Background: β-cell dedifferentiation has been identified as the process responsible for the functional “disappearance” of β-cells from the islets of diabetic subjects. We recently demonstrated that the islets of diabetic subjects are about 3 times more innervated than controls, with a stepwise increase in innervation correlated with worsening glucose tolerance and a direct correlation with the dedifferentiation score. The remission of Type 2 Diabetes after bariatric surgery is well known but the mechanisms which determine it are still on debate. Aim: To test the hypothesis that the anatomical removal of entero-pancreatic innervation induces a reduction of sympathetic innervation with the consequent re-differentiation of β cells, supporting the idea that innervation represents the key mechanism responsible for β-cell dedifferentiation. Methods: Obese diabetic rat Zucker FA/FA have been fasted overnight for 14 h followed by a glucose tolerance test (GTT) before and 6 weeks after the Roux-en-Y gastric bypass (RYGB) surgery or sham. The morphological analysis of noradrenergic fibers and dedifferentiation score has been performed on the pancreas samples. Results: total glucose level determined by area under the curve (AUC) resulted significantly reduced in the RYGB group compared to sham group (p<0.0001) confirming the remission of type 2 diabetes after bariatric surgery. We observed a 64% reduction of the number of noradrenergic fibers in RYGB group compared to sham group (p=0.04) as well as a 53% reduction in the dedifferentiation score (p=0.01). The data confirm that noradrenergic fiber might be directly involved in the process of dedifferentiation, providing a new potential explanation of the recovery of β-cell function and glucose homeostasis in type 2 diabetic patients following RYGB surgery. Reversing β-cell dedifferentiation state represents a promising approach for diabetes therapy.