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A M James Shapiro

Publications and source records attributed to A M James Shapiro.

At least 19 recordsLinked to original sources
PubMed2007

Factors influencing the collagenase digestion phase of human islet isolation.

Substantial advances in human islet isolation technology have occurred during the past decade. However, it is still difficult to recover the entire quantity of islets contained in a pancreas. A major obstacle to successful human islet isolation has been the variability of the collagenase digestion phase of islet isolation. Future advances in enzyme technology will make it possible to optimally liberate islets with enzyme blends "tailor-made" for each individual donor pancreas. Such innovative strategies will be advantageous in improving islet isolation efficiency, recovery, viability, and ultimately posttransplant function.

Bacterial Proteins↗
PubMed2007

Changes in renal function after clinical islet transplantation: four-year observational study.

Tight glycemic control can reduce progression of diabetic nephropathy (DN) while the histological changes may regress after pancreas transplantation. Clinical islet transplantation (CIT) can restore euglycemia but the effects of CIT and concomitant immunosuppression on renal function are not known. Renal function (modification of diet in renal disease estimated glomerular filtration rate [GFR]) is reported in 41 type 1 diabetes subjects followed for 29.8 (6-57) months after CIT who received sirolimus and tacrolimus. HbA(1c) improved by 3 months (6.1 +/- 0.5 vs. 8.1 +/- 1.3%, p < 0.001) and was sustained. Over 4 years estimated GFR (eGFR) declined (repeated measures ANOVA: p = 0.0011). The median rate of change in eGFR was -0.39 mL/min/1.73 m(2)/month but was highly variable (range: +1.62 to -2.79 mL/min/1.73 m(2)/month). Progression of albuminuria was observed in ten individuals while regression of microalbuminuria was observed in only one (chi square = 22.51, df = 4, p = 0.0002). Despite improved glycemia, CIT and concomitant immunosuppression, was associated with a fall in eGFR and progression of albuminuria over 4 years of observation. The rate of decline in eGFR was extremely variable and difficult to predict. The risk of progressive nephrotoxicity with decline in eGFR should be discussed with prospective CIT candidates and the risk: benefit ratio carefully considered in individuals with pre-existing renal impairment.

Adult↗
PubMed2006

Follow-up study of the first successful living donor islet transplantation.

BACKGROUND: Islet transplantation has become an option for the treatment of insulin-dependent diabetes mellitus and is usually performed using brain-dead heartbeating donors. However, we have very limited number of such donors in Japan; therefore, it is not allowed to perform islet transplantation with brain-dead donors. In order to perform islet transplantation in Japan, we need to seek new donor resources. METHODS: We performed the first successful living-donor islet transplantation. In this case, the recipient had brittle diabetes with hypoglycemic unawareness. The donor was deemed qualified after undergoing both metabolic and preoperative assessments. Distal pancreatectomy was performed using open laparotomy and more than 400,000 islets were isolated and transplanted immediately. RESULTS: The recipient has been insulin independent posttransplant with positive C-peptide for more than one year. She no longer suffers from hypoglycemic unawareness and displayed a substantial improvement in hemoglobulin (Hb) A1C. The donor's clinical course was uneventful, which allowed her to return to her job within one month. She maintained normal fasting C-peptide and HbA1C levels during follow-up period. CONCLUSION: In our first case of living donor islet transplantation, both the donor and the recipient have been maintaining excellent glycemic control with no untreatable complications for more than one year.

Adolescent↗
PubMed2006

Compaction of islets is detrimental to transplant outcome in mice.

