Superiority of Small Islets in Human Islet Transplantation

Superiority of Small Islets in Human Islet Transplantation Roger Lehmann 1 , Richard A. Zuellig 1 , Patrick Kugelmeier 2 3 , Philipp B. Baenninger 1 , Wolfgang Moritz 3 4 , Aurel Perren 5 , Pierre-Alain Clavien 5 , Markus Weber 3 4 and Giatgen A. Spinas 1 6 1 Department of Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland 2 Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland 3 Zurich Center for Integrative Human Physiology, Zurich, Switzerland 4 Department of Visceral Surgery, University Hospital Zurich, Zurich, Switzerland 5 Department of Pathology, University Hospital Zurich, Zurich, Switzerland 6 Competence Center for Systems Physiology and Metabolic Diseases, Zurich, Switzerland Address correspondence and reprint requests to R. Lehmann, MD, Head of Clinical Islet Transplantation Program, Department of Endocrinology and Diabetes, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. E-mail: roger.lehmann{at}usz.ch Abstract Many factors influence the outcome of islet transplantation. As islets in the early posttransplant setting are supplied with oxygen by diffusion only and are in a hypoxic state in the portal system, we tested whether small human islets are superior to large islets both in vitro and in vivo. We assessed insulin secretion of large and small islets and quantified cell death during hypoxic conditions simulating the intraportal transplant environment. In the clinical setting, we analyzed the influence of transplanted islet size on insulin production in patients with type 1 diabetes. Our results provide evidence that small islets are superior to large islets with regard to in vitro insulin secretion and show a higher survival rate during both normoxic and hypoxic culture. Islet volume after 48 h of hypoxic culture decreased to 25% compared with normoxic culture at 24 h due to a preferential loss of large islets. In human islet transplantation, the isolation index (islet volume as expressed in islet equivalents/islet number), or more simply the islet number, proved to be more reliable to predict stimulated C-peptide response compared with islet volume. Thus, islet size seems to be a key factor determining human islet transplantation outcome. IEQ, islet equivalent TUNEL, terminal dUTP nick-end labeling Footnotes R.L. and R.A.Z. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article mus