Progressive Hyperglycemia in Tolerant Miniature Swine Recipients of Composite Islet-kidney Grafts Is not due to Islet Loss but Rather to Increased Insulin Demand With Growth.

BACKGROUND

Intraportal pancreatic islet transplantation could potentially provide a cure for type 1 diabetes, but this procedure usually requires >1 infusion along with loss of function with time posttransplant. We have previously demonstrated in a major histocompatibility complex (MHC) inbred miniature swine large animal model that the construction of an "islet-kidney" (IK) by implantation of autologous donor islets under the kidney capsule several weeks before transplantation reduces the extent of islet loss. The long-term islet function in juvenile recipients, tolerant to allogeneic IKs, is evaluated in this study.

METHODS

We transplanted IKs across minor (n = 3) and full MHC (n = 1) mismatches, using a tolerance-inducing regimen consisting of 12-d treatment with either cyclosporine A or FK506. All 4 recipients experienced an increase in their body mass over time and this weight gain coincided significantly (P < 0.01) with the development of hyperglycemia. To test the hypothesis that the hyperglycemia in these recipients might be due to increased body mass rather than islet loss, the grafts were subsequently retransplanted into MHC-matched, diabetic miniature swine, similar in weight to the original recipients, using the same tolerance-inducing regimen.

RESULTS

All 4 of the secondary graft recipients regained glycemic control initially, with a similar, significant correlation between body weight and fasting blood glucose (P < 0.001) over time.

CONCLUSIONS

These findings indicate that loss of function of a vascularized IK graft with time is likely due to increased insulin demand in a growing animal and not due to islet loss.