Hybrid insulin peptides – the trigger for type I diabetes?

Type I diabetes is an autoimmune disease of unknown etiology against pancreatic ß cells which is distinct from type II diabetes which is largely triggered by lack of exercise and obesity. Great progress has been made developing targeted gene and cell therapies to reverse type I diabetes. However these therapies have a limited duration of effect due to the return of the pre-existing autoimmune disease which triggered the symptoms of diabetes in the first place (see here). This makes basic research into the underlying autoimmune disease extremely important. Hybrid insulin peptides have just been discovered in a mouse model of type I diabetes [1]. These may provide the elusive drug target required to prevent the underlying autoimmune disease.

Hybrid insulin peptides (HIPs) are a covalent linkage between the protein pro-insulin and other proteins present in the ß cell. The covalent junction is an antigen for T-cells which then attack the ß cells.  It has been found that antibodies from the blood of people with type I diabetes recognise the mouse HIPs suggesting that a human equivalent exists [1]. Clearly the next steps will be to isolate these human HIPs and determine the exact mechanism of their generation which could involve the proteasome [2]. This could reveal a druggable target to eliminate the underlying autoimmune disease. The question remains as to whether HIP generation is a universal trigger of type I diabetes or just one of several mechanisms in which autoimmunity is generated. This caveat aside the identification of HIPs are an extremely exciting development that could remove the last barrier to a cure for type I diabetes – the autoimmune reaction.

Refs

  1. Delong, Thomas, Timothy A. Wiles, Rocky L. Baker, Brenda Bradley, Gene Barbour, Richard Reisdorph, Michael Armstrong, et al. ‘Pathogenic CD4 T Cells in Type 1 Diabetes Recognize Epitopes Formed by Peptide Fusion’. Science 351, no. 6274 (11 February 2016): 711–14. doi:10.1126/science.aad2791.
  2. Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde BJ. An antigenic peptide produced by peptide splicing in the proteasome. Science. 2004 Apr 23;304(5670):587-90. PubMed PMID: 15001714.
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