Can islet cell transplantation treat diabetes?BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7262.651 (Published 16 September 2000) Cite this as: BMJ 2000;321:651
Small studies show promise, now multicentre trials are going ahead
- Steven A White, lecturer,
- Michael L Nicholson, professor,
- Bernhard J Hering, director of islet transplantation
- Department of Surgery, University of Leicester, Leicester LE4 5PW, England
- Diabetes Institute for Immunology and Transplantation, University of Minnesota, Box 195, 420 Delaware Street S.E. Minneapolis 55455 United States
Type 1 diabetes mellitus is a major burden on patients and healthcare economies. The early identification of patients at risk of developing chronic complications would allow timely intervention thus reducing complications, improving the quality of life, prolonging life expectancy, and lowering the cost of treatment. The main determinant of developing chronic complications is prolonged exposure to hyperglycaemia.1 There is no doubt that intensive insulin regimens can reduce the onset and progression of complications from diabetes but they are non-physiological and have an increased risk of causing severe hypoglycaemia. They are also labour intensive and difficult for patients to implement.
The only way to restore long term euglycaemia is by transplanting a vascularised pancreas. This procedure has been performed in over 15 000 recipients worldwide and has an 85% rate of graft survival at one year— that is, these recipients remained insulin independent.2 During the past decade vascularised pancreatic transplantation has shown the advantages of endocrine cell replacement therapy over the daily ritual of subcutaneous insulin injections. Prospective case control studies suggest that vascularised pancreatic transplantation can prevent and ameliorate the progression of complications from diabetes, such as nephropathy and neuropathy. 3 4 It also improves a patient's quality of life, increases the overall survival of patients, and is cost effective.5-7
While simultaneous pancreas-kidney transplantation has emerged as the treatment of choice for most diabetic patients with end stage renal disease, transplantation of the pancreas alone in patients with diabetes who are not uraemic is seen as more controversial.8 The argument against transplanting only the pancreas is that the improved quality of life is offset by the combined risks of immunosuppression and major surgery.
The success of islet cell transplantation
In comparison with vascularised pancreatic transplantation, islet cell transplantation can provide a minimally invasive means of restoring euglycaemia and insulin independence early in the course of diabetes. Islet cell transplantation, which avoids the surgical complications associated with vascularised pancreatic transplantation, could also improve the safety of endocrine cell replacement and reduce the cost and, consequently, increase the availability of endocrine cell replacement. Unfortunately data from the International Islet Transplant Registry show that only 12% of the 267 patients who received islet allografts were insulin independent for more than seven days, and only 8% were insulin independent at one year.9
Clearly, these results do not match the success of whole pancreas transplants. Yet islet cell autotransplants for patients with benign pancreatic diseases have been more successful: between 30% and 50% of patients have become insulin independent. 10 11 The reasons for this discrepancy relate to the absence of alloimmunity, autoimmunity, and diabetogenic immunosuppression.
An increase in the success rate of islet allografts has recently been reported by the University of Alberta in Edmonton, Canada.12 Sequential islet allotransplants prepared from two donor pancreases were performed 2-10 weeks apart and consistently reversed insulin dependence in non-uraemic recipients. These patients were given an immunosuppression regimen without steroids that included an interleukin 2 receptor antibody (daclizumab), sirolimus (rapamycin), and low dose tacrolimus.12
This strategy was designed to provide potent synergistic immunosuppression, thus avoiding the diabetogenic impact of steroids and high dose calcineurin inhibitors (for example cyclosporin) in the presence of a limited reserve of β cell transplant tissue. All seven recipients were normoglycaemic and insulin independent. HbA1c concentrations were normal after a mean follow up of 11 months. More importantly, severe adverse side effects were not documented in any of the recipients. This study shows that islet allografts can work. Notably, this success was accomplished in non-uraemic recipients, a cohort that is historically prone to allograft rejection after transplantation of pancreas alone.8
This study has stimulated a renewed interest among funding organisations. The Immune Tolerance Network, one of the clinical research projects of the US National Institutes of Health and the US Juvenile Diabetes Foundation, will soon start a multicentre controlled trial to coordinate implementation of the protocol developed in Edmonton. Hopefully, in the next few years clinical trials will assess the safety and efficacy of islet cell transplantation in conjunction with emerging immunotherapeutic and tolerogenic regimens that have shown promise in experimental models. Successful completion of these trials will provide a basis for the introduction of islet transplantation as a treatment option for people with type 1 diabetes—an option that has been promised for many years.
MLN is conducting a clinical trial using sirolimus in patients with renal transplants, funded by Wyeth, which manufactures the drug.
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