Beyond the Hormone: Insulin as an Autoimmune Target in Type 1 Diabetes

Insulin is not only the hormone produced by pancreatic beta-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 (beta-cell dysfunction, insulin resistance) and immunological components (inflammation and beta-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 beta-cell autoimmunity, we will explain the role of insulin and its precursors as target antigens expressed not only by beta-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 beta-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 beta-cell autoimmunity as an immune modulatory reagent. (Endocrine Reviews 32:623-669, 2011)