Amyloid formation results in recurrence of hyperglycaemia following transplantation of human IAPP transgenic mouse islets.

AIMS/HYPOTHESIS: Islet transplantation is a potential cure for diabetes; however, rates of graft failure remain high. The aim of the present study was to determine whether amyloid deposition is associated with reduced beta cell volume in islet grafts and the recurrence of hyperglycaemia following islet transplantation. METHODS: We transplanted a streptozotocin-induced mouse model of diabetes with 100 islets from human IAPP (which encodes islet amyloid polypeptide) transgenic mice that have the propensity to form islet amyloid (n = 8-12) or from non-transgenic mice that do not develop amyloid (n = 6-10) in sets of studies that lasted 1 or 6 weeks. RESULTS: Plasma glucose levels before and for 1 week after transplantation were similar in mice that received transgenic or non-transgenic islets, and at that time amyloid was detected in all transgenic grafts and, as expected, in none of the non-transgenic grafts. However, over the 6 weeks following transplantation, plasma glucose levels increased in transgenic but remained stable in non-transgenic islet graft recipients (p < 0.05). At 6 weeks, amyloid was present in 92% of the transgenic grafts and in none of the non-transgenic grafts. Beta cell volume was reduced by 30% (p < 0.05), beta cell apoptosis was twofold higher (p < 0.05), and beta cell replication was reduced by 50% (p < 0.001) in transgenic vs non-transgenic grafts. In summary, amyloid deposition in islet grafts occurs prior to the recurrence of hyperglycaemia and its accumulation over time is associated with beta cell loss. CONCLUSIONS/INTERPRETATION: Islet amyloid formation may explain, in part, the non-immune loss of beta cells and recurrence of hyperglycaemia following clinical islet transplantation.

An examination of beta-cell function measures and their potential use for estimating beta-cell mass.

A characteristic and dominant feature of type 2 diabetes is a reduction in beta-cell function that is associated with a decrease in beta-cell volume. A decline in the first-phase insulin response following intravenous glucose administration can be demonstrated as the fasting glucose concentration increases. This response is completely absent before the glucose threshold that defines diabetes has been reached and at a time when beta-cells are clearly still present, implying that a functional beta-cell lesion has to exist independent of beta-cell loss. Surgical or chemical reductions of up to 65% of beta-cell volume demonstrate that functional adaptation of the normal beta-cell prevents a rise in fasting glucose or reduction in first-phase insulin response. However, the ability of glucose to potentiate the beta-cell's response to non-glucose secretagogues is reduced and is more closely associated with the reduction in beta-cell volume. The future, in terms of prevention and treatment of type 2 diabetes, lies in the ability to prevent and revert both beta-cell loss and dysfunction. However, until beta-cell volume can be quantified reliably and non-invasively, we will need to rely on the ability of glucose to potentiate insulin release as the best surrogate estimate of the number of beta-cells.