Regimens of IGF-I treatment in fetal pancreas transplantation

Abstract

Transplantation of fetal pancreas (FP) is a potential treatment for diabetes mellitus. FP has remarkable proliferative capacity and may be induced to expand sufficiently to provide a functional β cell mass in adult recipients. We have demonstrated that local delivery of recombinant insulin- like growth factor-I (IGF-I) onto FP isografts is sufficient to reverse streptozotocin-induced diabetes in animals receiving as few as 4 fetal pancreata. In this current study we investigated other regimens of IGF-I delivery in an attempt to define whether its effects on FP required local delivery or whether other, more clinically feasible, forms of treatment would suffice. In our model, diabetic Lewis rats received isografts of 16 FP into the anterior thigh intramuscular (IM) site. In the group of FP recipients treated with vehicle alone, no animals converted to euglycemia (0/8). When the IM site was pretreated locally with 14 days of continuous IGF-I administration (69 μg/kg per day) prior to FP transplantation, 100% of the recipients (10/10) became euglycemic with a mean interval from transplant to euglycemia of 35 ± 15 days (P < 0.001 when compared to vehicle alone). No significant advantage over the vehicle alone group was gained either when the FP tissue was cultured for 48 hr in the presence of IGF-I (100 μg/ml) and then implanted (27% conversion to euglycemia, 3/11) or when FP isografts were treated with continuous subcutaneous delivery of IGF-I (69 μg/kg per day over 14 days) distant from the transplant site (0% conversion to euglycemia, 0/6). IGF-I increased the rate of conversion to euglycemia either when delivered locally to FP isografts or when delivered to the transplant bed prior to transplantation. This suggests an active role of the IGF-I-treated transplant bed in the success of FP transplantation.