Insulin resistance and increased demand for insulin secretion occur after successful pancreas transplantation. To investigate the potential effects of immunosuppression and pancreas transplantation on fasting -cell function, we studied fasting proinsulin and 32,33 split proinsulin secretion cross-sectionally and longitudinally in segmental pancreatic graft recipients (SPx, n = 18); in whole-pancreas graft recipients (WPx, n = 13); in nondiabetic kidney transplant recipients (Kx, n = 14) and in normal subjects (Ns, n = 14). Basal insulin secretion rates were significantly increased in SPx 15.8 (1.7), WPx 24.4 (4.5) and Kx 22.1 (2.1) vs Ns 9.7 (1.6) pmol min ؊1 l ؊1 , p Ͻ 0.05, mean (SEM). Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were significantly higher in all the transplanted groups than in normal subjects (p Ͻ 0.05), whereas the total proinsulin to C-peptide ratio and the 32,33 split proinsulin ratio were higher in SPx than in WPx, Kx and Ns ( Ͻ 0.05). In the longitudinal study, -cell function in terms of proinsulin secretion remained stable for 1 year. In conclusion, fasting glucose homeostasis in pancreas-kidney transplant recipients is obtained at the expense of increased proinsulin secretion and increased insulin secretion rates, primarily induced by immunosuppression. In segmental pancreas graft recipients, increased fasting proinsulin and 32,33 split proinsulin relative to the number of -cells transplanted indicate more stress on the residual -cell and therefore higher secretory demand than in whole pancreas transplant recipients.