Eskind Diabetes Center Searches for Clues to Type 1 Diabetes
Eskind Diabetes Center Searches for Clues to Type 1 Diabetes

Margo Black, RN, TrialNet Study Coordinator, and Dr. William E. Russell, Principal Investigator and Director of Pediatric Endocrinology at Vanderbilt help Dustin Davis, who turned five on Halloween, learns about his type 1 diabetes.
With so much energy and research going into the prevention and management of type 2 diabetes — by far the most prevalent form of the disease in America — the clinicians at Vanderbilt’s Eskind Diabetes Center want to make sure that healthcare providers don’t lose sight of the lifelong battle faced by those diagnosed with type 1 diabetes mellitus (T1D).

According to 2005 CDC estimates, T1D affects one in every 400-600 Americans under age 18 and is actually one of the most common chronic childhood diseases. Despite the recent surge of type 2 diabetes among children and adolescents, the vast majority of diabetes cases in those under 18 are still T1D. Although it is often diagnosed during childhood, type 1 can occur well into adulthood and accounts for an estimated 5-10 percent of all diagnosed cases of the disease.

With type 1, the body’s immune system destroys the pancreatic beta cells, which make the hormone insulin that regulates blood glucose. The proteins, or autoantibodies, that attack the beta cells can be found in the bloodstream up to 10 years before onset.

Predicting, delaying or preventing the disease in those at increased risk for T1D and effectively intervening in the newly diagnosed is the major focus of TrialNet, an international consortium of research centers in North America, Europe and Australia launched several years ago. Today there are 15 clinical centers, 14 major affiliates and numerous blood draw centers where researchers are working to yield genetic clues to the disease.

Dr. William E. Russell, director of Pediatric Endocrinology and the principal investigator for TrialNet at the Eskind Diabetes Center, said Vanderbilt was selected to be a major affiliate last year in what proved to be a highly competitive process.

Vanderbilt’s study coordinator, Margo Black, RN, noted, “To get to answers with children when you have a fairly small population, you want to partner with other people; that global partnership is really key to getting to those answers faster.

“We’re testing different protocols,” she said of the international effort, “but we’re testing them in the same way as other centers and sites in TrialNet.”

Ultimately, Dr. Russell continued, the group’s mission is fairly straightforward. “The goal of TrialNet is to develop strategies to prevent and or to ameliorate the course of type 1 diabetes,” he stated, adding that the primary focus is on prevention among high-risk groups.

A major component at Vanderbilt is the Natural History Study, which screens and monitors individuals between 12 months and 45 years of age with a first-degree relative (parent, child or sibling) with type 1 diabetes or those from 12 months to 20 years of age with either a first-, second- or third-degree relative — living or deceased — diagnosed with T1D. Russell noted that the global goal is to screen 200,000 people as part of the Natural History Study. In the first year, Vanderbilt has already screened close to 400 relatives.

“If you’re related to someone with type 1 diabetes, your risk goes up quite a bit,” he explained. “Generally accepted numbers are that if you have nobody in your family with type 1 diabetes, your risk is about 1 in 250, but if you have a sibling (or parent) with type 1 diabetes, it’s 1 in 20, so the risk is more than 10 times higher.”

Black added that a blood draw is used for the Natural History Study with all samples going to the TrialNet Central Lab for quality control. The blood is tested for four autoantibodies, which are commonly present at the onset of T1D: Insulin Autoantibody (IAA), Glutamic Acid Decarboxylase (GAD), Islet Cell Autoantibody (ICA) and ICA512. It takes about six weeks for participants to receive results.

“If they’re negative and under the age of 18, we re-test annually,” noted Black. “That’s because immunity changes as children grow. If they’re over 18 and they’re negative, we don’t re-test because their immune systems are fairly well developed by then.”

Those who test positive for one or more of the predictive markers receive a phone call from Black. Patients are stratified for risk based on antibody levels. Patients are then either called back for a confirmatory lab or for a more thorough assessment of where they are in terms of progressing to diabetes, which is accomplished through the use of an oral glucose tolerance test.

Russell added, “What TrialNet has been telling us is that their collective experience has been about 3 percent will test positive. We’re closer to 5 percent … really almost 6 percent here at Vanderbilt are testing positive.”

He said the reason for the statistical variance locally is unknown but could be attributed to several factors such as a higher prevalence rate in our region, the fact that Vanderbilt is a newer site or the high number of first-degree relatives that have been screened as opposed to second- and third-degree relatives.

“If you have the presence of autoantibodies, the next question for us is ‘do you already have diabetes?’” said Black. She added that for purposes of the prevention study, clinicians want to “make sure the pancreas is healthy and that the autoimmune attack that has been launched has not yet damaged a significant fraction of the islet cells in the pancreas … so insulin is still being made.”

For those who meet the criteria, the next step is to assess their suitability to enter a prevention trial such as the oral insulin trial, which is placebo controlled. Children in this prevention trial are monitored twice a year to check pancreatic function. Black said that a participant’s oral glucose tolerance is re-tested, and the autoantibody levels are studied to see if there has been an increase or decrease since the last visit.

Russell stressed that the whole purpose of the screenings is to get participants enrolled in preventative trials. Although nothing has yet been proved, he said research has progressed to the point where “there are some really good ideas” about warding off T1D. TrialNet, Russell added, provides a state-of-the-art framework in which to test those theories. He also noted that the oral insulin trial already has solid data to back it up and that it is just the first in a series of preventative measure trials.

In addition to the Natural History Study and the oral insulin prevention trial, Vanderbilt has been heavily involved in the Genetics Consortium. The clinicians recently wrapped up enrollment for a sibling study but are still actively looking for Mexican-American and African-American families in which one or more children over the age of 12 months has been diagnosed with type 1 diabetes.

In the next six months Vanderbilt plans to institute other TrialNet studies focused on early intervention. Within the first several months after diagnosis of T1D, individuals will be treated with immune modulating protocols. The goal is to maintain the 10-30% of islet cells that are functional at the time of diagnosis. One protocol, using an anti-CD3 monocolonal antibody, has been shown to significantly delay the loss of residual islet function over a period of two years.

“TrialNet is working hard to make an impact on the burden that T1D poses on our society,” Russell said. “Finding a cure is a clear priority, but that victory will be greatly enhanced if we can prevent new cases of T1D from ever occurring.”

Black added, “Parents often test the blood sugars of their other children to see if they are developing diabetes; but if the blood sugars are altered, it’s too late to prevent the damage to the islet cells. When families find out about our prevention efforts, they are eager to partner with us in reshaping the course of this disease.”

The Eskind Diabetes Center at Vanderbilt cares for approximately 1,600 children with type 1 and type 2 diabetes and sees about 250 new cases of T1D annually. In addition to the preventative trials, clinicians are also instituting early intervention studies at the center to try to slow the progress of type 1 diabetes in those who are newly diagnosed.

November 2007