Pancreatic islet transplantation in type 1 diabetes: Current state and future perspectives
Journal
Journal of diabetes investigation
Journal Volume
14
Journal Issue
2
Date Issued
2023-02
Author(s)
Kuo, Chun-Heng
Abstract
Recently, Braulio Marfil-Garza et al.1 reported long-term outcomes after islet transplantation in individuals with type 1 diabetes. In the report, 255 patients with type 1 diabetes receiving allogenic islet transplantation were included and followed for up to 20 years at the University of Alberta Hospital, Edmonton, Canada. As shown in Table 1, graft survival decreases by time and becomes stabilized at nearly 50% 15 years after islet transplantation. The median time of graft survival was 5.9 years. Glycemic control was significantly improved after islet transplantation. Near half of the patients maintained good glycemic control (defined by hemoglobin A1c 0.1 nmol/L (>0.3 ng/mL).1 Furthermore, as the cut-off value for C-peptide level is higher in the Igls criteria (0.17 nmol/L or 0.5 ng/mL), the percentage of participants with graft survival in the Canadian report should be even lower by the Igls criteria. In the report, combined use of anakinra plus etanercept and a high BETA-2 score within 1 year after the first islet infusion were predictors of sustained graft survival. In this cohort, the use of anti-inflammatory drugs included anakinra alone, etanercept alone, anakinra plus etanercept, infliximab and none. Only the use of anakinra plus etanercept was significantly higher in patients with sustained graft survival, compared with patients with non-sustained graft survival. In contrast, use of infliximab or without the use of anti-inflammatories were lower in patients with sustained graft survival. These findings suggest that dual anti-inflammatories, anakinra plus etanercept, might be a better choice over other anti-inflammatory drugs for graft survival. In contrast, BETA-2 score represents a combined evaluation of graft survival, glycemic control and insulin requirement, which is derived from a formula using data of fasting C-peptide, insulin dose, fasting plasma glucose and hemoglobin A1c. Findings from the Canadian report extend its usefulness to the prediction of long-term graft survival. During the 20-year follow-up period, mortality and the percentage of participants with end-stage renal disease (ESRD), dialysis or kidney transplantation were not reduced in patients with sustained graft survival, compared with patients with non-sustained graft survival in the report.1 These findings show that although patients with sustained graft survival had a better glycemic control, percentage and duration of insulin independence, and lower insulin requirement, the differences were not large and long enough to result in a reduction in the risk of ESRD and mortality. In addition, as the report only compared the risk of ESRD or mortality in patients with sustained and non-sustained graft survival, it remains unknown if islet transplantation would decrease the risk of ESRD and mortality or not, when compared with patients who did not receive islet transplantation. To cure type 1 diabetes is one of the goals of β-cell replacement therapy. However, there are currently two major hurdles for islet transplantation, including shortage of β-cell source and the method to overcome the recipient's immune response. Several strategies have been investigated for these hurdles.6 For the shortage of β-cell source, new technologies are developing to produce β-like cells from embryonic stem cells or induced pluripotent stem cells. However, there are still some problems to be solved before their clinical application, especially the improvement in differentiation efficiency, interpatient variability of β-like cells' function, and long-term graft survival and safety data. In addition to stem cell-derived β-like cells, xenogeneic islets, especially pig islets, are another potential source of β-cells. Although safety regarding zoonosis is a concern, some successful reports have shown its feasibility by using islets from pigs raised in pathogen-free facilities. In contrast, to overcome the recipient's immune response, development of new technologies to induce immune tolerance, use of physical barriers and development of genetically engineered immune-evasive insulin-producing cells have been continuously investigated. Although some promising results have been reported, there are still more to be explored and solved. In conclusion, the successes and drawbacks of the current state of islet transplantation are summarized in Table 2. Based on current data, islet transplantation successfully reduces severe hypoglycemia and insulin requirement. However, graft survival is still not good enough, which leads to a low rate of insulin independence and an unsatisfactory long-term glycemic control. These drawbacks might be important causes for the lack of benefit in the risk of ESRD and mortality in patients receiving islet transplantation. In addition, the need for two or more islet infusions makes the source of β-cells a big problem to be solved. Currently, several strategies to overcome the shortage of β-cells and the recipient's immune response are being developed. In the future, with the success of these new technologies, it is believed that islet transplantation or β-cell replacement therapy will be an important clinical treatment option for patients with type 1 diabetes. The authors declare no conflict of interest.
SDGs
Publisher
WILEY
Type
journal article