The report by Hirshberg et al. (1) describes the National Institutes of Health (NIH) experience in islet-only transplantation using the medical indication of severe hypoglycemia. Although the report details islet transplantation, there was little hypoglycemic information. Because of the potential side effects comparing the medical indication and the treatment, we have scientific, educational, and ethical concerns.
The first concern is the relative morbidity and mortality between severe hypoglycemia and islet transplantation. The mortality associated with severe hypoglycemia is unclear, but estimates show that 0–4% of type 1 diabetic patients die of hypoglycemia (2–4). Is there a mortality estimate with the immunosuppression regimen plus transplantation? Regarding morbidity, hypoglycemic rates appear significant in the Diabetes Control and Complications Trial (DCCT), but these events generated a hospitalization rate of only 1.1 per 100 patient years (4). At least 2 of 6 patients in the transplant group had life-threatening side effects and a hospitalization rate of over 22 per 100 patient- years.
It would be appropriate to define and quantitate hypoglycemic events before and after transplantation. Hypoglycemic complications, e.g., accidents, emergency room visits, and all-cause hospitalizations before and after transplantation should be compared. It was unclear whether islet transplantation or changes in exogenous insulin regimens reduced the rates of severe hypoglycemic events.
There was no description of the methods and personnel involved in the management of severe hypoglycemia before transplantation. Successful educational methods are reported; were educational methods used? Were patients treated with the most effective regimens currently available, e.g., ultralente twice a day, glargine insulin, and rapid-acting insulin analogs? It should be clear that NPH and regular insulins were not being used before transplantation. Was continuous subcutaneous insulin infusion (CSII) used, and were CSII basal rate–only methods used? For future studies, the use of glucose sensor devices may also appear useful. Since continuous intraperitoneal insulin infusion (CIPII) has been described to markedly reduce severe hypoglycemic events, were the patients offered compassionate use of CIPII? All of the above treatments, when used by experienced clinicians, appear considerably safer than the procedures described for islet transplantation.
Regarding ethics, did consent forms advise patients of the above successful severe hypoglycemia treatments?
Since additional U.S. sites will use islet transplantation for treatment of severe hypoglycemia, such teams must include collaborators with expertise regarding severe hypoglycemia. In future islet transplantation studies, the transplantation teams may wish to standardize not only a definition of severe hypoglycemia, but also diagnostic and treatment protocol algorithms before islet transplantation. The NIH would seem the obvious site to initiate such protocols.
M.A.C. has received honoraria for speaking engagements from Aventis Pharmaceuticals, and Aventis provides funds to the research center in order to conduct studies on glargine insulin.