GLUCOSE CONTROL AND LONG-TERM SURVIVAL IN BIOBREEDING/WORCESTER RATS AFTER INTRAPERITONEAL IMPLANTATION OF HYDROPHILIC MACROBEADS CONTAINING PORCINE ISLETS WITHOUT IMMUNOSUPPRESSION1


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Abstract

Background.We investigated the effectiveness of implanted macrobeads containing porcine islets as long-term therapy for type I diabetes mellitus in Biobreeding/Worcester (BB/Wor) rats, an animal model of spontaneous type I human diabetes. End points included acute co0ntrol 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°C. Their clinical courses and selective histological observations were compared with those of animals maintained on Linplant insulin-release implants (6 rats) or protamine zinc 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 without exogenous insulin, immunosuppressive treatment, or lactated Ringer's therapy. All appeared healthy and maintained their body weights (mean 356±21 g) throughout this period, even though their nonfasting blood glucose levels 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 comparison, 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 body weight of 283±23 g, and a mean nonfasting glucose level of 340±90 mg/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 hypoglycemia were more common in both these groups than in the PIMI animals. Glucose tolerance tests comparing diabetic animals treated with porcine islet macrobead implants, exogenous insulintreated diabetic BB/Wor rats, and normal 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 responses. Light microscopic examination of the PIMI and Linplant animals' kidney sections appeared normal, whereas those of the exogenous insulin-injected BB rats showed moderate focal tubular atrophy and an increased mesangial matrix. Macrobeads retrieved from the peritoneal cavity at necropsy were found to secrete insulin, C-peptide, and glucagon, indicating that they were 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 rats are capable of normalizing glucose control, permitting a normal life span, and preventing the renal changes normally associated with diabetes. Therefore, further short- and long-term studies of porcine islet macrobead implantation in chemically induced and naturally occurring diabetes in rodents, as well as larger animals including dogs, monkeys and possibly humans, are merited.

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