Key Points

• Islet cell transplantation was successful in restoring C-peptide secretion and glycemic control and eliminating severe episodes of hypoglycemia in seven patients
  
  
• More than one transplant procedure was required in all patients to achieve independence from exogenous insulin
  
  
• The shortage of suitable islet cell donors limits the widespread implementation of this procedure
  
  

The ultimate therapy for type 1 diabetes would be to restore endogenous insulin secretion by the pancreas through islet cell replacement. This slide shows the results of a study involving seven patients (age range 29-54 years) with type 1 diabetes, demonstrating the feasibility of this approach.

The seven patients received a mean of 11,547 islet equivalents per kilogram body weight, and the mean follow-up time was 11.9 months. All patients underwent glucocorticoid-free immunosuppression therapy including sirolimus, low-dose tacrolimus, and daclizumab beginning immediately before the transplant procedure and continuing for 3 or more months afterward. Antibiotic therapy was also administered for 14 weeks after the transplant procedure. Islet cells were harvested from brain-dead donors and matched to recipients' blood type and cross-matched for lymphocytotoxic antibodies. No HLA matching was performed.¹

Insulin therapy was discontinued after transplantation. If blood glucose values rose above 200 mg/dL, insulin therapy was reinstated and the patient was scheduled for another procedure. Six patients underwent two transplant procedures; one required a third. However, once adequate islet cell mass had been transplanted, all seven patients did not require exogenous insulin. By 3 months after transplantation, all patients had detectable C-peptide levels. As shown on the right side of the slide, by 6 months posttransplant, fasting C-peptide levels had reached a mean of 2.5 ng/mL, and the mean 90-minute postprandial C-peptide level was 5.7 ng/mL (P<0.001 from baseline).¹

Most importantly, as shown on the left side of the slide, 6 months after transplantation the mean A1C among the seven patients significantly declined from a baseline level of 8.4% to 5.7%, a value in the normal A1C range (P<0.001). However, five of the seven patients had an impaired response to a 2-hour OGTT, and two patients had fasting glucose levels elevated above the normal range. Prior to the transplant procedure, all patients had suffered from recurring severe hypoglycemia, but none experienced an episode after islet transplantation was complete, resulting in greatly improved quality of life.¹

These data are greatly promising, but more research is needed. A recent report from the Collaborative Islet Transplant Registry indicated that over half (57.9%) of 86 patients receiving islet allografts were insulin-independent at 12 months.² Preliminary investigations suggest that failure may be related to the quality and type of cells transplanted, in addition to immunorejection.³ Also, because pancreatic islet cells must currently be harvested from organ donors, supply is limited. Advances in stem cell research may offer the potential to resolve supply limitations, but this resolution is a decade in the future, at best. Gene therapy may also provide some hope for "curing" diabetes in the future.

References

1. Shapiro AMJ, Lakey JRT, Edmond AR, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343:230-238.
   
   
2. Collaborative Islet Transplant Registry. Annual Report. Rockville, Md: CITR Coordinating Center. 2004; Available at: http://spitfire.emmes.com/ study/isl/reports/reports.htm. Accessed September 27, 2004.
   
   
3. Street CN, Lakey JRT, Shapiro AMJ, et al. Islet graft assessment in the Edmonton protocol: implications for predicting long-term clinical outcome. Diabetes. 2004;53:3107-3114.