Type 1 diabetes mellitus is an autoimmune disease that results when the body’s own immune system attacks the insulin producing beta cells of the pancreas. This leads to the eventual destruction of the beta cells. Destruction of the beta cells in the pancreas results in insufficient production of insulin which causes the development of diabetes and unregulated glucose metabolism. The T-cells of the immune system attack and destroy the beta cells after being presented with antigens by the antigen presenting cells. Another key component of this process is the co-stimulation of the T-cells by binding of the CD 28 protein to the B7 protein on the antigen presenting cell. Disruption of the co-stimulatory process can lead to decreased destruction of beta cells and ultimately preserve their insulin secreting function. This has been hypothesized as a method to slow down and delay the development of type 1 diabetes mellitus. Abatacept (Orencia, produced by Bristol-Myers Squibb) is a fusion protein molecule that inhibits the co-stimulation of T cells by binding to the B7 protein on the antigen presenting cell. By doing this, the T-cells are not activated and thus do not go on to destroy the beta cells of the pancreas. Researchers lead by Dr. Jay Skyler, from the University of Miami Diabetes Research Institute, have presented data at the American Diabetes Association annual meeting that shows that abatacept may help delay the progression of type 1 diabetes mellitus. Their findings were also published online in the journal The Lancet. Their study was a TrialNet multicenter, double blind, randomized trial that involved 112 participants aged 6 to 45 years old with newly diagnosed type 1 diabetes. The study participants were randomly assigned to receive a placebo or abatacept intravenously on days 1, 14, 28, and then monthly for a total of 27 infusions over a 2 year period. C-peptide, which is a marker of beta cell function, was measured in the study participants are various time point during the study. Adjusted C-peptide was 59% higher at 2 years in the group that had received abatacept compared to the placebo group. It was also found that there was a 9.6 month delay in C-peptide reduction among the abatacept group compared to the placebo group. The researchers wrote, “Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time”. Future research will need to address whether a shorter course of treatment with abatacept will yield the same results as the effects appeared to fade at the 6 month time point. The researchers also noted that the current administration regimen may not be clinically feasible due to the intravenous route and long course used. The manufacturer is developing a subcutaneous version that may be more clinically applicable but will need to be evaluated for similar effectiveness. These results are encouraging and suggest that modulation of the autoimmune response in the development of type 1 diabetes will have a role in future treatment.
Tihamer Orban et al. “Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomized, double-blind, placebo-controlled trial” The Lancet, early online publication, 28 June 2011
See Dr. Skyler’s discussion at the American Diabetes Association meeting below: