Islet transplantation: an evidence-based analysis.
OBJECTIVE
The Medical Advisory Secretariat undertook a review of the evidence on the effectiveness and cost-effectiveness of islet transplantation alone (ITA) in non-uremic patients with type 1 DM who have severe hypoglycemia and uncontrolled diabetes (brittle diabetics).


RESULTS
In a health technology assessment from Alberta, Guo et al. (2003) stated that limited evidence from the Edmonton series suggested that islet cell transplantation (ITA) (using the Edmonton Protocol) is effective in 1) controlling labile diabetes and 2) protecting against unrecognized hypoglycemia in highly selected patients in the short term. This conclusion by Guo et al. (2003) was based on the results of 11/17 insulin independent patients who were followed up for a median of 20.4 months in the trial by Ryan et al. (2002). In contrast, Paty et al. (2002) concluded that glucagon and epinephrine responses and hypoglycemic symptom recognition were not improved by islet transplantation in patients receiving the procedure in Edmonton, despite prolonged insulin independence and near-normal glycemic control. Paty et al. (2002) (a member of the Edmonton team) examined 7 ITA recipients, 7 type 1 DM patients (nonITA), and 7 nondiabetic control patients.The follow-up for most studies was short. It was suggested that the modifications to the conventional ITA approaches, including the steroid free immunosuppressive regimen, islet preparation in xenoproteins free media and transplantation of fresh islets from multiple donors were associated with improved success.The effects of ITA on beta cell function (secretion of insulin) look promising, however, the effects of ITA on pancreatic alpha cell function (secretion of counter-regulatory hormones such as glucagon and epinephrine) in long standing type 1 diabetes remain unclear.The most important barriers to more widespread islet transplantation using the Edmonton protocol are the availability of sufficient donor organs and the uncertainty of long term steroid free immunosuppressive therapy.Because the number of cadaveric pancreas donors is inadequate to the treat the increasing numbers of individuals on organ transplant waiting lists, isolated islet transplantation is unlikely to become practical for treatment of diabetes if each recipient requires islets from several (2-4) donors (Markmann et al., 2003). Therefore, it is important that the experience of the Edmonton investigators be validated by other centres not only in terms of effectiveness of the new immunosuppressive protocol, but also in the need for multiple transplants (Markmann et al., 2003).Preliminary results from a multinational trial indicate wide variation in the success of ITA between different sites. This raises concern about the reproducibility of the results.


CONCLUSIONS
The current evidence on the use of ITA for non-uremic type 1 diabetic patients is limited since it is based on studies with weak methodological design (Level 4). The assessment of ITA is based on several small case series studies or small clinical studies studies (Ryan et al., 2002; Goss et al., 2002; Meyer et al., 1998; Paty et al., 2002). The results from these studies were mixed since the objectives and the protocols differed at each centre. In particular, many jurisdictions have, to date, been unable to reproduce results achieved in Edmonton (success rate of 23% versus 90%) - this is the focus of an ongoing multicentre study.Ryan et al. (2002) reported that the median follow-up time for the 17 patients undergoing the Edmonton Protocol was 20.4 months from the first transplant. As of January, 2002, 11/17 patients remained insulin independent. Three of the 11 insulin independent patients had negative C-peptide secretion, indicative of impaired islet function.The effect of ITA on restoring hormonal responses to hypoglycemia is inconclusive.ITA in non-uremic type 1 diabetic patients with hypoglycemia unawareness or uncontrolled diabetes is an evolving procedure with promising preliminary, but inconclusive final results.