Daily News: Disease

Diabetes prevention focus of clinical trials

1SF

10-30-13

Oct. 30--Jonathan Marks doesn't have diabetes. Not yet.

But three of his eight family members -- his father, a younger brother and sister -- have Type 1 diabetes, and that puts Jonathan at a greater risk than most people of developing it himself someday.

It's not something the 13-year-old worries about. In a way, he's lived his whole life with diabetes, and if he does get it, "that'll be something I can share with my dad," he said with a shrug.

Jonathan explained his lack of concern from a reclining chair at UCSF, where he had just finished an intravenous infusion of either a placebo or, he hopes, an immune-suppressing drug that may keep diabetes at bay. He's part of a double-blind clinical trial, one of several taking place worldwide to find a way to prevent Type 1 diabetes.

"For our family, diabetes is like braces or glasses. It's just something all the kids have grown up with," said Jonathan's mother, Heather Marks, who travels from the small town of Brookings, Ore., with her son once a month to participate in the UCSF trial.

"But what if you could prevent it or delay it?" she said. "He has a 25 to 50 percent chance of getting diabetes. We want to know as much as we can."

Almost 24 million people in the United States have diabetes, but the vast majority -- more than 90 percent -- are Type 2. Those cases typically develop in adulthood and are often associated with being overweight or obese. In Type 2 diabetes, the body becomes resistant to insulin, the hormone that is critical for converting sugar into energy. Type 2 diabetes often can be kept under control with lifestyle changes, such as improving diet and exercising more often.

Auto-immune disease

Type 1 diabetes almost always occurs in childhood, and is caused by an auto-immune reaction -- the immune system attacks and destroys the cells that produce insulin. People with Type 1 diabetes need to give themselves a regular supply of insulin, usually through shots or a pump, to maintain a healthy level of sugar in their blood.

Doctors don't know what causes Type 1 diabetes. Genetics certainly plays a role, since people with even one close relative with Type 1 are 10 to 20 times more likely to develop the disease than people without any cases in their family. But 90 percent of people with Type 1 have no relatives with diabetes.

There is almost definitely an environmental cause of Type 1, too, but finding it will be exceedingly difficult -- there are just too many variables, doctors say.

That's one of the goals of the trials that Jonathan is part of. The research, known collectively as Type 1 Diabetes TrialNet, plans to enroll hundreds of people worldwide who are at increased risk of developing the disease or are newly diagnosed with it. Both UCSF and Stanford are involved in the TrialNet studies.

The ultimate goal is prevention, but along the way, scientists hope to better understand what triggers the autoimmune reaction that sets someone on the path toward diabetes. And they hope to identify multiple places to attack the disease.

"In the big picture, we're trying to figure out what causes diabetes and how we can stop it," said Dr. Stephen Gitelman, chairman of pediatric diabetes and the lead investigator for TrialNet at UCSF.

"Families have to be brave and adventurous enough to get screened and find out what their risk is. Then they have to be brave again and decide if they want to enter a trial," he said. "They're helping us understand the natural course of diabetes, better understand the underlying physiology, and come up with better treatments."

Genetic link

The people in the prevention trials must have at least one close relative with Type 1 diabetes. Although these cases make up a minority of the total Type 1 diagnoses, they are easy to identify. Researchers have ways to screen for diabetes based on certain markers found in the blood, but screening every person in the country would be cost prohibitive.

Anyone age 45 and under with a close relative with Type 1 diabetes can enroll in TrialNet and take part in the monitoring program, which is designed to follow people at risk for the disease and catalog their health history. Doctors hope to use that information to help identify more risk factors.

Four prevention trials are currently under way at dozens of sites around the country, including both Stanford and UCSF. Two, including the one Jonathan is in, are looking at immune-suppressing drugs. One trial involves daily insulin pills; researchers believe that oral insulin, rather than regular injections, may stop or delay diabetes in people who are at risk. The fourth trial is studying a nutrient found in breast milk, called docosahexaenoic acid, that is being given to pregnant women and infants as a potential early intervention to prevent diabetes.

Researchers hope to begin trials as early as next year involving pig whipworm eggs, which, when blended into a slurry and drunk, have shown some promise in treating irritable-bowel syndrome and other autoimmune diseases.

Some value already

All of the therapies that are being studied as part of TrialNet have proved at least somewhat useful in smaller diabetes trials -- often as a treatment shortly after diagnosis, to protect the remaining insulin-producing cells -- or in other autoimmune disorder studies.

In fact, diabetes researchers have identified hundreds of drugs that may help alter the course of Type 1 diabetes -- but most of that work has been done in mice.

"It's fairly easy to prevent and treat diabetes in mice," said Dr. Darrell Wilson, chief of pediatric endocrinology and diabetes and one of two lead investigators for TrialNet at Stanford. "But that hasn't translated well to humans."

And so progress toward understanding, preventing and curing Type 1 diabetes has been sluggish. Even now, "we're still in the wide open western frontier" of diabetes prevention research, Wilson said.

"There are lots of drugs that are offered up as potentials," he said. "But we don't have the resources to pick 15 of them at once, so we have to make our best guesses. It's delicate work."

Ironically, one thing that hinders the research in human subjects is just how good the current insulin-based regimen is for treating the disease. Long-term complications of diabetes are serious -- blindness and poor circulation, for example, plus an increased risk of heart attack and stroke.

But many people with Type 1 diabetes can live relatively normal lives with good diet and insulin control. That makes it morally irresponsible for scientists to offer them experimental drugs with potentially serious side effects.

It's even less acceptable to risk the health of people who don't have the disease yet, doctors say. The drug that Jonathan may be getting, for example, is designed to alter his immune system, but not entirely suppress it, which would leave him vulnerable to infections.

'Roll with it' attitude

Jonathan doesn't worry much about the risks, which probably has as much to do with his youth as his father's "roll with it" attitude, his mother said as they waited for him to be released from the UCSF infusion clinic. Nearby, Jonathan's 10-year-old sister, Ella, waits too; she's diabetic, but came on this trip just for fun.

Maybe his infusion is a placebo, Jonathan said, and maybe it's a drug that won't help him. No matter what, he figures he wins.

"I don't really care about diabetes. If I have it, I have it," he said. "There's not really a downside to doing this. And hey, if it does work? Great, I helped solve diabetes."

Erin Allday is a San Francisco Chronicle staff writer. E-mail: eallday@sfchronicle.com

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