METABOLIC OUTCOMES AFTER ISLET TRANSPLANTATION
Garth L. WarnockMark MelocheJerry ShapiroZ. AoPaul KeownJames D. JohnsonC. Bruce VerchereN. PartoviDavid Thompson
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Warnock, G L.; Meloche, M; Shapiro, J; Ao, Z; Keown, P; Johnson, J D.; Verchere, B; Partovi, N; Thompson, D Author InformationObjectiveTo observe and compare the efficacy of two types of microencapsulated rat islets xenotransplanted into diabetic mice. MethodsThe mice diabetic model made with injecting 3% Streptozotosin through tail vein. Four groups were assigned: control group, naked islet transplantation group, alginate-BaCl_2 microencapsulated islet transplantation group, agarose-PSSa microencapsulated islet transplantation group.300 islets were transplanted under the renal envelope of each diabetic mice respectively. ResultsThere were no significant difference in mean level of the blood glucose before transplantation among four groups. One week after transplantation, the respective mean level of the blood glucose in four groups were (7.26±1.56) mmol/L in alginate-BaCl_2 microencapsulated islet transplantation group, (7.14±1.04) mmol/L in agarose-PSSa microencapsulated islet transplantation group, (7.42±1.52) mmol/L in naked islet transplantation group and (22.54±1.24) mmol/L in control. There were significant difference between the two encapsulated islet groups and the other two groups. The survived period of the two encapsulated islet transplantation groups were longer than that of the other two groups. The survived period of the alginate-BaCl_2 microencapsulated islet transplantation group was longer than that of the agarose-PSSa microencapsulated islet transplantation group (92 d vs 56 d),the same as the time of keeping nomal blood glucose level (76 d vs 41 d). ConclusionMicroencapsulated rat islets with this two materials can survive in diabetic mice with their biological activity, and the alginate-BaCl_2 microcapsules are better than the agarose-PSSa microcapsules.
Agarose
Xenotransplantation
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Renal capsule
Pancreatic Islets
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Introduction: Encapsulated allogeneic islet grafts in TheracyteTM devices are protected from graft rejection. However,other aspects of the metabolic control by encapsulated grafts is not yet studied. The aim of our study is to characterize the insulin secretion-pattern and the resulting metabolic control when encapsulated islets are implanted s.c. in rat transplantation models. Methods: Male Lewis rats were used as donors and female Lewis rats or Wister-Furth rats with streptozotocin induced diabetes were used as recipients. Age matched healthy female rats were used as controls. Theracyte devices were implanted three month prior to transplantation. Oral glucose tolerance tests (OGTT) were performed at one and five months after transplantation and intra-venous glucose tolerance tests (IVGTT) were performed three months after transplantation. In a syngeneic model, transplantation of non-encapsulated islets was also studied. Morphometry of encapsulated islets were compared one and six months after transplantation. Results: In the syngeneic model, the minimum islet numbers to cure a diabetic rat was 1000 for encapsulated grafts, 800 non-encapsulated islets for the portal vein injected group. The peak of plasma insulin concentration in OGTT was observed10 minutes after glucose challenge in healthy controls, 10-20 minutes in the non-encapsulated islet transplantion group and after 30 minutes in the encapsulated islet transplantation group. The encapsulated islet transplanted rats showed clearly delayed recovery of blood glucose compared to healthy or nonencapsulated islet transplanted rats. Furthermore, the recovery of blood glucose in the encapsulated islet transplantation group was significantly slower in OGTT at five months after transplantation compared to at one month after transplantation, but the amount of plasma insulin was not significantly different. Table 1 shows area under the curve (AUC) of blood glucose during OGTT at one and five months after transplantation. In the allogeneic encapsulated islet transplantation model, five out of the seven rats that received 2000 encapsulated islets and two out of eight transplanted with 1000 encapsulated islets showed hypoglycemia (< 3 mM) between 90-120 minutes in OGTT at 1 month after transplantation, but this was not seen 5 months after transplantation.Table: [Comparison of AUC glu 0-120 min. in OGTT]In IVGTT, healthy controls and the non-encapsulated islet transplantation group had a quick insulin release (peak 3 minutes), but that response was much slower in the encapsulated islet transplantation group. In histological examinations of the encapsulated grafts, we found that the endocrine cell volume was similar between one and six months after transplantatio. However, the fibroblast volume inside the devices increased by four times in devices harvested at six months after transplantation compared to at one month after transplantation. Conclusion: During the earlier period after encapsulated islet transplantation, hypoglycemia may be observed in response to acute increase of blood glucose. Overgrowth of fibroblasts inside the device could be a reason to cause delayed sensitivity in glucose tolerance tests long term after transplantation.
