Eighty years after insulin: parallels with modern islet transplantation.

© 2002 Canadian Medical Association or its licensors T his year marks the 80th anniversary of the publication in CMAJ of the discovery of insulin by Frederick Banting and his colleagues at the University of Toronto. Some interesting historical parallels have emerged with the success of islet replacement therapy in diabetes. Up until just a few weeks ago, human islet cells were being prepared in the very same basement laboratories at the University of Alberta where the biochemist James Bertram Collip once worked on ethanol extraction of insulin, before he moved to Toronto and joined Banting’s team (Fig. 1). The original process used to extract insulin is analogous to the complex extraction process used today to prepare islets for transplantation from scarce cadaveric pancreata. In fact, our work is foreshadowed in an entry in Banting’s notebook on June 9, 1921, in which he documents a detailed experimental plan to study transplantation of non-ascularized grafts of the pancreas in dogs, placed either “free in the peritoneum” or “subcutaneously” or prepared as a nonpurified “emulsion” analogous to the preparation of islets for transplantation today (Fig. 2). Banting was not the first to explore the concept of cellular replacement therapy in diabetes. Von Merring and Minkowski treated a diabetic dog with subcutaneous fragments of its own pancreas in 1892. A remarkable case report published in the British Medical Journal in 1894, 27 years before the discovery of insulin, describes the attempt by Watson-Williams and Harsant to treat a 13-year-old boy dying from ketoacidosis with subcutaneous implants of a sheep’s pancreas; they noted temporary improvement in glycosuria before the boy rejected the xenograft and died 3 days later. In 1916, Pybus carried out similar clinical studies in Newcastle, England, but used subcutaneous implants of fragments of a human cadaveric pancreas. The modern procedure for implantation of islets is simple and relatively noninvasive. It is carried out without surgery under local anesthetic using fluoroscopic guidance. Islets are implanted into the portal vein where they embolize to the liver, nest and develop a new blood supply. The procedure is often completed as a day case, with patients discharged from hospital in less than 24 hours. Clinical outcomes for islet transplantation were transformed in 2000 with the introduction of the Edmonton Protocol; a series of 7 consecutive patients with type 1 diabetes mellitus were all rendered insulin independent after receiving an average of 850 000 islets. The success of this protocol has been attributed to the use of potent antirejection therapy without corticosteroids, combined with delivery of a sufficient number of high-quality islets prepared from an average of 2 donor organs. The preparation of islets from a cadaveric pancreas is a complex and demanding process that takes 4 technicians up to 7 hours to complete. A number of institutions worldwide have collaborated in the evolution of the techniques. Collagenase enzyme is pumped down the pancreatic duct in a controlled perfusion system designed to cleave islets from their acinar restraining matrix. The pancreas is then chopped into pieces and transferred to a recirculating Ricordi digestion chamber. After extensive washing, islets are purified on a continuous Ficoll density gradient in a cell apheresis cenEighty years after insulin: parallels with modern islet transplantation