• Diabetes Mellitus

As type 1 diabetes continues to be a worldwide epidemic, researchers persist in exploring new ways to prevent the disease from developing or to delay its development, especially in young children. Several studies have evaluated the safety and efficacy of immunomodulatory therapies, both as prevention strategies and as interventions for new-onset disease.

No studies to date have demonstrated effectiveness in preventing diabetes. In the Diabetes Prevention Trial-Type 1 (DPT-1), oral insulin did not prevent or delay diabetes in subjects who were at increased risk for the disease. However, when subsets of subjects with high insulin autoantibody (IAA) levels were analyzed, there was a 4.5- to 5-year delay (IAA levels ≥80 nU/mL) and a 10-year delay (IAA levels ≥300 nU/mL) [Skyler JS et al. Diabetes Care 2005]. This finding suggests a clinically meaningful benefit for a specific subpopulation, said Desmond Schatz, MD, Diabetes Center, University of Florida Health Science Center, Gainesville, Florida, USA.

In intervention studies, treatment with anti-CD3 (rituximab) led to significantly higher C-peptide levels (measured as the area under the curve) compared with controls for up to 1 year, as well as lower HbA1C levels and lower insulin dose (p<0.001 for all) [Pescovitz MD et al. New Engl J Med 2009]. Dr. Schatz said that the study indicated an immunological effect, in that the treatment completely depleted CD19 cells, with a near recovery of β-cells over the course of a year. An important finding was that the difference in outcomes between the treatment and control groups began at 3 to 6 months after the initiation of treatment. Dr. Schatz noted that anti-CD20 (teplizumab) and DiaPep277 (a synthetic heat shock protein 60 peptide) also led to significantly higher C-peptide levels, with the difference also emerging at 3 to 6 months [Herold KC et al. New Engl J Med 2002; Herold KC et al. Diabetes 2005]. These data suggest that the effectiveness of a prevention strategy could be identified early.

Dr. Schatz and his colleagues explored the use of autologous cord blood for stem cell therapy. He explained that cord blood has a high capacity for T cell regulation, has a greater regenerative capacity than bone marrow, and has been used effectively for other autoimmune diseases. In addition, cord blood may be naïve to the environmental insult that initiated the autoimmunity and, therefore, induce tolerance. The researchers' Phase 1 study enrolled 24 young children who received a transfusion when they were aged a mean of 5.25 years (range: 3.1 to 7.3 years). The treatment substantially reduced HbA1C levels and insulin requirements, which were maintained through 2 to 2.5 years of follow-up [Haller MJ et al. Diabetes Care 2009]. The level of regulatory T cells increased between 0 and 6 months, which suggested that the treatment favored a regulatory/protective immune response, said Dr. Schatz. He pointed out that the results should be interpreted with caution, as a limitation of the study is the use of historical controls as the comparator group.

The results of these studies are encouraging, but none of the treatments has improved insulin production, which is necessary to reverse the disease process. The one exception is a study in which nonmyeloablative stem cell transplantation increased insulin production in a study of 15 subjects (aged 14 to 31 years) with new-onset diabetes, with significant increases in C-peptide levels that were maintained at a mean of nearly 30 months of follow-up. Most subjects were insulin-independent and had good glycemic control [Voltarelli JC et al. JAMA 2007; Couri CE et al. JAMA 2009]. Despite the positive results, Dr. Schatz noted that the potential morbidity and mortality of the approach may be unacceptable.

• © 2011 MD Conference Express