BACKGROUND: Despite recent progress in clinical islet transplantation, the cumulative world experience remains small. Optimizing protection of islets throughout the isolation, purification, and peritransplant period remains critical to outcome. We herein investigate the potential detrimental impact of maintaining islets in a pelleted state for periods preceding implantation. We hypothesize that periods of islet compaction lead to impairment if islet function in vivo. METHODS: In this study, 250-islet marginal mass transplants were conducted in the BALB/c syngeneic mouse model using islets either preincubated as an islet pellet or suspended in culture during the 30 min immediately preceding transplant. Nonfasting blood glucose, intraperitoneal glucose tolerance test, graft histology, and graft insulin content were all used to monitor graft function up to four weeks posttransplant. RESULTS: Maintaining islets in a compact pellet for 30 min prior to transplantation significantly reduces the proportion of transplant recipients that achieve normoglycemia (from 100% to 38%, P=0.026) and increases the proportion of apoptotic beta-cells. CONCLUSION: Our findings confirm that damage induced by sustained islet compaction results in poor graft outcome in mice. These findings raise concerns relating to potential damage to human islets prior to clinical transplantation, and this will be explored in further studies.

Animals↗
PubMed2006

Islet isolation and transplantation outcomes of pancreas preserved with University of Wisconsin solution versus two-layer method using preoxygenated perfluorocarbon.

BACKGROUND: Previous small clinical trials indicate that the two-layer method (TLM) for pancreas preservation improves islet isolation outcome. However, the effect of TLM has not been evaluated in large-scale study. In addition, a direct benefit of TLM on islet transplantation outcome has not been addressed in the setting of any randomized controlled trials. METHODS: Between April 2003 and October 2005, human pancreata from brain-dead donors were preserved by TLM using preoxygenated perfluorocarbon (n = 75) or in University of Wisconsin (UW) solution (n = 91) prior to islet isolation. Islet isolation and transplantation outcomes were compared between the two groups. RESULTS: We did not find any significant differences in adenosine triphosphate content in pancreatic tissue after preservation, pre and postpurification islet yields, in vitro insulin secretory function, or utilization ratio of transplantation between the two groups. Transplanted mass and functional viability of islet isolated from TLM-preserved pancreas were similar to those from UW-preserved pancreas. Patients receiving the TLM-islet or the UW-islet showed a marked decrease in insulin requirement after transplantation. However, no significant difference was observed in a decrease in insulin requirement between patients receiving the TLM-islet and the UW-islet. CONCLUSIONS: No beneficial effect of TLM on islet isolation and transplantation outcomes was observed. Our findings bring into question the true merit of routine use of TLM prior to islet isolation.

Adenosine↗
PubMed2006

Neonatal porcine islets exhibit natural resistance to hypoxia-induced apoptosis.

BACKGROUND: Despite the success of the Edmonton protocol for human islet transplantation, an alternate source of islet tissue must be developed if beta-cell replacement therapy is to see widespread application. Neonatal porcine islets (NPI) represent one potential source of tissue. When human or rodent islets are transplanted, the majority of cells undergo hypoxia-induce apoptosis soon after the grafts are placed in the recipient. In the present study, we investigated whether NPI were similarly sensitive to hypoxia. METHODS: NPI were exposed to hypoxia and hypoxia/reoxygenation using an in vitro hypoxic chamber. Afterwards, viability, frequency of apoptosis, and beta-cell function were evaluated. NPI and adult porcine islets were transplanted into chemically diabetic, immunodeficient mice and graft apoptosis was assessed 24 hours and seven days posttransplant. RESULTS: NPI demonstrated a remarkable capacity to resist apoptosis and maintain insulin secretion despite severe stresses such as hypoxia/reoxygenation. One day after transplantation, NPI grafts showed limited apoptosis, confined to rare strongly insulin positive cells. In contrast, adult porcine islet grafts underwent widespread apoptosis. Western blotting revealed that NPI express high levels of at least one potent endogenous antiapoptotic protein (XIAP). CONCLUSIONS: The majority of cells within transplanted human islets undergo apoptosis soon after portal infusion. In contrast, NPI have the capacity to resist this early posttransplant apoptosis, with likely reduced antigen release and diminished immune stimulation. NPI appear to contain a population of insulin-low to insulin-negative pre-beta-cells, which are resistant to hypoxia-induced apoptosis and still capable of differentiating into mature beta-cells.

