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The introduction of the potent immunosuppressive drugs tacrolimus (FK) and cyclosporine (CSA) has markedly improved the outcome of solid organ transplantation. However, these drugs can cause posttransplantation diabetes mellitus. Abnormalities in the glucose metabolism are of particular significance in pancreas transplantation.We studied 26 pancreas allograft biopsies, performed 1-8 months posttransplantation, from 20 simultaneous kidney-pancreas transplant recipients, randomized to receive either FK or CSA. The biopsies were studied by light microscopy, immunoperoxidase stains for insulin and glucagon, in situ DNA-end labeling for detection of apoptosis, and electron microscopy. The islet morphology was correlated with the mean and peak levels of CSA and FK in serum, with corticosteroid administration and with glycemia.On light microscopy cytoplasmic swelling, vacuolization, apoptosis, and abnormal immunostaining for insulin were seen in biopsies from patients receiving either FK or CSA. The islet cell damage was more frequent and severe in the group receiving FK than in the group receiving CSA (10/13 and 5/13, respectively) but the differences were not statistically significant. Significant correlation was seen between the presence of islet cell damage and serum levels of CSA or FK during the 15 days previous to the biopsy, as well as with the peak level of FK. Toxic levels of CSA or FK and administration of pulse steroids were associated with hyperglycemia when these occurred concurrently (P = 0.005). Toxic levels of CSA or FK by themselves were associated with hyperglycemia in a minority of cases (8 and 26%, respectively). Electron microscopy showed cytoplasmic swelling and vacuolization, and marked decrease or absence of dense-core secretory granules in β cells; the changes were more pronounced in patients on FK. Serial biopsies from two hyperglycemic patients receiving FK and evidence of islet cell damage demonstrated reversibility of the damage when FK was discontinued.The structural damage to β cells demonstrated in this study is similar to morphological and functional abnormalities previously described in experimental animal models and can at least partially account for the glucose metabolism abnormalities seen in patients receiving these drugs. Toxic levels of CSA or FK and higher steroid doses potentiate each others' diabetogenic effects.