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U of Colorado Researchers ID Hybrid Insulin Peptides Potentially Linked to Diabetes

NEW YORK (GenomeWeb) – A team led by researchers at the University of Colorado School of Medicine, Denver have identified a group of hybrid insulin peptides that could be linked to type 1 diabetes.

Detailed in a paper published last week in Science, the study used mass spec analysis of pancreatic β cell extracts to detect the peptides. Beyond diabetes, such hybrid peptides could prove important in the development of a variety of autoimmune disorders, the authors noted.

Type 1 diabetes stems from an inappropriate response of T cells to self-antigens in pancreatic β cells, and past work has identified a number of potential β cell proteins that likely trigger T cell response. This includes recent work by a U of C-led group, in which they identified two new autoantigens for T cells, the proteins chromogranin A (ChgA) and islet amyloid polypeptide (IAPP).

This discovery included the observation that the ChgA peptide cleavage product WE14 was found to stimulate a T-cell response both in a mouse model of type 1 diabetes and in diabetes patients. This response was weak, however, leading the researchers to speculate that the actual antigen responsible T-cell activation in type 1 diabetes is a modified form of WE14.

Specifically, they hypothesized that C-peptide fragments of proinsulin bind with naturally occurring peptides like WE14, creating hybrid insulin peptides (HIPs) that stimulate strong T-cell responses.

To test this notion, they built a synthetic library of HIPs using chemical crosslinking and screened it against a set of mouse T cell clones, finding that WE14 and IAPP2 HIPs were strongly antigenic for the T cells but that the WE14 and IAPP2 peptides alone were not.

They then determined that these HIPs were present in the β cells of their mouse models by using mass spec to analyze β cell extracts, identifying in these extracts the WE14 and IAPP2 HIPs.

The researchers also investigated whether T cells from type 1 diabetes patients recognized various HIPs, screening a group of 16 HIPs against CD4 T cells taken from two patients and finding that these T cell populations included clones exhibiting strong responses to several HIPs.

"Although pathogenicity of human T cells cannot be directly demonstrated, the presence of HIP-specific CD4 T cells within the pancreatic islets of individuals with T1D supports the contention that these cells play a pathogenic role in human T1D," the authors wrote.

They noted as well that HIPs represent "a new family of autoantigens in T1D" and that "hybrid peptides may form in the secretory granules of other endocrine tissues and could be a source of self-antigens in other autoimmune disorders."

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