Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes

Diabetes. 2019 Sep;68(9):1830-1840. doi: 10.2337/db19-0128. Epub 2019 Jun 7.


We recently established that hybrid insulin peptides (HIPs) are present in human islets and that T cells reactive to HIPs are found in the residual islets of organ donors with type 1 diabetes (T1D). Here, we investigate whether HIP-reactive T cells are indicative of ongoing autoimmunity in patients with T1D. We used interferon-γ enzyme-linked immune absorbent spot analyses on peripheral blood mononuclear cells (PBMCs) to determine whether patients with new-onset T1D or control subjects displayed T-cell reactivity to a panel of 16 HIPs. We observed that nearly one-half of the patients responded to one or more HIPs. Responses to four HIPs were significantly elevated in patients with T1D but not in control subjects. To characterize the T cells reactive to HIPs, we used a carboxyfluorescein succinimidyl ester-based assay to clone T cells from PBMCs. We isolated six nonredundant, antigen-specific T-cell clones, most of which reacting to their target HIPs in the low nanomolar range. One T-cell clone was isolated from the same patient on two different blood draws, indicating persistence of this T-cell clone in the peripheral blood. This work suggests that HIPs are important target antigens in human subjects with T1D and may play a critical role in disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantigens / immunology*
  • Autoimmunity / immunology
  • Child
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Humans
  • Insulin / immunology*
  • Islets of Langerhans / immunology
  • Leukocytes, Mononuclear / immunology
  • Male
  • T-Lymphocytes / immunology*
  • Young Adult


  • Autoantigens
  • Insulin