Beta-cell transplantation in type 1 diabetic patients: a work in progress to cure.

Abstract

Type 1 diabetes is characterized by a selective destruction of the insulin producing beta-cells leading to frank hyperglycemia. Daily insulin injections are lifesaving but can often not avoid suboptimal glycemic control, an increased risk for hypoglycemia and the development of chronic diabetic complications. Therapies replacing the destroyed beta-cells aim to prevent or delay these detrimental complications while avoiding hypoglycemic episodes. The main objective of our multicenter study was to define conditions under which a beta-cell implant safely induces and maintains long-term metabolic control in type 1 diabetic recipients. We demonstrated that cultured beta-cell preparations, fully morphologically characterized by their cell number and cellular composition, and functionally correlated with beta-cell mass can be used to prepare grafts with reproducible clinical metabolic outcome. At least 2 million beta-cells per kg bodyweight were needed to achieve signs of functioning grafts, reduced glycemic variability and a reduced risk for hypoglycemic events. We demonstrated that the hyperglycemic clamp can be used to measure the in vivo functional beta-cell mass after transplantation. In insulin independent recipients of a beta-cell and pancreas-kidney graft, the functional beta-cell mass represents respectively 25 and 63% of that in healthy controls. We showed that ATG-sirolimus monotherapy resulted in a worse outcome of beta-cell transplantation compared to ATG-sirolimus-tacrolimus combination therapy. Moreover, use of sirolimus was accompanied with unacceptable side effects. In conclusion, we showed that characterizing the beta-cell graft in vitro, measuring the functional beta-cell mass in vivo and defining a save and efficient immunosuppressive regimen are important steps to a cure for diabetes.