To assess the metabolic consequences of hemipancreatectomy in humans, we determined pancreatic beta and alpha cell function in healthy donors. Donors examined cross-sectionally were found to have significantly decreased glucose-induced phasic insulin secretion and arginine-induced insulin and glucagon secretion as compared to age, sex, and body index-matched controls. However, their fasting glucose and insulin values were not different from controls. Similar observations were found in the prospective evaluation of eight donors before and 15 +/- 2 mo after hemipancreatectomy. Beta cell reserve, as measured by glucose potentiation of arginine-induced insulin secretion, was significantly decreased in donors (maximal acute insulin response [AIRmax]: donors = 666 +/- 84 pM vs controls = 1,772 +/- 234 pM) while the PG50 (the glucose value at which the half-maximal response was observed) was the same in the two groups. Donors and controls responded to 60-min continuous intravenous infusions of glucose by reaching identical serum glucose values, despite significantly lower insulin secretory responses in donors. We conclude that hemipancreatectomy in human donors is associated with decreased pancreatic alpha and beta cell function. Since donors generally maintain normoglycemia after hemipancreatectomy despite diminished insulin secretion, our data suggest that healthy humans may compensate for hemipancreatectomy by increasing glucose disposal.