Lowering of blood glucose to nondiabetic levels in a hyperglycemic pig by allografting of fetal pig isletlike cell clusters

Background Fetal pig isletlike cell clusters (ICCs) will differentiate when grafted into the thymus gland of outbred immunosuppressed nondiabetic pigs for up to 3 months. Whether these cells will survive for a similar period in a diabetic recipient and will mature with secretion of insulin to amelio rate the hyperglycemia is unknown. Methods, Between 40,000 and 125,000 ICCs (7,000 to 11,400 ICCs/kg) were inj ected into the thymus gland of five juvenile pigs immunosuppressed with cyc losporine and deoxyspergualin, and the animals were subsequently made diabe tic by the injection of streptozotocin, Insulin was administered subcutaneo usly, with one pig dying from hypoglycemia. The animal with the least numbe r of ICCs transplanted was killed 81 days later, and the graft was analyzed histologically. Blood glucose levels and porcine C-peptide in the remainin g animals were monitored for a median of 101 days. Results. Histological analysis of the graft showed numerous epithelial cell clusters; the percentage of cells that contained insulin, glucagon, somato statin, and pancreatic polypeptide were 61%, 64%, 25%, and 18%, respectivel y. Some cells contained more than one hormone. Porcine C-peptide was detect ed from 21 days after induction of diabetes but not before. In the pig rece iving the most ICCs, blood glucose levels were lowered to nondiabetic level s 109 days after transplantation. Plasma C-peptide levels in response to gl ucagon in this pig steadily increased after grafting; peak levels were 0, 0 .21, 0.45, and 0.52 ng/ml at 4, 21, 49, and 80 days after induction of diab etes compared to 0.09 ng/ml in control diabetic pigs, The secretion of C-pe ptide in response to oral and intravenous glucose and arginine also was gre ater than in untransplanted diabetic pigs, the pattern of secretion being c onsistent with developing fetal beta cells as the source of the C-peptide. Pancreatic insulin content was 0.1 mU/mg, 4% of that in nondiabetic pigs, a nd the number of beta cells per islet was 3 to 6 compared to 90 in nondiabe tic controls. Conclusions. ICCs will differentiate and function for up to 111 days when t ransplanted into outbred immunosuppressed pigs rendered diabetic. Blood glu cose levels can be lowered to nondiabetic levels when sufficient numbers of ICCs are grafted.