The effect of preexisting long-term diabetes on the outcome after islet transplantation in rats.

Studies of islet transplantation conducted immediately following diabetes induction may not accurately reflect the clinical situation. Long term preexisting diabetes with generalized microvasculature complication might adversely affect the outcome after islet transplantation. The present study testing this hypothesis by evaluating the effect of long-term preexisting diabetes on glucose-induced insulin secretion up to 6 months after transplantation of two different quantities of islets. One thousand two hundred or 2,400 islets were isotransplanted into the left renal subcapsular space at 10 days (acute diabetes), 3 months (chronic diabetes), or 6 months (long-term diabetes) after diabetes induction by streptozotocin in the rat. In addition, one group of diabetic rats in which normoglycemia was maintained with exogenous insulin treatment for 6 months was then transplanted with 1,200 islets. Intravenous glucose tolerance tests were performed at 10, 90, and 180 days after islet transplantation. Islet transplantation normalized the basal blood glucose levels within 24-48 h in all transplanted groups that remained normal for the entire study period of 6 months, with no differences among acute, chronic, or long-term diabetes. Basal plasma insulin levels were also normalized in all transplanted groups. Diabetic (acute, chronic, or long-term) rats transplanted with 2,400 islets achieved normal glucose-induced insulin secretion at 10 and 90 days after transplantation. In contrast, glucose-induced insulin secretion was impaired in rats transplanted with only 1,200 islets, with no differences among acute, chronic, and long term diabetes. However, at 180 days after transplantation, long term diabetic rats transplanted with 2,400 islets had impaired insulin secretion compared to normal controls. Insulin-treated long-term diabetic rats transplanted with 1,200 islets had normal glucose-induced insulin secretion at 10 days after transplantation. However, at 90 and 180 days after transplantation, insulin-treated long-term diabetic rats had impaired glucose-induced insulin secretion which was not different from nontreated transplanted long-term diabetic rats. It is concluded that long-term preexisting diabetes has no impact on the early outcome after islet transplantation. However, it may adversely affect the long-term function of the transplanted islets. Also, transplantation of a sufficient islet mass is the critical factor in achieving complete glucose homeostasis.