How Does Type 1 Diabetes Develop?

Despite decades of acknowledging that a loss of insulin-producing pancreatic β-cells is central to the disorder now referred to as type 1 diabetes, the specific roles for genetic susceptibility, environmental factors, the immune system, and β-cells themselves in the pathogenic processes underlying the disorder remain unclear (1,2). Looking back over this period, one can identify a handful of conceptualizations that were seminal in their attempt to address this issue, including that posited by Dr. Gian Franco Bottazzo in his 1986 article, “Death of a Beta Cell: Homicide or Suicide?” (3). Bottazzo questioned whether the disorder’s pathogenesis weighed more heavily (or exclusively) on processes related to immune responsiveness (i.e., homicide) or the fragility of β-cells leading to self-destruction (i.e., suicide). Many reasons exist with respect to why we are in this knowledge void, including the exceedingly complex nature of type 1 diabetes, the likelihood that this disorder may represent a disease with more than one etiology, as well as the complex interplay of genetics, the immune system, and the environment. One limitation in solving important pathogenic questions in type 1 diabetes has likely been suboptimal cross-talk among geneticists, epidemiologists, endocrinologists, and others. Our own approach to overcoming this limitation has been to try to increase collaboration between cell biologists and immunologists as a critical step in closing knowledge gaps regarding the disorder’s pathogenesis. The opinion put forward within this Perspectives article by this group of authors is one where multiple and clearly unique properties of the β-cell appear fundamental to the loss of immune tolerance, accompanied by immune-mediated destruction. The Bottazzo article (3) was unique in its form of presentation, in that the prose represented the equivalent workings of a legal stenographer recording the debate between two counsels: one for the prosecution (i.e., β-cell homicide) the other representing the …