Although both kidney and pancreas transplantation can restore renal and pancreatic endocrine functions, the accompanying immunosuppression may cause diminished glucose tolerance in some individuals. Therefore, we determined to what extent pancreas transplantation itself and the triple immunosuppressive therapy used in pancreas transplant recipients have adverse effects on insulin secretory reserve. β-cell secretory reserve was assessed by the method of glucose potentiation of arginine-induced insulin secretion in 25 normoglycemic pancreas recipients, 12 nondiabetic kidney recipients using the same immunosuppressive therapy, 3 psoriasis patients treated long term with cyclosporine, 5 arthritis patients treated long term with prednisone, and their respective sex-, age-, and body mass index-matched control subjects. Levels of fasting glucose, HbA(1c), and glucose disappearance rates were normal in all subjects. During the glucose potentiation study, pancreas recipients had significantly less insulin secretion than control subjects (maximal acute response [AR(max)] = 1,083 ± 93% vs. 3,938 ± 355%, P < 0.001). Insulin responses were also decreased in kidney recipients (AR(max) = 2,296 ± 290%) vs. control subjects (4,691 ± 554%, P = 0.001) and in psoriasis patients treated with cyclosporine (AR(max) = 2,153 ± 390%) vs. control subjects (3962 ± 88%, P = 0.011), but not as extreme as that seen in pancreas recipients. No abnormalities were observed in arthritis patients treated with steroids. We conclude that normoglycemic pancreas and kidney transplant recipients receiving triple immunosuppressive therapy have diminished β-cell secretory reserve. Because this defect was present in psoriasis patients treated long term with cyclosporine, but not in arthritis patients treated long term with prednisone, this adverse effect was probably caused in part by cyclosporine.