Long-Term Plasma Glucose Normalization in Experimental Diabetic Rats With Macroencapsulated Implants of Benign Human Insulinomas

Abstract

Permselective tubular membranes (1 mm i.d.) were filled with fragments of nine freshly resected human insulinomas, closed at both ends, and implanted in the peritoneal cavity of 30 streptozocin-induced diabetic rats. In 14 animals, nonfasting plasma glucose (PG) and insulin levels were normalized by these immunoprotected transplants for up to 1 yr (PG from 520 ± 12 to 142 ± 3 mg/100 ml; insulin from 6 ± 0.5 to 44 ± 3 μU/ml). These animals showed the same weight gain after 12 mo of observation as 20 controls. The remaining 16 animals showed an incomplete or transient correction of their diabetes and survived 4–6 mo, versus <8 wk in untreated animals. Removal of the membraneencapsulated insulin-secreting tissue from 8 successfully treated rats led to hyperglycemia and death within 10 days. Histology and electron microscopy of insulinoma tissue retrieved after long-term implantation showed functionally active endocrine cells and no evidence of graft rejection. In vitro perifusion gave similar results for encapsulated and nonencapsulated insulinoma tissue. The amount of insulin secreted was quite variable, and responsiveness of the insulinoma to changes in glucose concentration of the surrounding medium was observed in three out of the five tumors studied. These observations establish the effectiveness of immunoseparation by a synthetic membrane in a pancreatic xenograft model.