Aging↗
PubMed2006

International trial of the Edmonton protocol for islet transplantation.

BACKGROUND: Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). METHODS: We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. RESULTS: Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. CONCLUSIONS: Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Stem cell sources for clinical islet transplantation in type 1 diabetes: embryonic and adult stem cells.

Lifelong immunosuppressive therapy and inadequate sources of transplantable islets have led the islet transplantation benefits to less than 0.5% of type 1 diabetics. Whereas the potential risk of infection by animal endogenous viruses limits the uses of islet xeno-transplantation, deriving islets from stem cells seems to be able to overcome the current problems of islet shortages and immune compatibility. Both embryonic (derived from the inner cell mass of blastocysts) and adult stem cells (derived from adult tissues) have shown controversial results in secreting insulin in vitro and normalizing hyperglycemia in vivo. ESCs research is thought to have much greater developmental potential than adult stem cells; however it is still in the basic research phase. Existing ESC lines are not believed to be identical or ideal for generating islets or beta-cells and additional ESC lines have to be established. Research with ESCs derived from humans is controversial because it requires the destruction of a human embryo and/or therapeutic cloning, which some believe is a slippery slope to reproductive cloning. On the other hand, adult stem cells are already in some degree specialized, recipients may receive their own stem cells. They are flexible but they have shown mixed degree of availability. Adult stem cells are not pluripotent. They may not exist for all organs. They are difficult to purify and they cannot be maintained well outside the body. In order to draw the future avenues in this field, existent discrepancies between the results need to be clarified. In this study, we will review the different aspects and challenges of using embryonic or adult stem cells in clinical islet transplantation for the treatment of type 1 diabetes.

Adult↗
PubMed2006

Current status of pancreatic islet transplantation.

DM (diabetes mellitus) is a metabolic disorder of either absolute or relative insulin deficiency. Optimized insulin injections remain the mainstay life-sustaining therapy for patients with T1DM (Type I DM) in 2006; however, a small subset of patients with T1DM (approx. 10%) are exquisitely sensitive to insulin and lack counter-regulatory measures, putting them at higher risk of neuroglycopenia. One alternative strategy to injected insulin therapy is pancreatic islet transplantation. Islet transplantation came of age when Paul E. Lacy successfully reversed chemical diabetes in rodent models in 1972. In a landmark study published in 2000, Shapiro et al. [A. M. Shapiro, J. R. Lakey, E. A. Ryan, G. S. Korbutt, E. Toth, G. L. Warnock, N. M. Kneteman and R. V. Rajotte (2000) N. Engl. J. Med. 343, 230-238] reported seven consecutive patients treated with islet transplants under the Edmonton protocol, all of whom maintained insulin independence out to 1 year. Substantial progress has occurred in aspects of pancreas procurement, transportation (using the oxygenated two-layer method) and in islet isolation (with controlled enzymatic perfusion and subsequent digestion in the Ricordi chamber). Clinical protocols to optimize islet survival and function post-transplantation improved dramatically with the introduction of the Edmonton protocol, but it is clear that this approach still has potential limitations. Newer pharmacotherapies and interventions designed to promote islet survival, prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials, and it seems likely that clinical outcomes of islet transplantation will continue to improve at the current exponential pace.

Blood Glucose↗
PubMed2006

Assessment of glycemic control after islet transplantation using the continuous glucose monitor in insulin-independent versus insulin-requiring type 1 diabetes subjects.

