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AACE: Prediction and Prevention of Type 1 Diabetes

Drugs aimed at halting the molecular destruction of beta cells are likely the next step in the quest to stop the progression of autoimmune type 1 diabetes….

George Eisenbarth, MD, PhD, executive director of the Barbara Davis Center for Childhood Diabetes and professor of pediatrics, medicine, and immunology at the University of Colorado at Denver School of Medicine, stated that, “Most of the trials we do in are in recent-onset type 1 diabetes, when there are plenty of beta cells left — probably at least 20%…. If one could preserve them, it would be much easier to control patients; it’s like the honeymoon phase.” 

Today, autoantibody testing can predict an individual’s risk of developing autoimmune type 1 diabetes, and even the age of onset of the disorder — information that could one day guide the use of such preventive therapy, said Dr. Eisenbarth.

Such testing in random cadaveric donors suggests that half a million people in the United States might be in the early stages of developing type 1 diabetes, Dr. Eisenbarth wrote in a recent paper (Endocr Pract. Published online May 1, 2012), underscoring the urgency of finding preventive drugs.

Because the development of type 1 diabetes is a slow process, requiring genetic predisposition and a precipitating trigger followed by the gradual development of beta cell loss, prevention is a realistic goal.

People with genetic predispositions can develop type 1 diabetes at any stage in life, he explained. “If one is an identical twin of someone with type 1A diabetes, you’re never out of the woods — autoantibodies can appear later in life and full-blown diabetes even later,” he said. A second peak in the incidence of the disorder is seen in people 70 to 80 years of age, he added.

To date, 4 autoantibodies are implicated in the development of type 1 diabetes: the islet zinc transporter (ZnT8), insulinoma associated antigen, glutamic acid decarboxylases, and insulin autoantibodies.

Commercial assays are available for all 4 autoantibodies, enabling the screening of people with a family history of the disorder.

Detection of a single antibody suggests a risk of developing type 1 diabetes of about 5%, compared with 0.3% in the general population. However, in people with 2 or more autoantibodies, the risk is much higher — up to a 90% by the age of 10 in children followed from birth.

“Not only can we predict risk, now we can also predict the age at which type 1 diabetes will occur,” said Dr. Eisenbarth, explaining that there are 2 factors that predict age at onset. “If you combine these 2 parameters, you can explain about a third of the variation in age at which type 1 diabetes develops,” he said.

The first factor is the person’s age at autoantibody detection; “that makes sense if we think that the autoimmune process begins when that first autoantibody appears,” he said. “Overall, the older you are when the first autoantibody appears, the older you are when diabetes occurs.”

The second predictive factor is the level of insulin autoantibody at first detection. “This is specific for insulin [autoantibody],” he said. “The levels of none of the other autoantibodies correlated at all with how long it takes to develop type 1 diabetes.”

Currently, oral insulin (to induce tolerance) and immunosuppressive or immunomodulating drugs have been shown to preserve beta cells and to delay diabetes onset for 6 months to 1 year. However, work by Dr. Eisenbarth’s team is directed at more specific therapies that target the trimolecular complex: the interaction of peptides, T-cell receptors, and major histocompatibility complex molecules.

“I bet…we’re going to be able to — in many different ways — target this trimolecular complex, and hopefully develop a very specific and safe therapy,” he said. “It’s unusual to have a disease that we can predict so well, and know the autoimmunity, and not have an immunologic therapy in our armamentarium.”

The availability of autoantibody testing for type 1 diabetes autoantibodies is important to practicing clinicians, according to endocrinologists Shivani Narasimhan, MD, and Parul Kakaria, MD, from the Pinnacle Health System in Harrisburg, Pennsylvania, who attended the session. Dr. Eisenbarth’s lab “will screen family members between the ages of 2 and 45 for autoantibodies; that is very practical to me,” said Dr. Narasimhan.

Dr. Narasimhan said that her adult patients with type 1 diabetes are “very much concerned” about the risk of other family members and offspring developing the disease. “If they’re planning on having children or have just had children, they want to know.” “Just because we catch it doesn’t mean we have the treatment to prevent it.”

Still, screening has other benefits, said Dr. Kakaria. “Patients can potentially enroll in a clinical trial if they choose, they can have the blood tests done serially, and could be followed by a pediatric endocrinologist if they choose.”

Presented at the American Association of Clinical Endocrinologist (AACE) May 26, 2012.