- Dr. Tausif Alam, Principal Investigator
- Dr. Michael MacDonald, Consultant
- Dr. James Malter, Consultant
- Dr. John Young, Consultant
- University of Wisconsin Medical School, Madison, USA
- Glucose-Regulated Improved Insulin Production from Hepatocytes
Insulin-dependent diabetes mellitus (IDDM) is caused by selective autoimmune destruction of insulin-producing ß-cells of endocrine pancreas. Two therapies are currently available for IDDM and both have serious limitations. The first therapy, based on daily insulin injections, inadequately controls hyperglycemia and consequently does not prevent the long-term damage associated with the disease. The second therapy, transplantation of the whole pancreas or of pancreatic islets precisely regulates blood sugar levels, but limited availability of organs and lifelong use of immunosuppression limit the usefulness of this therapy. Advances in cellular and molecular engineering now make it possible to attempt replacing the function of a ß-cell by a non-ß-cell, engineered to provide insulin only when needed.
Our novel approach is based on recipient’s own liver cells, engineered for glucose-regulated de novo synthesis and secretion of insulin, eliminating the need to duplicate a complex and incompletely understood mechanism of regulated insulin secretion of ß-cells. The preliminary studies performed in cell culture and in diabetic rats support our hypothesis. The proposed use of vectors that allow long-term expression and optimization of our gene constructs will probably correct hyperglycemia in diabetic rats and lay the foundation for IDDM treatment by insulin gene-therapy in man. Using our approach, the diabetic recipients of insulin-gene-engineered hepatocytes may experience a transient, mild hyperglycemia in the minutes after eating, but should be able to avoid the chronic hyperglycemia that typically occurs with insulin injections alone, avoiding severe diabetes-associated complications. Success in our approach will provide a basis for future gene-therapy-based IDDM treatment that could be administered before the development of hyperglycemia-related serious complications. Furthermore, the use of autologous liver cells may eliminate the necessity for immunosuppression.