HISTORICAL MODEL OF TYPE 1 DIABETES PATHOGENESIS It may be considered unusual to consider a period of three decades “historical.” Yet, the evolution for our understanding of the natural history and pathogenesis of type 1 diabetes has been greatly advanced by a vast number of studies aimed at validating a model (1), proposed by the late Dr. George Eisenbarth in 1986 (2). As a result of this work, the majority of current conventional wisdom portrays type 1 diabetes as a T cell–mediated autoimmune disease involving the specific destruction of insulin-producing pancreatic β-cells.

In this model, persons destined to develop type 1 diabetes are assumed to begin life with a full cadre ofβ-cells. However, a “triggering” insult, likely environmental, initiates a process involving the recruitment of antigen-presenting cells. Antigen-presenting cells sequester self-antigens released by injured β-cells, followed by their transport to pancreatic lymph nodes where they are subsequently presented to autoreactive T cells. These T cells, rogue constituents brought to life due to genetically driven failures of thymic deletion (ie, central tolerance) combined with defects in mechanisms designed to induce peripheral immune tolerance, come into play (3). This toxic duo, imparting lackof-tolerance formation, again in the context of genetic susceptibility, allows for migration of self-reactive T cells to islets, mediating β-cell killing and promoting further inflammation (4). When 85–90% of pancreaticβ-cells meet their demise, symptoms of the disease occur. In the final stage of the model, the autoimmune process ends with the complete elimination of β-cells.