Although it is well established that diabetes can also develop as a result of diseases or maneuvers on the exocrine pancreas, the complex relationship between glucose disorders and underlying pancreatic disease is still debated. There is evidence that several features linked to pancreatic diseases can modify endocrine and metabolic conditions before and after surgery. However, pancreatic surgery provides a rare opportunity to correlate in vivo endocrine and metabolic pathways with ex vivo pancreatic samples, to examine the endocrine and metabolic effects of acute islet removal, and finally to clarify the pathogenesis of diabetes. This approach could therefore represent a unique method to shed light on the molecular mechanisms, predicting factors, and metabolic consequences of insulin resistance, islet plasticity, 13 cell failure, and type 2 diabetes.