Significant advances in the field of segmental pancreatic transplantation have led to a dramatic increase in the number of transplants performed in Type I diabetics over the past three years. To date, however, graft survival has been disappointingly low when compared to other solid organ transplants. The major factor contributing to these results is complications related to persistence of pancreatic exocrine secretions, and it is imperative that effective methods of exocrine suppression be identified. In this project, pharmacologic suppression of exocrine secretion will be investigated with glucagon, somatostatin, dimethyl prostaglandin E2, terbutaline and verapamil. Optimal dosage and duration of action for each agent will be determine in vivo, using animals with chronic pancreatic fistulae, and, in vitro, utilizing pancreatic tissue slices. The concentration of each agent associated with maximal suppression of octapeptide cholecystokinin (OPCCKO stimulated exocrine secretion will then be evaluated in a canine pancreatic tail autotransplant model. In our laboratory, we have documented only 20-40% autograft functional survival following optimal harvest and 24 hours of cold storage preservation and, therefore, a comparison of the experimental groups with these (control) groups will be accomplished. Agents found effective in this model will then be investigated during longer intervals of cold ischemia. In all preservation experiments, pancreatic slices will be prepared at the beginning and end of preservation and after transplantation. By analysis of in vitro basal and stimulated insulin release, a correlation with each treatment modality and transplant function will be accomplished. It is anticipated that effective methods of exocrine suppression will be identified during the course of this investigation. Once established, the major impediment to successful pancreatic transplantation will be eliminated allowing for a significant improvement in clinical results. In addition, predictable short term preservation, by allowing for sharing organs between centers, will allow optimal histocompatability matching between donor-recipient pairs. These improvements, along with other advances in transplantation (i.e. DR typing, cyclosporine, monoclonal antibodies, etc.) will result in a safe and effective treatment method for diabetes. Ultimately, the morbidity and mortality of insulin-dependent diabetes will be reduced, assuring an improved quality of life for these patients.
