Metabolic Control after Encapsulated Islet Transplantation in Rats

Introduction: Encapsulated allogeneic islet grafts in TheracyteTM devices are protected from graft rejection. However,other aspects of the metabolic control by encapsulated grafts is not yet studied. The aim of our study is to characterize the insulin secretion-pattern and the resulting metabolic control when encapsulated islets are implanted s.c. in rat transplantation models. Methods: Male Lewis rats were used as donors and female Lewis rats or Wister-Furth rats with streptozotocin induced diabetes were used as recipients. Age matched healthy female rats were used as controls. Theracyte devices were implanted three month prior to transplantation. Oral glucose tolerance tests (OGTT) were performed at one and five months after transplantation and intra-venous glucose tolerance tests (IVGTT) were performed three months after transplantation. In a syngeneic model, transplantation of non-encapsulated islets was also studied. Morphometry of encapsulated islets were compared one and six months after transplantation. Results: In the syngeneic model, the minimum islet numbers to cure a diabetic rat was 1000 for encapsulated grafts, 800 non-encapsulated islets for the portal vein injected group. The peak of plasma insulin concentration in OGTT was observed10 minutes after glucose challenge in healthy controls, 10-20 minutes in the non-encapsulated islet transplantion group and after 30 minutes in the encapsulated islet transplantation group. The encapsulated islet transplanted rats showed clearly delayed recovery of blood glucose compared to healthy or nonencapsulated islet transplanted rats. Furthermore, the recovery of blood glucose in the encapsulated islet transplantation group was significantly slower in OGTT at five months after transplantation compared to at one month after transplantation, but the amount of plasma insulin was not significantly different. Table 1 shows area under the curve (AUC) of blood glucose during OGTT at one and five months after transplantation. In the allogeneic encapsulated islet transplantation model, five out of the seven rats that received 2000 encapsulated islets and two out of eight transplanted with 1000 encapsulated islets showed hypoglycemia (< 3 mM) between 90-120 minutes in OGTT at 1 month after transplantation, but this was not seen 5 months after transplantation.Table: [Comparison of AUC glu 0-120 min. in OGTT]In IVGTT, healthy controls and the non-encapsulated islet transplantation group had a quick insulin release (peak 3 minutes), but that response was much slower in the encapsulated islet transplantation group. In histological examinations of the encapsulated grafts, we found that the endocrine cell volume was similar between one and six months after transplantatio. However, the fibroblast volume inside the devices increased by four times in devices harvested at six months after transplantation compared to at one month after transplantation. Conclusion: During the earlier period after encapsulated islet transplantation, hypoglycemia may be observed in response to acute increase of blood glucose. Overgrowth of fibroblasts inside the device could be a reason to cause delayed sensitivity in glucose tolerance tests long term after transplantation.