Insulin Independence Following Isolated Islet Transplantation and Single Islet Infusions

Markmann, James F.; Deng, Shaoping; Huang, Xiaolun; Desai, Niraj M.; Velidedeoğlu, Ergun; Lui, Chengyang; Frank, Adam M.; Markmann, Eileen; Palanjian, Maral; Brayman, Kenneth L.; Wolf, Bryan A.; Bell, Ewan; Vitamaniuk, Marko; Doliba, Nicolai M.; Matschinsky, Franz M.; Barker, Clyde F.; Naji, Ali

doi:10.1097/01.sla.0000072110.93780.52

Cited by 142 publications

(101 citation statements)

References 19 publications

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“…We feel, however, that the high levels of sirolimus to which the animals are exposed may accurately represent the high peak drug concentrations within the portal circulation, to which human and large animal islet grafts are exposed after being infused into the recipient liver [37]. Similar decreases in insulin response to glucose have been reported in an allograft porcine model of islet transplantation and in the clinical setting of patients who receive islet transplantation [27,38]. In both reports transplant recipients received sirolimus as part of their immunosuppressive regime and demonstrated elevated glucose following a glucose challenge test.…”

Section: Discussionmentioning

confidence: 97%

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

et al. 2006

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Aims/hypothesis The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue. Methods HDCs (n=4), NPIs (n=9) and human islets (n=5) were cultured with and without sirolimus (20 ng/ml) for 6 days. Results HDCs and NPIs cultured with sirolimus showed a 50 and 28% decrease, respectively, in cell number relative to control (p<0.05). Control cultures expanded 1.65-and 2.44-fold relative to time 0. Decreases in cell number of sirolimus-treated HDCs were not due to apoptosis as measured by TUNEL staining. No functional effects on human islets or NPIs were observed following static incubation with high glucose. Treatment of syngeneically transplanted and naïve BALC/c mice with sirolimus resulted in altered OGTT profiles with prolonged elevation of hyperglycaemia and weight gain. There was no difference in graft and organ insulin content between treatment groups. Conclusions/interpretation Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance.

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Section: Discussionmentioning

confidence: 97%

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

et al. 2006

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“…In the donor population, the disease incidence is even higher given the average older age and the selection for patients who died of cardiovascular disease, which is more likely to lead to brain death criteria for donation than other causes of death. The recent success of islet transplantation relies on the delivery of a large number of islets and usually requires all of the islets that can be obtained by processing two to four pancreata (28,32). In view of the already existing imbalance between the number of potential donors and available recipients, this represents a major obstacle preventing greater application of islet transplantation to type 1 diabetic patients (33,34).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Abnormalities in the Islets Isolated From Type 2 Diabetic Subjects

et al. 2004

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Type 2 diabetic subjects manifest both disordered insulin action and abnormalities in their pancreatic islet cells. Whether the latter represents a primary defect or is a consequence of the former is unknown. To examine the ␤-cell mass and function of islets from type 2 diabetic patients directly, we isolated islets from pancreata of type 2 diabetic cadaveric donors (n ‫؍‬ 14) and compared them with islets from normal donors (n ‫؍‬ 14) matched for age, BMI, and cold ischemia time. The total recovered islet mass from type 2 diabetic pancreata was significantly less than that from nondiabetic control subjects (256,260 islet equivalents [2,588 IEq/g pancreas] versus 597,569 islet equivalents [6,037 IEq/g pancreas]). Type 2 diabetic islets were also noted to be smaller on average, and histologically, islets from diabetic patients contained a higher proportion of glucagon-producing ␣-cells. In vitro study of islet function from diabetic patients revealed an abnormal glucosestimulated insulin release response in perifusion assays. In addition, in comparison with normal islets, an equivalent number of type 2 diabetic islets failed to reverse hyperglycemia when transplanted to immunodeficient diabetic mice. These results provide direct evidence for abnormalities in the islets of type 2 diabetic patients that may contribute to the pathogenesis of the disease. Diabetes 53: 624 -632, 2004

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“…The islet transplant recipients (n ϭ 6) were studied a mean 7.5 (range 6 -12) months after their last transplant. The procedure for islet transplantation at HUP has been previously reported (18). In short, subjects underwent one to three intraportal islet infusions under daclizumab induction immunotherapy.…”

Section: Methodsmentioning

confidence: 99%

Islet Cell Hormonal Responses to Hypoglycemia After Human Islet Transplantation for Type 1 Diabetes

et al. 2005

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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. Diabetes 54: 3205-3211, 2005

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Insulin Independence Following Isolated Islet Transplantation and Single Islet Infusions

Abstract: This report confirms the efficacy of the Edmonton immunosuppressive regimen and indicates that insulin independence can often be achieved by a single transplant of sufficient islet mass.

Cited by 142 publications

References 19 publications

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

Structural and Functional Abnormalities in the Islets Isolated From Type 2 Diabetic Subjects

Islet Cell Hormonal Responses to Hypoglycemia After Human Islet Transplantation for Type 1 Diabetes

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