The ectopic expression of insulin in Type 1 diabetes.

Type 1 Diabetes is characterised by an absolute deficiency in insulin due to the autoimmune destruction of the insulin-producing pancreatic J3 cells. A large body of literature has demonstrated that insulin itself is one of the key autoantigens in this process. In a parallel stream of research the insulin gene has been widely established as a susceptibility gene to Type 1 Diabetes and further more it has been shown that ectopic expression of this gene, particularly in the thymus, is important in establishing tolerance to this autoantigen. The exact molecular mechanisms underlying this phenomenon have not been fully elucidated to date. Preliminary data from the Autoimmunity Research Laboratory, JCSMR, Australian National University suggested that a set of2 GG to AA mutations discovered in the human insulin promoter was associated with loss of expression of a linked indicator protein in immunological cells in a sub line of transgenic mice. It was hypothesised that there was a these mutations interfered with promoter activation in immunological cells and loss of ectopic expression. To test this hypothesis separate transgenic mouse lines were generated carrying the original, unmutated human insulin promoter and its mutated counterpart. Analysis of the pattern of activation of the promoters in these transgenic mouse lines demonstrated evidence of ectopic expression in transgenic lines carrying the mutated promoter but not in the transgenic mouse line carrying the unmutated promoter, thus disproving the hypothesis. More detailed characterisation of the pattern of human insulin promoter expression in the transgenic mouse lines showed that a small subset of haematopoietic progenitor cells in the bone marrow was capable of activating the promoter. Subsequent experiments in a series of human bone marrow samples did not demonstrate any evidence of pro insulin expression in the CD34+ subset of haematopoietic progenitor cells.