Glucose control and long-term survival in biobreeding/Worcester rats afterintraperitoneal implantation of hydrophilic macrobeads containing porcine islets without immunosuppression

Background. We investigated the effectiveness of implanted macrobeads conta ining porcine islets as long-term therapy for type I diabetes mellitus in B io-breeding/Worcester (BB/Wor) rats, an animal model of spontaneous type I human diabetes. End points included acute control of glucose, weight gain, survival time, and the renal changes associated with diabetes. Materials and Methods. Eighteen chronic spontaneously diabetic BB/Wor rats were each implanted with 56-150 porcine islet macrobeads secreting 1.3-5.2 U of insulin/24 hr in culture medium at 37 degrees C. Their clinical course s and selective histological observations were compared with those of anima ls maintained on Linplant insulin-release implants (6 rats) or protamine zi nc insulin alone (10 rats). Results. The rats that underwent porcine islet macrobead implantation (PIMI ) survived for a mean of 171 days (range, 79-288) after implantation withou t exogenous insulin, immunosuppressive treatment, or lactated Ringer's ther apy. All appeared healthy and maintained their body weights (mean 356+/-21 g) throughout this period, even though their nonfasting blood glucose level s fluctuated significantly, with the mean for the group being 245+/-102 mg/ dl (range, 157-320 mg/dl). There was mild glucosuria in some animals. In co mparison, the 10 BB/Wor rats maintained on exogenous protamine zinc insulin had a mean survival time of 53 days (range, 10-217), a "last entry" mean b ody weight of 283+/-23 g, and a mean nonfasting glucose level of 340+/-90 m g/dl. The six Linplant implant animals had a mean survival time of 164 days (range, 1-264 days), a "last entry" mean body weight of 374+/-21 g, and a mean nonfasting glucose level of 189+/-91 mg/dl (range, 135-219). Episodes of ketonuria, abrupt loss of body weight, dehydration, and symptomatic hypo glycemia were more common in both these groups than in the PIMI animals. Gl ucose tolerance tests comparing diabetic animals treated with porcine islet macrobead implants, exogenous insulin-treated diabetic BB/Wor rats, and no rmal nondiabetic Wistar-Furth rats showed that the responses of those with the macrobead implants were similar to those of the normal rats, while the exogenous insulin-treated diabetic BB/Wor rats had the expected abnormal re sponses. Light microscopic examination of the PIMI and Linplant animals' ki dney sections appeared normal, whereas those of the exogenous insulin-injec ted BB rats showed moderate focal tubular atrophy and an increased mesangia l matrix. Macrobeads retrieved from the peritoneal cavity at necropsy were found to secrete insulin, C-peptide, and glucagon, indicating that they wer e still functional after 199 or more days in the peritoneal cavity. Conclusions. Our results indicate that macrobeads containing porcine islets implanted intraperitoneally in natural insulin-dependent diabetic BB/Wor r ats are capable of normalizing glucose control, permitting a normal life sp an, and preventing the renal changes normally associated with diabetes. The refore, further short- and long-term studies of porcine islet macrobead imp lantation in chemically induced and naturally occurring diabetes in rodents , as well as larger animals including dogs, monkeys and possibly humans, ar e merited.