Different effects of islet transplantation and Detemir treatment on the reversal of streptozotocin-induced diabetes associated with β-cell regeneration

Here we examined whether new β-cell formation occurs when β cells face being severely destroyed and hyperglycemia is restored. Animals were made diabetic by a single i.p. injection of a high dose of streptozotocin, and blood glucose levels were kept in the normal range with twice-daily Detemir (long-acting human insulin analog) injection or islet transplantation for 10 weeks. Although Detemir injection could effectively reverse hyperglycemia and glycemic control was successful, there was no β-cell increase, new formation, or recovery of islet morphology in Detemir-treated mice. In contrast, β-cell regeneration was restored when hyperglycemia was reversed by islet transplantation. The number of β cells and islets was increased, and islet structure was greatly recovered. We further evaluated whether replication or new formation contributes to the recovery. Newly born β cells, as observed as scattered singlets-doublets of insulin-positive cells or clusters of less than 6 β cells across, were frequently seen in transplanted mice, suggesting that neogenesis of β cells was enhanced in transplanted mice. Ki67-positive islets were increased in transplanted mice, suggesting that β-cell proliferation is enhanced. Thus, this recovery involved both increased new formation and replication. Our results suggest that the effects of Detemir on pancreatic β cells were very different from those of islet transplantation and that islet transplantation could be a trigger for the induction of new formation and replication.