Islet Transplants and Impact on Secondary Diabetic Complications: Does C-Peptide Protect the Kidney? (original) (raw)
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Succesful transplantation of human islets in recipients bearing a kidney graft
Diabetologia, 2002
Refinements in procedures of pancreas enzymatic digestion, and new immunosuppression strategies have allowed clinical trials of islet transplantation in patients with Type I (insulin-dependent) diabetes mellitus . Until recently, the majority of transplants were done in patients who also receive kid-ney allografts . Clinical results in these patients have not been satisfactory, with a 12 month survival of islet allografts (as defined by basal C-peptide > 0.17 nmol/l) being achieved in less than 40 % of recipients, and insulin independence in only 13 % of recipients . The number of recipients who become insulin independent after transplantation is low and so the procedure has also been considered successful when recipients maintained detectable serum C-peptide during follow-up [3±4] or HbA 1 c was normalized . Regardless of which outcome measure is used, around 30 % of the cases reported in the International Registry of Transplantation (ITR) showed the absence of islet function af- Diabetologia (2002) 45: 77±84 Abstract Aims/hypothesis. Islet transplantation is a minimally invasive approach to curing Type I (insulin-dependent) diabetes mellitus. Success has recently been reported in patients receiving solitary islet transplants but the outcome in patients receiving islets together with, or after, kidney transplants has been limited and unpredictable. Methods. Here we report successful islet transplantation in a cohort of 15 patients with Type I diabetes who were followed for at least 1 year after islet transplantation, after having already received kidney allografts because of end-stage nephropathy. Results. C-peptide after transplantation was higher than 0.17 nmol/l in all 15 recipients, reflecting the absence of primary non-function. Insulin requirement was reduced by over 50 % in all but one patient, and insulin independence was achieved in 10 (66 %) recipients, five of whom now have stable, prolonged insulin independence, well controlled fasting glycae-mia, a substantial first-phase and normal secondphase response to glucose, normal insulin sensitivity (HOMA analyses) and HbA 1 c of under 6.2 % (33, 26, 18, 13 and 12 months after transplantation respectively). Of importance for patient management, an assessment of fasting blood glucose and proinsulin values following overnight withdrawal of insulin administration one month after transplantation was a potent predictor of insulin independence, and could be used to decide patients who should have further islet preparations. Conclusion/interpretation. These findings support the use of islet transplantation as a cure for Type I diabetes in patients with severe complications. [Diabetologia (2002) 45: 77±84]
-Cell Function Following Human Islet Transplantation for Type 1 Diabetes
Diabetes, 2004
Islet transplantation can provide metabolic stability for patients with type 1 diabetes; however, more than one donor pancreas is usually required to achieve insulin independence. To evaluate possible mechanistic defects underlying impaired graft function, we studied five subjects at 3 months and four subjects at 12 months following intraportal islet transplantation who had received comparable islet equivalents per kilogram (12,601 ± 1,732 vs. 14,384 ± 2,379, respectively). C-peptide responses, as measures of β-cell function, were significantly impaired in both transplant groups when compared with healthy control subjects (P < 0.05) after intravenous glucose (0.3 g/kg), an orally consumed meal (600 kcal), and intravenous arginine (5 g), with the greatest impairment to intravenous glucose and a greater impairment seen in the 12-month compared with the 3-month transplant group. A glucose-potentiated arginine test, performed only in insulin-independent transplant subjects (n = 5), d...
β-Cell Function Following Human Islet Transplantation for Type 1 Diabetes
Diabetes, 2004
Islet transplantation can provide metabolic stability for patients with type 1 diabetes; however, more than one donor pancreas is usually required to achieve insulin independence. To evaluate possible mechanistic defects underlying impaired graft function, we studied five subjects at 3 months and four subjects at 12 months following intraportal islet transplantation who had received comparable islet equivalents per kilogram (12,601 ± 1,732 vs. 14,384 ± 2,379, respectively). C-peptide responses, as measures of β-cell function, were significantly impaired in both transplant groups when compared with healthy control subjects (P < 0.05) after intravenous glucose (0.3 g/kg), an orally consumed meal (600 kcal), and intravenous arginine (5 g), with the greatest impairment to intravenous glucose and a greater impairment seen in the 12-month compared with the 3-month transplant group. A glucose-potentiated arginine test, performed only in insulin-independent transplant subjects (n = 5), d...
