Location of Thesis Examination

Room H 410 Health Sciences Addition

Degree

Doctor of Philosophy

Program

Pathology

Supervisor

Dr. David White

Delay of Publication

1

Abstract

Type 1 diabetics require daily injections of exogenous insulin to control hyperglycemia. Unfortunately, patients are still plagued by vascular and hypoglycemic complications. Beta cell replacement therapy by either whole organ pancreas or islet transplantation has been shown to restore carbohydrate control to these patients. A major barrier to successful islet transplantation is the lack of a reliable pre-transplant assay of post-transplant function thus providing an objective measure of whether a particular islet isolation should be transplanted. Such an assay would also prove to be a valuable tool in the experimental evaluation of innovative islet isolation strategies and technologies. The initial aim of this graduate work was to study existing pre-transplant assays of islet function and to critically examine which if any are of value in predicting post-transplant reversal of diabetes. During the progress of the research while analyzing the data a novel methodology for predicting in vivo islet graft function from a simple in vitro evaluation emerged. This approach of ascertaining islet transplant function prior to engraftment incorporated the influence of islet morphology to the islet’s ability to consume oxygen (OCR/II). The content of this thesis describes the evolution of this methodology from validating pre-existing rodent transplant models, to the discovery of this unique technique for predicting (porcine) islet function post-transplant. In addition herein, we describe the processes involved in translating these initial results performed in athymic mice, to clinically more relevant large animal studies through the development and subsequent testing of the methodology in porcine islet auto- and allograft transplant models. In all cases this OCR/II index proved to have a significantly greater predictive capacity of the ability of a given islet isolation to restore glucose control compared to other pre-transplant assays currently in use. Taken together these studies highlight data which demonstrate the efficacy of a rapid, simple, inexpensive in vitro test which predicts subsequent in vivo islet function, as exemplified and validated in a variety of transplant studies. In the near future it is hoped that the knowledge gained from this work will be employed in clinical islet transplantation.