METABOLIC COROLLARIES IN ISLET TISSUE DURING TRANSPLANTATION

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In order to contribute to an increased understanding and highly efficacy of pancreatic islet transplantation as treatment of type I and type II diabetes a two pronged long range approach of research is outlined in the present component grant of the program project: 1) Quantitative Histochemistry (QH) will be applied to study glucose and energy metabolism of islet tissue in situ following transplantation into monoglycemic and diabetic animals. Parameters of metabolism to be studied will include glucose transport, glucose phosphorylation, glucose-6-P hydrolysis, the cellular redox and phosphate potentials. The dosage and metabolic state of the islet and the fuel homeostasis of the recipient will be manipulated to discover the factors that determine graft survival. Animal models of type I (BB/W rats) and type II (BHEcdb rats) diabetes will be used enhance the relevance in this approach. The research will gather important new information not obtainable by methods commonly applied to study islets during transplantation. 2) Modern techniques of genetic engineering using adenoviral vectors will be perfected to accomplish biologically and therapeutically useful alterations of glucose metabolism in islets that are to be used for transplantation. One important goal is reducing the immunogenicity of the viral vectors. Genetic engineering will include alterations of beta-cell glucokinase, glucose-6-phosphatase, lactic acid dehydrogenase and glycero-P-dehydrogenase, enzymes critically involved in glucose sensing. The impact of the genetic manipulation of islet tissue will be first assessed in vitro and the, after efficacy of the beta-cell transfection has been demonstrated, by OH analysis of the transplanted islet in situ and by evaluating the curative impact of the transplant.