title: Beyond the hormone: insulin as an autoimmune target in type 1 diabetes.
abstract: Insulin is not only the hormone produced by pancreatic β-cells but also a key target antigen of the autoimmune islet destruction leading to type 1 diabetes. Despite cultural biases between the fields of endocrinology and immunology, these two facets should not be regarded separately, but rather harmonized in a unifying picture of diabetes pathogenesis. There is increasing evidence suggesting that metabolic factors (β-cell dysfunction, insulin resistance) and immunological components (inflammation and β-cell-directed adaptive immune responses) may synergize toward islet destruction, with insulin standing at the crossroad of these pathways. This concept further calls for a revision of the classical dichotomy between type 1 and type 2 diabetes because metabolic and immune mechanisms may both contribute to different extents to the development of different forms of diabetes. After providing a background on the mechanisms of β-cell autoimmunity, we will explain the role of insulin and its precursors as target antigens expressed not only by β-cells but also in the thymus. Available knowledge on the autoimmune antibody and T-cell responses against insulin will be summarized. A unifying scheme will be proposed to show how different aspects of insulin biology may lead to β-cell destruction and may be therapeutically exploited. We will argue about possible reasons why insulin remains the mainstay of metabolic control in type 1 diabetes but has so far failed to prevent or halt β-cell autoimmunity as an immune modulatory reagent.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 986, DeAR Lab Avenir, Saint Vincent de Paul Hospital, and Paris Descartes University, 82 avenue Denfert Rochereau, 75674 Paris Cedex 14, France.
authors.forename: Vedran
authors.initials: V
authors.lastname: Brezar
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Carel
authors.forename: Christian
authors.initials: C
authors.lastname: Boitard
authors.forename: Roberto
authors.initials: R
authors.lastname: Mallone
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004777:Environment; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000502:physiology; D007333:Insulin Resistance / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D023421:Models, Animal; D008969:Molecular Sequence Data; D011384:Proinsulin / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011498:Protein Precursors / Q000737:chemistry / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D011913:Rats, Inbred BB; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007328:Insulin; D011498:Protein Precursors; D014157:Transcription Factors; C013737:preproinsulin; D011384:Proinsulin