REVIEWS NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | APRIL 2004 | 259 Diabetes mellitus comprises a series of clinically and genetically heterogeneous disorders associated by dis- turbances of carbohydrate, fat and protein metabolism, the most common sign of which is HYPERGLYCAEMIA.The prevalence of diabetes increases with age, from less than 1% of western populations affected before age 20 to more than 13% above age 75. Approximately 90% of adult patients with diabetes have the ‘type 2’variant, previously referred to as non-insulin dependent, which is generally associated with hyperglycaemia and insulin resistance, eventually leading to defects in insulin secre- tion. The most severe form of diabetes is the ‘type 1’ variant, which results from autoimmune destruction of the insulin-secreting cells (β-cells) contained in the pan- creatic islets. In type 1 diabetes, daily treatment with exogenous insulin is required to support life. The meta- bolic abnormalities associated with diabetes can lead to a significant percentage of patients developing a series of chronic and degenerative complications, including retinopathy,nephropathy,neuropathy,atherosclerosis and lipid disorders. Experimental models and recent clinical trials have shown that islet transplantation could be an alternative to exogenous insulin treatment, as it results in normalization of metabolic control, which has been almost impossible to obtain with administration of exogenous insulin. The results of clinical islet trans- plantation have greatly improved owing to the intro- duction of more efficient methods for the separation of islets and more effective immunosuppressive strategies. The marked improvement in clinical results has been paralleled by a renewed enthusiasm and interest in this approach, but major challenges remain to be addressed, including the need for life-long recip- ient immunosuppression, which severely limits the current indications for islet transplantation. This arti- cle outlines the history of and recent progress in the field (TIMELINE) , as well as the present immunological challenges and strategies for tolerance induction to avoid continuous recipient immunosuppression after islet transplantation. The history of islet transplantation The first attempts. In 1893, the English surgeon Watson Williams attempted to transplant sheep pancreatic fragments into a 15-year-old boy with end-stage dia- betes 1 . This first ‘islet xenograft’was carried out at a time of intense debate as to whether the pancreas was producing a sugar-destroying substance. Minkowsky 2 CLINICAL ISLET TRANSPLANTATION: ADVANCES AND IMMUNOLOGICAL CHALLENGES Camillo Ricordi* and Terry B. Strom ‡ Type 1 diabetes mellitus results from autoimmune destruction of the insulin-secreting cells in the pancreas. Daily treatment with exogenous insulin is required, but because of difficulties in achieving physiological control of blood-glucose concentrations, chronic and degenerative complications still occur in a marked fraction of patients. Islet transplantation can normalize metabolic control in a way that has been virtually impossible to achieve with exogenous insulin, but life-long immunosuppression of the recipients is required, limiting the procedure to the most severe forms of diabetes. This article outlines the history of and recent progress in the field, as well as the present immunological challenges and possible strategies for tolerance induction that are crucial to make clinical islet transplantation more widely available. HYPERGLYCAEMIA Increased plasma-glucose concentrations that are above defined normal standards. *University of Miami School of Medicine, Diabetes Research Institute, Miami, Florida 33136, USA. ‡ Harvard Medical School, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. Correspondence to C.R. e-mail: CRicordi@med. miami.edu doi:10.1038/nri1332