The overall objective of this research application is to establish clinical protocols for simultaneous islet-kidney (SIK) transplantation in type 1 diabetic recipients that will provide long-term euglycemia and insulin-independence. Based on prior human islet transplants and experimental evidence, this clinical trial of SIK transplantation will apply proven and recently emerging methods and medications to achieve this goal. Overall, 10% or less of islet transplant recipients have achieved insulin-independence for any sustained period. The best reported results from a single center are four of 12 patients (25%) achieving insulin-independence following islet-kidney transplants.
The specific aims are to overcome three obstacles that prevent better results in islet transplants: 1) low engrafted islet mass; 2) high metabolic demand and 3) immunologic graft loss. Preliminary data suggest that an improved two-step method for islet isolation, using a better preservation solution, is a means to increase the engrafted islet mass. Treatment of recipients with pravastatin may also increase the islet mass through its ability to prevent non-specific inflammatory damage to islets, as demonstrated in animal models. State of the art glycemic control with insulin pump therapy and subcutaneously implanted glucose sensors will help to prevent glucotoxicity. The investigators will use recipient treatment with thiazolidinedione class medications to lower the metabolic demand by increasing peripheral sensitivity to insulin. Anti-IL2 receptor monoclonal antibodies effectively prevent immunologic graft loss in animal models for diabetes. This trail will employ basiliximab, a chimeric anti-IL2 receptor antibody. Transplantation of peripancreatic lymphoid cells will also be used to prevent autoimmune destruction of the grafts. Outcome measures that will test the effectiveness of this protocol are arginine induced insulin release, euglycemic clamp insulin sensitivity indices and islet graft survival. Improvements in the success of SIK transplantation may eventually lead to more wide spread application of islet transplantation to the cure of type 1 diabetes.
| Kuroda, Akio; Rauch, Tibor A; Todorov, Ivan et al. (2009) Insulin gene expression is regulated by DNA methylation. PLoS One 4:e6953 |
