Researchers target type 1 diabetes prevention

Type 1 diabetes, often viewed as inevitable for those predisposed to it, could one day be as preventable as its well-known relative, type 2.

Such a shift in understanding would be revolutionary. It also would create a need for primary care physicians to take on screening and prevention for type 1 with the same vigor as they currently do for type 2.

For now, though, prevention of type 1 is a proposition of someday, spoken of in terms of "if," not "when." Even so, many experts believe that they now possess important clues that will help them solve the mystery of how to stop it before it starts.

To that end, the National Institute of Diabetes and Digestive and Kidney Diseases in June launched TrialNet, an international network of 18 centers that will study interventions that may prevent development of the disease and improve the prospects for those newly diagnosed with it.

"This will absolutely be in the purview of primary care physicians once we have something that we really think delays or prevents diabetes," said Ellen Leschek, MD, TrialNet's program director. "Even if you're talking about delaying by just two or three years, that's substantial, because every moment that you have diabetes, those are moments that are contributing towards having the long-term effects."

The network is building on the work of the Diabetes Prevention Trial-Type 1, also funded by NIDDK and launched in 1995, which examined the use of low doses of injectable insulin or oral insulin to prevent the development of the disease in those at high risk.

The results, published in the New England Journal of Medicine May 30, 2002, clearly showed that neither intervention worked. In the process, however, researchers learned how to predict who was most likely to progress to type 1 diabetes.

"We can now identify who's at risk for diabetes. It's just a matter of time before we find agents that will actually prevent diabetes," said H. Peter Chase, MD, one of TrialNet's principal investigators and a professor of pediatrics at the University of Colorado Health Sciences Center.

Being able to make this determination allows researchers to target interventions to those who would benefit the most. This testing is also most likely to be the first innovation out of the initial trial and TrialNet to make inroads into clinical practice -- although not just yet.

TrialNet's fine-tuning

Meanwhile, the challenges involved in an undertaking such as TrialNet are significant. Researchers know how to find the subjects but are still fine-tuning the interventions they will test.

Some centers are expected to try lifestyle changes such as nutritional supplements for high-risk infants or the same diet and exercise recommendations usually given to people at high risk for type 2 diabetes. Other centers will be testing rheumatoid arthritis drugs and other pharmaceutical approaches. New interventions will probably be introduced as the trial progresses. The benefits for a healthy person must be carefully weighed against the risks.

"We're very conservative," Dr. Leschek said. "The challenge is to find something that works without having toxicity."

Recruitment is also a challenge. Type 1 is far less common than type 2, making the pool of eligible people smaller. Researchers have been culling subjects from those who already have a first- or second-degree relative with the disease. Some are eager. Others are more hesitant.

"Either they are absolutely excited about participating or people really don't want to know they're at risk because they feel that there's nothing good out there that's going to prevent it anyway," Dr. Leschek said.

Still, experts say relatives do benefit from knowing their actual risk. They are more likely to be diagnosed earlier in the disease's course than those not in the study.

They also have options that people outside of the trial might have a hard time accessing. In addition to standard treatments for the newly diagnosed diabetic, the subjects who actually develop the disease will be able to switch to another study within the network. That one will investigate the use of low doses of drugs usually prescribed to organ transplant recipients to prevent rejection.

The hope is that these medications will prevent the destruction of the pancreas' beta cells if initiated within three months of disease onset.

"If you still have some of your beta cells, you have an easier time controlling your diabetes," said Jay Skyler, MD, study chair and professor of medicine, pediatrics and psychology at the University of Miami. "This study is trying to stop the autoimmune destruction of these cells and keep the disease from getting worse."

Similar drugs have been tried before with benefits to the pancreas but damage to other organs. Researchers hope that using newer, improved organ rejection drugs at lower doses will now change the risk-benefit calculation for those with the disease.

"The possibility of serious adverse events will be very, very carefully monitored to maximize avoidance," said David M. Brown, MD, principal investigator and professor of pediatrics and pathology at the University of Minnesota.

Those not associated with the study are watching carefully. Most praise the herculean efforts needed to run a trial of this size and complexity and feel the approach is appropriate. Experts also suggest, however, that the intervention that will probably be most successful is not yet on the table.

"What we need is a specific ability to turn off the antibody production that affects beta cells," said Anne Peters, MD, director of the clinical diabetes program at the University of Southern California. "I know that some brilliant researcher somewhere is going to come up with the answer, but it isn't there yet.