Advances in β-cell replacement therapy for the treatment of type 1 diabetes

Abstract

The main goal of treatment for type 1 diabetes is to control glycaemia with insulin therapy to reduce disease complications. For some patients, technological approaches to insulin delivery are inadequate, and allogeneic islet transplantation is a safe alternative for those patients who have had severe hypoglycaemia complicated by impaired hypoglycaemia awareness or glycaemic lability, or who already receive immunosuppressive drugs for a kidney transplant. Since 2000, intrahepatic islet transplantation has proven efficacious in alleviating the burden of labile diabetes and preventing complications related to diabetes, whether or not a previous kidney transplant is present. Age, body-mass index, renal status, and cardiopulmonary status affect the choice between pancreas or islet transplantation. Access to transplantation is limited by the number of deceased donors and the necessity of immunosuppression. Future approaches might include alternative sources of islets (eg, xenogeneic tissue or human stem cells), extrahepatic sites of implantation (eg, omental, subcutaneous, or intramuscular), and induction of immune tolerance or encapsulation of islets.

Figure 1:. Innovating treatments for type 1 diabetes

Three approaches for treatment of type 1 diabetes: technological improvement of insulin delivery progressively evolving towards a closed loop system; β-cell replacement therapy either with islet transplantation or with pancreas transplantation; and preservation and regeneration of residual native β cells. *Potential future approaches.

Figure 2:. Indications for allogeneic islet β-cell replacement therapy in type 1 diabetes

Pancreas transplantation alone or pancreas-after-kidney transplantation might be indicated in patients aged up to 55 years without cardiovascular morbidity. A threshold for C-peptide of <0·3 ng/mL (100 pmol/L) is often considered but it might vary according to kidney function and the technique of measurement. In some centres, an insulin requirement of <60 units per day is used as a cutoff point. HbA_1C=glycated haemoglobin. eGFR=estimated glomerular filtration rate.

Figure 3:. Current and future approaches to β-cell replacement therapy in type 1 diabetes

Green=the current clinical approach, which uses allogeneic islets isolated from a deceased donor as the β-cell source, delivery via portal vein infusion for intrahepatic engraftment, and standard T-lymphocyte directed induction and maintenance immunosuppression. Yellow=a case of successful transplantation of allogeneic islets into an omental pouch created with a thrombin bioscaffold has been reported and a case of successful intrahepatic transplantation of allogeneic islets has operational islet-transplant tolerance following withdrawal of maintenance immunosuppression (Stock P G, University of California San Francisco, USA, personal communication). These provide proof of concept for the possibility of extrahepatic and immunosuppression-free islet transplantation in humans. Blue=mainly preclinical approaches, with some case studies or phase 1 and 2 studies that do not show reversal of diabetes.