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Although culturing islets before transplantation provides flexibility for evaluation of isolated islets and pretreatment of patients, it is well-known that isolated islets deteriorate rapidly in culture. In this study, we evaluated optimal temperature for culture/preservation of isolated human islets before transplantation.Isolated islets were cultured or preserved for 48 hr in the following culture/preservation conditions: preservation at 4 degrees C in University of Wisconsin solution and culture at 22 degrees C or 37 degrees C in culture medium.Islet morphology after 4 degrees C preservation was similar to that of fresh islets, whereas islet diameter after 37 degrees C or 22 degrees C culture was smaller than that of fresh islets. Islet yield significantly decreased at higher temperatures (24% loss in 37 degrees C culture and 19% loss in 22 degrees C culture, but <5% loss in 4 degrees C preservation). Cultured/preserved islets were transplanted into diabetic nude mice. The attainability of posttransplantation normoglycemia was significantly higher in the 4 degrees C preservation group than in 22 degrees C and 37 degrees C culture groups.Preservation of isolated islets at 4 degrees C improves the outcome of islet transplantation more efficiently than preservation at 22 degrees C or 37 degrees C. Based on these data, we have performed short-time cold storage of isolated islets instead of culturing for current clinical islet transplantation.
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Organ culture
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Islet cell transplantation
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Beta cell replacement is an exciting field where new beta cell sources and alternative sites are widely explored. The liver has been the implantation site of choice in the clinic since the advent of islet transplantation. However, in most cases, repeated islet transplantation is needed to achieve normoglycemia in diabetic recipients. This study aimed to investigate whether there are differences in islet survival and engraftment between a first and a second transplantation, performed 1 week apart, to the liver. C57BL/6 mice were accordingly transplanted twice with an initial infusion of syngeneic islets expressing green fluorescent protein (GFP). The second islet transplant was performed 1 week later and consisted of islets isolated from non-GFP C57BL/6-mice. Animals were sacrificed either 1 day or 1 month after the second transplantation. A control group received a saline infusion instead of GFP-expressing islets, 1 week later obtained a standard non-GFP islet transplant, and was subsequently sacrificed 1 month later. Islet engraftment in the liver was assessed by immunohistochemistry and serum was analyzed for angiogenic factors induced by the first islet transplantation. Almost 70% of islets found in the liver following repeated islet transplantation originated from the second transplantation. The vascular density in the transplanted non-GFP-expressing islets did not differ depending on whether their transplantation was preceded by a primary islet transplantation or saline administration only nor did angiogenic factors in serum prior to the transplantation of non-GFP islets differ between animals that had received a previous islet transplantation or a saline infusion. We conclude that first islet transplantation creates, by unknown mechanisms, favorable conditions for the survival of a second transplant to the liver.
Islet cell transplantation
Viaspan
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For clinical islet transplantation, isolated islets deteriorate rapidly in culture, although culturing islets prior to transplantation provides flexibility for evaluation of isolated islets and pretreatment of patients. In the present study, we compared human fresh islets to cultured islets with in vitro and in vivo assays. After culture for 24, 48, and 72 h, islet yield significantly decreased from 2,000 to 1,738 ± 26 (13% loss), 1,525 ± 30 (24% loss), or 1,298 ± 18 IEQ (35% loss), respectively. The ATP contents were significantly higher in the 6-h cultured group (near fresh group) than in 48-h culture groups. The stimulation index was relatively higher in the 6-h cultured group than in 48-h cultured group. Human islets with or without culture were transplanted into diabetic nude mice. The attainability of posttransplantation normoglycemia was significantly higher in fresh group than in the culture groups. Intraperitoneal glucose tolerance testing (IPGTT) showed that the blood glucose levels of mice transplanted with fresh islets were significantly lower than with cultured islets at 30, 60, 90, and 120 min after injection. These data suggest that human islet transplantation without culture could avoid the deterioration of islets during culture and improve the outcome of islet transplantation. Based on these data, we have transplanted fresh islets without culture for our current clinical islet transplantation protocol.
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The evaluation of engraftment is important to assess the success of islet transplantation, but it is complex because islet transplantation usually requires two or more donors to achieve euglycemia. Islet transplantation from NHBDs was evaluated using new assessment forms for the secretory unit of islet in transplantation (SUIT) and engrafted islet rate (EIR) indexes. Insulin independence was obtained when the SUIT index was more than 28, which might indicate that 28% of the β-cell mass of a normal subject is required for insulin independence. Because the average EIR for a single transplantation is about 30, the percentage of engrafted islets following one transplantation is about 30%, assuming that a normal subject has 1 million islet equivalents. Although few cultured islet transplants have been performed, the increase of the SUIT and EIR indexes in patients who received cultured islets was significantly lower than in patients who received fresh islets, suggesting that fresh islets may be more effective than cultured islets. The SUIT and EIR indexes are thus considered to be useful values for evaluating islet transplantation, especially for single islet transplantation.
Islet cell transplantation
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Pancreatic Islets
Islet cell transplantation
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