Insulin Treatment of Mice Recipients Preserves β-Cell Function in Porcine Islet Transplantation

Abstract

Encapsulation of islets of Langerhans confers protection against cell-mediated immune destruction and so should allow the transplantation of islets without immunosuppression. Xenotransplantation of encapsulated islets of Langerhans might therefore help overcome problems of human organ donor shortage. Given that islets exposed to sustained hyperglycemia show impaired β-cell function, we set out to determine whether recipient treatment with insulin could improve transplantation success rate. Islets of Langerhans were obtained from Specific Germ-Free (SPF) pig pancreas and cultured overnight. Islets were encapsulated in AN69 fibers and implanted into the peritoneal cavity of diabetic mice. A group of implanted mice was treated with exogenous insulin from day 3 to day 7 after grafting. Islet implantation depressed plasma glucose in all the mice, both insulin treated and untreated. Glycemia slowly increased in the non-insulintreated mice, whereas the decrease observed in the insulin-treated mice was maintained until day 29 of follow-up. We found significant differences between the two groups ( p < 0.05 at day 18 and day 20, p < 0.001 at day 23 and day 29). No improvement of hyperglycemia was observed in diabetic mice implanted with empty fibers. When islet-containing fibers were removed from the peritoneal cavity of mice 1 month after the graft plasma glucose increased markedly. We demonstrate that treatment of recipients with exogenous insulin in the immediate posttransplantation period has a positive effect on β-cell function in transplanted macroencapsulated porcine islets.

Increased β-Cell Replication and β-Cell Mass Regeneration in Syngeneically Transplanted Rat Islets Overexpressing Insulin-Like Growth Factor II

“…β-Cell apoptosis peaks around day 3 after transplantation and plays a major role in this early β-cell death (5,11). The cause of the initial β-cell apoptosis is multifactorial (12), with hypoxia playing a fundamental role (10), and other factors such as anoikis (47), nonspecific inflammation (29,38,46), and hyperglycemia (5,15,26,33) also contributing to islet damage. Several strategies that have successfully increased the long-term outcome of islet transplantation have been, however, unable to increase the initial survival of islets (11).…”

Delayed functional maturation of neonatal porcine islets in recipients under strict glycemic control

“…In neonatal rat islet grafts, Hayek et al reported that poorly controlled diabetes by only a small amount of insulin therapy had a cure rate of only 30%, whereas it increased to 100% in strictly controlled diabetic rats by a previous islet transplant [28]. It has also been shown that treatment of mice with daily insulin injections had a beneficial effect on transplanted adult islets [29][30][31]. Brown et al reported that diabetes was cured by transplanting a single fetal pancreas with insulin treatment in rats [32].…”

AN69 Hollow Fiber Membrane will Reduce but Not Abolish the Risk of Transmission of Porcine Endogenous Retroviruses

“…fibers (2,9,20). The mean cut-off weight of the fibers is Since the work of Patience, it has been established that 70-100 kDa, 5-10 nm according to the manufacturer's PERVs secreted by PK15 and Shimozuma cell lines inestimate.…”

“…After encapsulation, cells were maintained in culture. We verified cell proliferamoglycemia in diabetic mice following the transplantation of porcine islets encapsulated in AN69 fibers (2,9,20).…”