Type 1 diabetes: pathogenesis and prevention

Abstract

Type 1 diabetes results from the autoimmune destruction of insulin-producing beta cells in the pancreas. Genetic and, as yet undefined, environmental factors act together to precipitate the disease. The excess mortality associated with the complications of type 1 diabetes and the increasing incidence of childhood type 1 diabetes emphasize the importance of therapeutic strategies to prevent this chronic disorder. Why is it considered that type 1 diabetes might be preventable? Different strands of diabetes research are coming together to suggest therapeutic targets. Islet cell autoantibody assays make it possible to accurately identify people at risk of future disease. In most cases, a long prodrome provides a window of opportunity to reverse the autoimmune process. Although no current "cure" exists, recent genetic data and preliminary trial results suggest T cells as a target for preventive strategies. Another potentially attainable target is induction of tolerance to the beta-cell proteins such as insulin that are inappropriately recognized. Other strategies involve beta-cell replacement, but currently there are insufficient donor cells available. This may be overcome as the processes controlling the differentiation of pancreatic and nonpancreatic progenitors as well as replication of existing islet beta cells are unravelled.

Fig. 1: Geographic variation in annual incidence of type 1 diabetes.

Fig. 2: Representation of the process whereby antigen (in this case peptides of proinsulin) is presented to CD4 T cells by human leukocyte antigen (HLA) class II molecules on the antigen presenting cell. This results in T-cell activation. In this diagram the 4 major genes associated with type 1 diabetes are present. CTLA-4 is an inhibitor of T-cell activation, as is lymphoid tyrosine phosphatase (LYP), which is encoded by the gene PTPN22. The complex of LYP–C-terminal Src kinase (CSK) inhibits Lck signalling after engagement of the T-cell antigen receptor (TCR). Photo by: Lianne Friesen and Nicholas Woolridge

Fig. 3: Potential targets for therapeutic intervention of type 1 diabetes.