Immunological aspects of diabetes mellitus: prospects for pharmacological modification

It is now well known that insulin-dependent diabetes is a chronic progressive autoimmune disease. The prolonged prediabetic phase of progressive beta-cell dysfunction is associated with immunological abnormalities. A prediabetic period is suggested by the appearance of islet cell antibodies, anti-insulin antibodies, and anti-insulin receptor antibodies. The existence of activated T lymphocytes and abnormal T cell subsets are also other markers. There is still no concensus about the use of the immunosuppression superimposed upon conventional insulin therapy in early diagnosed IDDM and the follow-up of the relatives of IDDM patients who share the genetic predisposition and serological markers for the risk of future onset of IDDM. Treatment in the prodromal period cannot be justified because a link between the disease and early markers such as ICA has not been established with certainty (Diabetes Research Program NIH, 1983). Many immunopharmacological manipulations were reported to be effective in animal models. However, most of them are not readily applied to human subjects. Moreover, IDDM patients are now believed to be heterogeneous, with a complex genetic background. HLA-DR, and more recently DQ, are closely related to the genetic predisposition to IDDM but those genes are not themselves diabetogenic. The contribution of autoimmunity does not appear to be uniform, and in some cases, the contribution of virus is considered more important. There is a lack of a marker for the future onset of IDDM. ICA and ICSA were found after mumps infection, but the existence of those autoantibodies and even the co-existence of HLA-DR3 do not always indicate the future trend to insulin dependency. More precise markers will be disclosed through the biochemical analysis of the target antigens on pancreatic beta-cell for islet antibodies and effector T cells. Much safer and more effective immunopharmacological treatment will be developed through animal experimentation using rat and mouse models. The recent development and interest in this field will further facilitate the attainment of the goal for the complete prevention of IDDM.