Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes

Mol Med. 1995 Sep;1(6):625-33.


Background: Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but no molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-518) (G. Rudy, unpublished). In order to test the hypothesis that this region of similarity is implicated in the pathogenesis of IDDM, we assayed T cell reactivity to these two peptides in subjects at risk for IDDM.

Materials and methods: Subjects at risk for IDDM were islet cell antibody (ICA)-positive, first degree relatives of people with insulin-dependent diabetes. Peripheral blood mononuclear cells from 10 pairs of at-risk and HLA-DR matched control subjects were tested in an in vitro proliferation assay.

Results: Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than controls (proinsulin; p < 0.008; GAD; p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost entirely confined to the at-risk subjects.

Conclusions: This is the first demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal peptide region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecular basis for the conjoint autoantigenicity of proinsulin and GAD in IDDM.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Autoantibodies / blood*
  • Autoantibodies / immunology
  • Autoantigens / chemistry*
  • Child
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Glutamate Decarboxylase / chemistry
  • Glutamate Decarboxylase / immunology*
  • Glutamate Decarboxylase / pharmacology
  • Humans
  • Islets of Langerhans / immunology
  • Islets of Langerhans / physiology*
  • Lymphocyte Activation / drug effects*
  • Mice
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology*
  • Peptide Fragments / pharmacology
  • Prediabetic State / genetics
  • Prediabetic State / immunology*
  • Proinsulin / chemistry
  • Proinsulin / immunology*
  • Proinsulin / pharmacology
  • Risk Factors
  • Sequence Homology, Amino Acid
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*


  • Autoantibodies
  • Autoantigens
  • Peptide Fragments
  • islet cell antibody
  • Proinsulin
  • Glutamate Decarboxylase