Regression of diabetic complications by islet transplantation in the rat
Diabetologia, 2009
Aims/hypothesis Type 1 diabetes is a chronic disease leading to complications such as peripheral neuropathies, nephropathy and cardiovascular disease. Pancreatic islet transplantation is being extensively investigated for blood glucose control in animals and in human type 1 diabetic patients, but the question of whether it can reverse long-term diabetic complications has not been fully explored. We investigated the effects of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes.
Islet Cell Hormonal Responses to Hypoglycemia After Human Islet Transplantation for Type 1 Diabetes
Diabetes, 2005
Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.
Transplantation, 2013
Background. In the absence of a reliable islet potency assay, nude mice (NM) transplantation is the criterion standard to assess islet quality for clinical transplantation. There are factors other than islet quality that affect the transplant outcome. Methods. Here, we analyzed the transplant outcomes in 335 NM receiving islets from human (n=103), porcine (n=205), and nonhuman primate (NHP; n=27) donors. The islets (750, 1000, and 2000 islet equivalents [IEQ]) were transplanted under the kidney capsule of streptozotocin-induced diabetic NM. Results. The proportion of mice that achieved normoglycemia was significantly higher in the group implanted with 2000 IEQ of human, porcine, or NHP islets (75% normoglycemic) versus groups that were implanted with 750 IEQ (7% normoglycemic) and 1000 IEQ (30% normoglycemic). In this study, we observed that the purity of porcine islet preparations (P e0.001), islet pellet size in porcine preparations (P e 0.01), and mice recipient body weight for human islet preparations (P =0.013) were independently associated with successful transplant outcome. NHP islets of 1000 IEQ were sufficient to achieve normoglycemic condition (83%). An islet mass of 2000 IEQ, high islet purity, increased recipient body weight, and high islet pellet volume increased the likelihood of successful reversal of diabetes in transplanted mice. Also, higher insulin secretory status of islets at basal stimulus was associated with a reduced mouse cure rate. The cumulative incidence of graft failure was significantly greater in human islets (56.12%) compared with porcine islets (35.57%; P e0.001). Conclusion. Factors affecting NM bioassay were identified (islet mass, islet purity, pellet size, in vitro insulin secretory capability, and mouse recipient body weight) and should be considered when evaluating islet function.
The Clinical Impact of Islet Transplantation
American Journal of Transplantation, 2008
Islet cell transplantation has recently emerged as one of the most promising therapeutic approaches to improving glycometabolic control in diabetic patients and, in many cases, achieving insulin independence. Unfortunately, many persistent flaws still prevent islet transplantation from becoming the gold standard treatment for type 1 diabetic patients. We review the state of the art of islet transplantation, outcomes, immunosuppression and-most important-the impact on patients' survival and long-term diabetic complications and eventual alternative options. Finally, we review the many problems in the field and the challenges to islet survival after transplantation. The rate of insulin independence 1 year after islet cell transplantation has significantly improved in recent years (60% at 1 year posttransplantation compared with 15% previously). Recent data indicate that restoration of insulin secretion after islet cell transplantation is associated with an improvement in quality of life, with a reduction in hypoglycemic episodes and potentially with a reduction in long-term diabetic complications. Once clinical islet transplantation has been successfully established, this treatment could even be offered to diabetic patients long before the onset of diabetic complications.
Diabetes, 1991
A standardized procedure was developed for the preparation of rat islet cell grafts with selected cell number and composition. After collagenase digestion of pancreases and elutriation of tissue fragments, islets were isolated and dissociated, and cells were purified by autofluorescence-activated cell sorting. Approximately 30% of the initial p-cell mass was lost during digestion and elimination of small mostly exocrine particles. Fifty percent was recovered in isolated islet preparations and 30% in the purified pcell suspensions of >95% purity and viability. Sorting according to cellular flavin adenine dinucleotide content discriminated islet p-cells from islet endocrine non-p-cells, fibroblasts, leukocytes, and exocrine cells. Purified endocrine islet cell grafts were prepared by aggregating 10 6 pure p-cells with or without 8 x 10 5 pure endocrine non-p-cells. In contrast to intact islets, the purified aggregates were devoid of nonendocrine and damaged cells. Intraportal implantation of a pure p-cell graft rapidly and permanently normalized the diabetic state of streptozocin-administered animals. The standardized preparation of purified p-cell grafts allows us to address several metabolic and immunological questions concerning islet cell transplantation in diabetes. Diabetes 40:908-19,1991 I n rodents with chemically induced diabetes, the signs of absolute insulin deficiency can be corrected by transplantation of an entire pancreas (1), pancreatic fragments (2), isolated islets (3), or reaggregated islet cells (4). Adult (1-4), neonatal (5), and fetal (6) tissue has been suc-From the