In the basal state and after oral ingestion of carbohydrate, the normal pancreas secretes insulin into the portal vein in a pulsatile manner. The end organ of the portal vein is the liver, where approximately 80% of pancreatic insulin is extracted during first pass. In Type 1 diabetes, pancreatic insulin secretion is nearly or completely absent whilst in Type 2 diabetes the normal pattern is absent, abnormal, or blunted. Exogenous subcutaneous insulin treatment results in plasma insulin concentrations that are not pulsatile and a fraction of normal portal vein levels. Oral hypoglycemic agents also do not result in normal pulsatile response to a glucose load. Due to hypoglycemia risk, intensive treatment is not recommended after serious complications develop. Consequently, no conventional therapy has proved effective in treating advanced diabetes complications. Beta-cell replacement using whole pancreas or islet transplantation has been utilized to treat certain problems in Type 1 diabetic patients, but still unavailable for all diabetics. Pulsatile intravenous insulin therapy (PIVIT) is an insulin therapy, which mimics the periodicity and amplitude of normal pancreatic function. Numerous studies show PIVIT effective in preventing, reversing, and reducing the severity and progression of diabetes complications, however, the mechanisms involved with the improvement are not clearly understood. Here, we review the cellular basis of normal and abnormal insulin secretion, current treatments available to treat diabetes, the physiologic basis of PIVIT and possible mechanisms of action.