Long-term normalization of glucose metabolism is necessary to prevent or ameliorate diabetic complications. Although pancreatic grafting is able to restore normal blood glucose and glycated haemoglobin, the degree of normalization of the deranged diabetic metabolism after pancreas transplantation is still questionable. Consequently glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide responses to oral glucose and i.v. arginine were measured in 36 Type 1 (insulin-dependent) diabetic recipients of pancreas and kidney allografts and compared to ten healthy control subjects. Despite normal HbA1 (7.2 +/- 0.2%; normal less than 8%) glucose disposal was normal only in 44% and impaired in 56% of the graft recipients. Normalization of glucose tolerance was achieved at the expense of hyperinsulinaemia in 52% of the subjects. C-peptide and glucagon were normal, while pancreatic polypeptide was significantly higher in the graft recipients. Intravenous glucose tolerance (n = 21) was normal in 67% and borderline in 23%. Biphasic insulin release was seen in patients with normal glucose tolerance. Glucose tolerance did not deteriorate up to 7 years post-transplant. In addition, stress hormone release (cortisol, growth hormone, prolactin, glucagon, catecholamines) to insulin-induced hypoglycaemia was examined in 20 graft recipients and compared to eight healthy subjects. Reduced blood glucose decline indicates insulin resistance, but glucose recovery was normal, despite markedly reduced catecholamine and glucagon release. These data demonstrate the effectiveness of pancreatic grafting in normalizing glucose metabolism, although hyperinsulinaemia and deranged counterregulatory hormone response are observed frequently.