ADA Outstanding Scientific Achievement Lecture 2004. Thirty years of investigating the autoimmune basis for type 1 diabetes: why can't we prevent or reverse this disease?

Thirty years ago, a convergence of investigational observations lead to the now widely accepted notion that type 1 diabetes results from an autoimmune destruction of insulin-producing beta-cells in subjects genetically predisposed to the disease. Improvements in understanding of the natural history of type 1 diabetes, the biochemical identification of autoantigens, the discovery of spontaneous animal models for the disease, the availability of immune-modulating agents, and other important facets, including disease prediction, drove an early sense of optimism that the prevention of type 1 diabetes was possible and, in some research circles, that ability was thought to be within a not-to-distant reach. Unfortunately, those early expectations proved overly optimistic, and despite the aforementioned knowledge gains, the generation of improved investigational tools, the identification of methods to prevent the disease in animal models, and the formation of very large disease prevention trials, a means to prevent type 1 diabetes in humans continues to remain elusive. Believing in the concept of "informative failures" (a.k.a., wise people learn from their mistakes), this lecture reviews the knowledge base collected over this time period and, when combined with an analysis of those research experiences, sets forth a proposal for future investigations that will, hopefully, turn discoveries into a means for the prevention or reversal of type 1 diabetes.