After attending the Juvenile Diabetes Research Federation (JDRF) Research Summit in Bethesda, Md., sponsored by the Capitol Chapter of JDRF, I learned about recent updates in both the search for the "cure" and the reality of the present. Much is going on in research communities: stem cell experimentation, "smart insulin," encapsulated islet cells," and the continuation of the Alpha 1 Antitrypsin trial.
Much is occurring in the cutting edge care of type 1 diabetes, especially the development of the "bionic" (aka the artificial pancreas) per Dr. Stuart Weinzimer of Yale University School of Medicine. However, all is not lost after the GAD 65 Antigen Therapy Trial failed to demonstrate primary efficacy (preservation of C-peptide). In a paper published in The New England Journal of Medicine, " GAD65 Antigen Therapy in Recently Diagnosed Type 1 Diabetes" (N Engl J Med 2012; 366:433-442, February 2, 2012), Ludvigsson et. al discuss the future of GAD-65 antigen therapy. In the previous study, treatment with GAD-65 in combination with alum was associated with the preservation of fasting c-peptide (marker of insulin production) 30 months after administration and preserved stimulated c-peptide at 15 months. According to the authors, the most persistence in terms of efficacy was in patients treated for less than 6 months after diagnosis, as these patients continued to have preservation of fasting c-peptide after 4 years. Unfortunately, the Phase 2 trial of GAD-alum in newly diagnosed type 1 diabetes patients did not show any clinical benefit. Thus, the authors conducted a phase 3 trial of GAD-alum initiated within 3 months after the diagnosis.
What were the results?
"Stimulated c-peptide levels showed a progressive decline from baseline to month 15 in all three study groups. The study showed that GAD-alum did not result in a significant benefit with respect to the change in stimulated c-peptide secretion from baseline to 15 months in patients with newly diagnosed T1DM." Sadly, there were no significant changes in the mean daily insulin dose or hb A1c. The authors postulated that the lack of efficacy in this phase 3 trial may be due to differences in populations or a greater number of clinicians with different approaches to conventional therapy. They also wondered if the possibility of seasonal variations in the immune system had a role. In addition, during the phase 3 trial, there was the presence of the H1N1 epidemic with the administration of the vaccine which may have played a role in the lack of efficacy. The authors note that the decline in c-peptide may be more rapid in younger patients. In addition, since the incidence of type 1 diabetes is higher in boys than in girls older than 15, perhaps there were differences in autoimmunity based on gender.
Despite the lack of efficacy of the GAD-65 alum, Dr. Ludvigsson and colleagues have not abandoned the hypothesis that GAD can preserve residual insulin secreation. He feels that much needs to be learned about dosing, population preferences, age, and gender effects. I believe that there will be multiple therapeutic agents that will be employed in the future to preserve the functioning of beta cells and production of insulin. As with a chronic diseases, there is generally no one form of therapy for every individual and based on the possibility of future genetic analysis, we may be able to tailor specific therapies for each individual.
The Department of Endocrinology and Diabetes at Children's National Medical Center is currently collaborating with the J Craig Venter Institute (JVI) (a cutting edge facility specializing in DNA analysis) in Rockville Maryland in a study to determine whether microbes in the intestine differ between children with type 1 diabetes and their siblings. This information may someday enable us to determine which children might develop diabetes earlier. We are also trying to determine if urinary proteins differ between children with type 1 and their siblings. Children/Adolescents that visit Children's National for diabetes outpatient visits, as well as those children/adolescents that participate in TrialNet, are eligible to participate if they qualify for the study. The project involves collecting samples of urine, stool, and one additional small sample of blood from your TrialNet family member. We also plan on collecting samples of stool, urine, and blood from your child with type 1 diabetes. The sibling must be within 4 years of each other and younger than 18. The study is IRB approved and informed consent will be obtained. For more information, contact Nanna Frimpon at 202-476-2992 or at NFrimpon@ChildrensNational.org.