Function, Mass, and Replication of Porcine and Rat Islets Transplanted into Diabetic Nude Mice

Abstract

Well-characterized aliquots of adult porcine and rat islets of comparable beta-cell mass were transplanted under the kidney capsule of streptozotocin-induced diabetic nude mice. In both porcine and rat islet grafts, beta-cell mass decreased significantly in the first 2 months and stabilized thereafter. As with beta-cell mass, insulin content decreased significantly in the first 2 months to almost 40% of that originally implanted. In porcine grafts, however, insulin content at 4 months was significantly higher than at 2 months. The endocrine non-beta-cell mass of grafts also decreased significantly after transplantation: in porcine grafts, the decrease was less than in rat and was limited to the first 2 months. beta-cell replication of engrafted islets was significantly lower in porcine than in rat grafts. Although beta-cell mass of porcine and rat grafts was similar at all time periods, recipients of porcine islets required a significantly longer time to reach normal glucose levels; nonetheless, their blood glucose levels continued to decrease and stabilized at levels significantly lower than those of normal mice. During oral and intraperitoneal glucose tolerance tests, blood glucose increased only slightly in both the recipients of porcine and rat grafts. When graft-bearing kidneys were perfused in situ, porcine islet grafts showed a 20-fold increase in insulin release in response to both glucose and arginine. In conclusion, this evidence that adult porcine islet grafts can bring glucose levels to those that are normal for humans provides further support of their potential for human islet replacement therapy.

Biocompatibility and function of microencapsulated pancreatic islets

“…In this study, the number of bovine islets required to achieve normoglycemia in transplanted diabetic rats was approximately 16,000 islet equivalents. In allogenic islet transplantation into diabetic rats 2000-3000 islets are suYcient to restore normoglycemia [21]. Our results showing that in islet xenotransplantation models 5-10 times more islet equivalents are required to maintain normoglycemia are in line with previous data [22], and suggest that to avoid the loss of islets due to the critical post-implantation period a higher amount of islets may enable the eVect of rejection to be delayed.…”

Current Status of Clinical Islet Transplantation

“…This figure may seem low, but it is only marginally lower than that reported after transplantation of rodent and human islets in experimental studies (14,15). It should, however, be remembered that the quality of the rodent islets, isolated immediately after retrieval of the pancreas from a young healthy donor, is better and far more standardized than that of human islets.…”

“…Together, these reports strongly suggest that only a small fraction of the transplanted islets successfully engraft. In experimental islet transplantation it is generally accepted that 50%-70% of the transplanted islets will be lost in the immediate posttransplantation period (14,15). Since glucocorticoids were not used in the Edmonton study, and thus could not have exerted any adverse effects on islet function, the authors emphasized that other adverse processes must be involved in the loss of islet tissue (11).…”

Current status of pancreatic islet transplantation

“…It is estimated that 50-70 % of islets are destroyed in the immediate post transplant period by either the IBMIR (instant blood-mediated inflammatory response) or by stress-induced apoptosis [54,55]. This immediate loss of islet not only means that excess islets must be transplanted in order to achieve a minimum amount of glucose-sensitive insulin-secreting tissue, but also inevitably leads to increased antigenic material being released in the host which may prime the adaptive immune response.…”