How Does Type 1 Diabetes Develop?

Abstract

espite decades of acknowledging that a loss of insulin-producing pancreatic b-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 b-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 b-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 b-cell appear fundamental to the loss of immune tolerance, accompanied by immune-mediated destruction.WHAT DID BOTTAZZO PORTEND?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., b-cell homicide) the other representing the defense (i.e., b-cell suicide).More important than the means for its presentation was the evidence noted for each case.Arguments for homicide included, but were not limited to, a theoretic scenario wherein type 1 diabetes was posed to be initiated by an ill-defined environmental attack resulting in the release of b-cell autoantigens (Fig. 1).Subsequently, those self-antigens were thought to be scavenged by macrophages, presented by major histocompatibility complex (MHC) class II molecules (i.e., HLA-DR), leading to the activation of helper T-cells, which would in turn activate B-cells to produce antibodies (e.g., islet cell cytoplasmic autoantibodies and complement-fixing autoantibodies) as well as activate killer cells and cytotoxic T-cells.Interestingly, Bottazzo did note the potential role for "suppressor T-lymphocytes" (i.e., a forerunner of today's regulatory T-cell), but left them out of the equation because of their ill-defined nature at the time of his writing.Other prosecutorial arguments included seasonality for the disease onset, typical age of onset, and questions related to genetic susceptibility to this disease.This prosecution was countered by a model of b-cell suicide, wherein the long latency period for type 1 diabetes formation was placed alongside a series of (then) timely genetic associations: chromosome 6 (HLA), 11 (insulin), 14 (Gm allotypes), and 2 (k light chains), allowing for regimented b-cell death.Most controversial to this case was the added consideration involving an expression of HLA class II molecules on b-cells.This suicide model suggested the death of a b-cell was a matter of destiny, imprinted at the time of conception.With a quarter century of research investigations since the initial presentation of these arguments, taken together with the benefit of hindsight, where do we currently stand in support of this polarizing issue of homicide versus suicide?Is it an either/or proposition?Do current genetic and physiologic insights enlighten the controversy?And finally, how will current technologies and basic biologic insights help to resolve this debate?Addressing these questions forms a major part of this Perspectives article.