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Healthy human volunteers occasionally elect to undergo surgical removal of the distal half of their pancreas for donation to a relative with type 1 diabetes. This provides the unusual opportunity to study segments of the same pancreas in two markedly different environments, i.e., the normal one of the donor and the unusual one of the ectopically transplanted recipient who is receiving immunosuppressant drugs that can diminish insulin secretion and cause insulin resistance.We studied eight donor/recipient pairs 9 to 18 years after the original surgery to assess the hypothesis that beta-cell mass is the primary determinant of glucose homeostasis. We measured levels of fasting glucose and hemoglobin A1c, intravenous glucose disappearance rates, acute insulin and C-peptide responses, and beta-cell secretory reserve.Comparisons of the mean data between the two groups revealed no significant differences in fasting plasma glucose, hemoglobin A1c, fasting insulin or C-peptide, acute insulin or C-peptide responses to arginine and to glucose, or beta-cell secretory reserve. Eight patients were obese; this subgroup contained all patients who developed mild diabetes (four donors and two recipients).The within-pairs metabolic outcomes support the primacy of pancreatic mass in determining glucose homeostasis, but the discordancy within pairs for developing postoperative diabetes implicates variables, especially obesity, as important secondary determinants in the risk of developing diabetes in donors and recipients. Our data suggest that obesity should be a contraindication to donation of pancreatic segments and that donors should assiduously avoid becoming obese.