BACKGROUND: The aim of this study was to assess and compare glycemic control using the continuous glucose monitor (CGMS, Medtronic Minimed, Northridge, CA) in type 1 diabetes mellitus (T1DM) subjects who are insulin-independent versus those who require insulin after islet transplantation alone (ITA). METHODS: Glycemic control was assessed using 72-h CGMS in eight T1DM subjects who were insulin-independent after ITA (ITA-II), eight T1DM subjects who were C-peptide-positive but insulin-requiring after ITA (ITA-IR), and eight non-transplanted (NT) T1DM subjects. RESULTS: Standard deviation of glucose values was not significantly different between ITA-II and ITA-IR subjects (ITA-II, 1.2 +/- 0.1 mM; ITA-IR, 2.0 +/- 0.3 mM; P = 0.072). Both ITA groups were more stable than NT subjects (NT, 3.3 +/- 0.3 mM; P = 0.001 vs. ITA). Mean high glucose values were significantly lower in ITA subjects compared with NT subjects (ITA-II, 10.5 +/- 0.6 mM; ITA-IR, 13.0 +/- 1.0 mM; NT, 16.1 +/- 1.1 mM; P = 0.002). Mean average glucose values were not significantly different among all groups (ITA-I, 6.7 +/- 0.2 mM; ITA-IR, 7.8 +/- 0.3 mM; NT, 7.7 +/- 0.6 mM; P = 0.198). Mean low glucose values were significantly higher in both ITA groups compared with NT subjects (ITA-II, 4.5 +/- 0.2 mM; ITA-IR, 4.3 +/- 0.3 mM; NT, 3.0 +/- 0.2 mM; P = 0.003). Duration of hypoglycemic excursions (<3.0 mM) was markedly reduced in both ITA groups (ITA-II, 0%; ITA-IR, 2.4 +/- 0.2%; NT, 11.8 +/- 4.2%). Glycated hemoglobin was not significantly different between ITA groups (ITA-II, 6.4 +/- 0.2%; ITA-IR, 6.5 +/- 0.3%) and was significantly higher in NT subjects (8.3 +/- 0.2%; P < 0.001 vs. ITA). CONCLUSIONS: CGMS monitoring demonstrates that glycemic lability and hypoglycemia are significantly reduced in C-peptide-positive islet transplant recipients, whether or not supplementary, exogenous insulin is used, compared with non-transplanted T1DM subjects.

Adult↗
PubMed2006

Current indications for pancreas or islet transplant.

Pancreas or islet transplantation can provide good glycaemic control and insulin independence. Pancreas transplantation has been associated with improvement in diabetic retinopathy, nephropathy, neuropathy and vasculopathy, but has the associated morbidity of major surgery. Both forms of therapy require long-term immunosuppression and its attendant risks and both achieve insulin independence rates of about 80% at 1 year. Pancreas transplantation at the same time as a renal transplant is a worthwhile option to employ, especially if the diabetes has been difficult to control. Diabetes associated with frequent severe hypoglycaemia or extreme lability, despite optimization of diabetes management, may benefit from either pancreas or islet transplant alone with the latter being the lower-risk procedure. More quantitative measures of hypoglycaemia and lability are now available to facilitate the assessment of the severity of these problems with glucose control. Diabetic patients with renal involvement (macroproteinuria, but no major elevation of creatinine) and unstable diabetes may be helped with an islet or pancreas transplant, but this approach should still be considered experimental and such a transplant may hasten the need for renal replacement therapy. In the setting of well-controlled diabetes and intact renal function, it is difficult to justify pancreas or islet transplant alone given the risks of immunosuppression.

Diabetes Mellitus, Type 1↗
PubMed2006

Advances in pancreatic islet transplantation in humans.

With recent advances in methods of islet isolation and the introduction of more potent and less diabetogenic immunosuppressive therapies, islet transplantation has progressed from research to clinical reality. Presently, several international centres have demonstrated successful clinical outcomes with high rates of insulin independence after islet transplantation. Ongoing refinements in donor pancreas procurement and processing, developments in islet isolation and purification technology, and advances in novel immunological conditioning and induction therapies have led to the acceptance of islet transplantation as a safe and effective therapy for patients with type 1 diabetes. This review provides a historical perspective of islet transplantation, outlines the recent advances and current clinical outcomes, and addresses the present challenges and future directions in clinical islet transplantation.

Diabetes Mellitus, Type 1↗
PubMed2006

Detection of insulin mRNA in the peripheral blood after human islet transplantion predicts deterioration of metabolic control.

