Diabetes TrialNet’s Natural History Study: 10 Years In

By Douglas G. Rogers, MD

Although understanding of the early metabolic abnormalities in type 1 diabetes (T1D) is steadily increasing, many unknowns remain regarding the natural history of T1D. In response, the National Institute of Diabetes and Digestive and Kidney Diseases has sponsored the Natural History Study of the Development of Type 1 Diabetes, which was launched a decade ago as part of the Diabetes TrialNet international network for the study, prevention and early treatment of T1D. The aim is to improve characterization of the demographic, immunologic and metabolic characteristics of individuals at risk of developing T1D.

Cleveland Clinic Children’s Center for Pediatric and Adolescent Endocrinology is proud to have been an active affiliate site for the NIH-sponsored multicenter Diabetes TrialNet network since October 2004, and we report here our experience to date in the natural history substudy and related Diabetes TrialNet investigations.

Diabetes TrialNet at a Glance

In view of T1D’s status as a T cell-mediated autoimmune disease, Diabetes TrialNet monitors the natural history of subjects who have tested positive for antibodies associated with T1D, indicating that they are at a high risk for developing T1D. A positive test is an early indication that damage to insulin-secreting beta cells in the pancreas may have begun. Relatives of individuals with T1D have an approximately 3 to 4 percent chance of testing positive for T1D-associated antibodies.

Diabetes TrialNet also enrolls selected subjects into substudies to determine whether any immunomodulating treatment may prevent or delay the onset of T1D — or may maintain some endogenous insulin secretion so that patients with T1D can remain in a state of partial remission of T1D, often referred to as the “honeymoon” period.

Cleveland Clinic Children’s Experience and Contributions

In Cleveland Clinic Children’s first 10 years as a Diabetes TrialNet affiliate site, we have screened 588 first- and second-degree relatives of individuals with T1D for antibodies associated with T1D. Although most of these subjects are relatives of children with T1D followed at Cleveland Clinic Children’s, we are happy to screen any relative of a patient with T1D.

Thirty-six subjects from our site have tested positive for antibodies associated with the development of T1D. Fourteen of those subjects have enrolled in the natural history monitoring substudy. These subjects have their antibody levels checked and undergo an oral glucose tolerance test twice a year in Cleveland Clinic’s general clinical research center.

One of our antibody-positive subjects had a very high level of insulin autoantibodies. This subject has enrolled in the Diabetes TrialNet oral insulin substudy (Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus) here at Cleveland Clinic Children’s to determine if this antigen-specific therapy can induce anergy or depletion of T cells attacking the beta cells.

Other antibody-positive subjects can enroll in a Diabetes TrialNet-sponsored anti-CD3 antibody study. This substudy targets activated T cells wherever they are in the body, with the aim of reducing the attack on the beta cells. There is also a study evaluating CTLA4-Ig therapy, which is known to regulate T-cell activation.

Broadening Benefits Beyond Today’s Patients

Cleveland Clinic Children’s is honored to offer Diabetes TrialNet study participation to relatives of patients with T1D throughout Northeast Ohio. Subjects can benefit by finding out if they are at elevated risk for developing T1D and, if so, initiating treatment before they become seriously ill from untreated T1D. Some subjects may have the opportunity to enter immunomodulating studies to determine if the development of T1D can be prevented, delayed or kept in a state of partial remission.

Dr. Rogers is Head of the Center for Pediatric and Adolescent Endocrinology.