Research Group

  • Prof. Ann Simpson, Principal Investigator
  • Dr. Ming Wei, Co-Investigator

Location

  • University of Technology, Sydney, Australia

Title

  • Correction of Diabetes Using Insulin-Secreting Liver Cells

Type I diabetes mellitus is caused by the autoimmune destruction of the β cells of the pancreas that secrete insulin. Permanent correction of diabetes by pancreas transplantation is restricted by the availability of normal human pancreatic issue and by the potential for further autoimmune damage to the transplanted pancreas. Moreover, substantial morbidity, due to life-long immunosuppression, inevitably follows pancreas transplantation. These problems could theoretically be overcome by engineering from the patient’s own cells an "artificial β cell", i.e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. We have engineered two liver cell lines that store and secrete insulin in response to glucose. However, the ultimate goal of this technology is to deliver the insulin gene directly to a patient’s own liver cells, which would regulate insulin secretion in response to glucose and other substances that stimulate insulin secretion, controlling blood glucose without the need for immunosuppression.
To accomplish this, it must be possible to deliver the insulin gene efficiently to primary liver cells (animal or human cells). Results from our laboratory using a non-pathogenic viral delivery system indicate that we can deliver genes to 90% of liver cells. We must also be able to engineer storage of insulin in primary liver cells. Based on preliminary studies, we have ascertained that certain β cell transcription factors (activating proteins, the expression of which is normally restricted to β cells), namely Neuro D and Neurogenin 3, promote storage of insulin in liver cell lines. In the current proposal we aim to express these transcription factors in primary liver cells. We also wish to look at the control of insulin expression in primary liver cells using a gene promoter that is glucose and insulin sensitive. The results from this research proposal should result in the delivery of the insulin gene to large numbers of primary liver cells that store and secrete insulin in response to glucose. These cells would control blood glucose levels in patients without the need for immunosupression and forestall the onset of the chronic complications of diabetes.