We reported recently that intrasplenic transplantation of syngeneic pancreatic islets failed to cure obese-hyperglycaemic mice, despite a considerable growth of the grafted islets. In the present study, the role of sustained hyperglycaemia and hyperinsulinaemia for regeneration of transplanted islet cells was evaluated in these animals. Islets implanted into alloxan-diabetic C57BL/6J mice in numbers insufficient to restore normoglycaemia did not grow. There was, however, a statistically significant correlation between the mean volume of implanted islets and the degree of normalization of hyperglycaemia. Insulin treatment of these suboptimally islet-implanted C57BL/6J mice resulted in a volume increase of the implanted islets. When corresponding experiments were undertaken with alloxan-diabetic C57BL/KsJ mice, no effect was noted on hyperglycaemia and there was a drastic decrease in the volume of implanted islets. Islets implanted into old obese-hyperglycaemic mice that had returned to normoglycaemia but still were hyperinsulinaemic, decreased markedly in size. The present data suggest that neither hyperglycaemia nor hyperinsulinaemia per se are primarily responsible for the growth of islets in obese-hyperglycaemic mice. Furthermore, it is obvious that the genetic background is very important for morphological and functional responses of the islets to a prolonged period of hyperglycaemic stress.