man, and whether the hypothesis is confirmed or refuted, we will gain valuable new insights into the mechanisms of improved glucose control early after RYGB.
