Type 1 diabetes: translating mechanistic observations into effective clinical outcomes

Abstract

Type 1 diabetes (T1D) remains an important health problem, particularly in western countries, where the incidence has been increasing in younger children. In 1986, Eisenbarth described T1D as a chronic autoimmune disease. Work over the past three-and-a-half decades has identified many of the genetic, immunological and environmental factors that are involved in the disease and have led to hypotheses concerning its pathogenesis. Clinical trials have been conducted to test these hypotheses but have had mixed results. Here, we discuss the findings that have led to our current concepts of the disease mechanisms involved in T1D and the clinical studies promoted by these studies. The findings from preclinical and clinical studies support the original proposed model for how T1D develops but have also suggested that this disease is more complex than was originally thought and will require broader treatment approaches.

Figure 1. Revision of the Eisenbarth model

Earlier concepts of the pathogenesis of T1D have been modified with new information. During childhood, there is an increased in β cell function, as a result of which older subjects present with T1D with higher C-peptide responses than younger subjects^,. The timing of the decline in β cell function may be more acute than previously appreciated. Nonetheless, the impairement seen at the time of diagnosis may reverse partially but invariably continues with time. Successful immune therapies have altered the decline in C-peptide.

Figure 2. Results of immune therapy trials

Clinical trials of rituximab, CTLA4Ig, anti-CD3 mAb have shown decreased rates of decline in C-peptide during the first 1 or 2 years of T1D, whereas others, such as antigens, MMF/DZB, thymoglobulin, or anti-IL-1 reagents have not^,,,,,,,. A trial of rapamycin and IL-2, thought to enhance Tregs showed transient decline in C-peptide responses. HSP60, believed to bind to TLR2 also showed effecdts on glucagon stimulated C-peptide responses. A trial of sTNF receptor (Etanercept) resulted in lower HgbA1c and increased insulin production in a pilot trial.

Figure 3. Seeding the periphery with ex-Tregs with pathogenic potential

In normal individuals, developing T cells that are not highly self reactive mature and leave the thymus whereas highly autoreactive T cells are deleted during development as part of negative selection. Regulatory T cells, which also develop in the thymus, are selected on self-antigens and demethylate the FOXP3 and express the protein (green dots). In patients with T1D, as well as other autoimmune diseases, cells that are autoreactive but retain the ability to make pathogenic cytokines and do not completely demethylate the FOXP3 gene. These cells are postulated to participate in pathologic immune responses to self antigens.