Recent updates of the Edmonton trial have shown that insulin independence is progressively lost in approximately 90% of islet transplant recipients over the first 5 years. Early prediction of islet graft injury could prompt the implementation of strategies attempting to salvage the transplanted islets. We hypothesize that islet damage is associated with the release and detection of insulin mRNA in the circulating blood. Whole blood samples were prospectively taken from 19 patients with type 1 diabetes receiving 31 islet transplants, immediately prior to transplantation and at regular time-points thereafter. After RNA extraction, levels of insulin mRNA were determined by quantitative reverse tran-scriptase-polymerase chain reaction. All patients exhibited a primary peak of insulin mRNA immediately after transplantation, without correlation of duration and amplitude with graft size or outcome. Twenty-five subsequent peaks were observed during the follow-up of 17 transplantations. Fourteen secondary peaks (56%) were closely followed by events related to islet graft function. Duration and amplitude of peaks were higher when they heralded occurrence of an adverse event. Peaks of insulin mRNA can be detected and are often associated with alterations of islet graft function. These data suggest that insulin mRNA detection in the peripheral blood is a promising method for the prediction of islet graft damage.

Adult↗
PubMed2006

Current status of clinical islet cell transplantation.

Clinical outcomes of pancreas transplantation were superior to that of islet transplantation until the introduction of the Edmonton protocol. Significant advances in islet isolation and purification technology, novel immunosuppression and tolerance strategies, and effective antiviral prophylaxis have renewed interest in clinical islet transplantation for the treatment of diabetes mellitus. The introduction of a steroid-free antirejection protocol and islets prepared from two donors led to high rates of insulin independence. The Edmonton protocol has been successfully replicated by other centers in an international multicenter trial. A number of key refinements in pancreas transportation, islet preparation, and newer immunological conditioning and induction therapies have led to continued advancement through extensive collaboration between key centers. This chapter provides an overview of the history of islet transplantation followed by a discussion of the state of the art of clinical islet transplantation. The challenges facing the clinician-scientist in the 21st century are also presented in this review.

Diabetes Mellitus, Type 1↗
PubMed2006

Progress in islet transplantation in patients with type 1 diabetes mellitus.

More than 500 patients with type 1 diabetes mellitus have now received islet transplants at over 50 institutions worldwide in the past 5 years. Rates of insulin independence at 1 year with current protocols are impressive. However, inexorable decay of islet function over time indicates that there are many opportunities for improvement. Improved control of glycosylated hemoglobin and reduced risk of recurrent hypoglycemia are seen as important benefits of islet transplantation, irrespective of the status regarding insulin independence. For the use of islet transplantation to expand it is essential that the donor-to-recipient ratio be reliably reduced to 1 : 1. Enormous opportunities lie ahead for the development of successful living donor islet transplantation, single donor protocols, improved engraftment, islet proliferation in vitro and in the recipient, alternative islet sources, and novel tolerizing drugs. With these emerging opportunities, islet transplantation may expand to include more patients with type 1 diabetes, including children, and will not be restricted to the most unstable forms of the disease, as it is today.

Diabetes Mellitus, Type 1↗
PubMed2006

Interventional strategies to prevent beta-cell apoptosis in islet transplantation.

A substantial proportion of the transplanted islet mass fails to engraft due to death by apoptosis, and a number of strategies have been explored to inhibit beta-cell loss. Inhibition of extrinsic signals of apoptosis (i.e., cFLIP or A20) have been explored in experimental islet transplantation but have only shown limited impact. Similarly, strategies targeted at intrinsic signal inhibition (i.e., BCL-2) have not yet provided substantial improvement in islet engraftment. Recently, investigation of downstream apoptosis inhibitors that block the final common pathway (i.e., X-linked inhibitor of apoptosis protein [XIAP]) have demonstrated promise in both human and rodent models of engraftment. In addition, XIAP has enhanced long-term murine islet allograft survival. The complexities of both intrinsic and extrinsic apoptotic pathway inhibition are discussed in depth.

Animals↗