FIG. 1.

Changes in β-cells during progression of type 1 diabetes and the selection of interventions: the initial event that primes the adaptive immune response is not known but is postulated to involve β-cell death. Antigen-specific immune interventions (red arrow) have the greatest chance of efficacy in this early stage. With progression of the response, there are increased rates of β-cell proliferation but also a loss of β-cells and expansion of the immune response. A greater proportion of replicating β-cells is seen in the islet as insulitis progresses, and some β-cells are unable to keep up with the metabolic demands. Most likely, a broader approach to immune intervention is needed at this point, since the autoreactive repertoire is broader than at the earlier stages. Left untreated, there is continued loss of β-cells. However, interventions such as immune modulators can prevent the ongoing adaptive immune response against β-cells and, with metabolic treatment, recovery of degranulated β-cells can occur.