β-Cell replacement in diabetes using pancreatic islets or β-cell surrogates is a research area undergoing intense scrutiny. Once this approach is demonstrated to be reproducibly successful, the next major issue will be the length of time that success will be sustained. Whole and segmental pancreas transplants are now successful for up to two decades. Study of these grafts can provide insight into and predictions about β-cell function and reserve when islet transplantation becomes a routine. The studies described herein investigated 102 human whole and segmental transplant recipients and control subjects to address the following five questions. 1) Is the usual reciprocal relationship between the acute insulin response to intravenous glucose (AIR gluc) and the level of fasting plasma glucose (FPG) maintained in pancreas transplant recipients? 2) Do recipients who have no AIRgluc have an acute insulin response to intravenous arginine (AIRarg)? 3) Do recipients of whole pancreata from cadaveric donors have twice the amount of insulin secretory reserve as that found in recipients of 50% segmental grafts from living, related donors? 4) What clinically accessible measure of insulin secretion best correlates with glucose potentiation of arginine-induced insulin secretion (GPAIS)? 5) Do successful pancreas transplant recipients evince time-dependent declines in β-cell function and glycemic regulation when studied long term and longitudinally? The results demonstrate that 1) the normal relationship between AIRgluc and fasting glucose levels is maintained despite systemic venous drainage of allografts and consequent hyperinsulinemia; 2) AIRgluc and AIRarg decrease in parallel as fasting glucose levels rise, although AIRarg is still present after AIRgluc disappears; 3) AIRarg and AIR gluc are strongly predictive of β-cell mass; 4) AIR arg and AIRgluc are strongly predictive of insulin secretory reserve; and 5) transplant recipients who have successfully maintained normoglycemia for an average of 10 years and up to 22 years nonetheless experience time-related declines in β-cell function.