C. Ronald Kahn chaired a congressionally mandated committee to find ways to slowthe rising toll in deaths and disability from diabetes. He is shown in his laboratory at Joslin Diabetes Center with Mathias Fasshauer. Photo by Kris Snibbe.

About 200,000 people will die from diabetes this year, more than double the toll from breast and prostate cancer combined. As many as 750,000 new cases of the disease will be diagnosed. These numbers, both of which are increasing annually, are so alarming that the U.S. Centers for Disease Control and Prevention calls it "the epidemic of our times."

To devise a way to combat the epidemic, Congress last year established the Diabetes Research Working Group (DRWG), which made its plan public in March. By last week, 279 members of Congress, more than half, had signed a letter in the plan's favor.

"That's very strong support," comments C. Ronald Kahn, chairman of the DRWG and director of the Harvard-affiliated Joslin Diabetes Center in Boston. "Some 210 members of Congress also take part in the Diabetic Caucus, the largest nonpolitical caucus on Capitol Hill."

The plan calls for increasing the annual budget for diabetes research from $442 million this year to $1.6 billion in 2004, almost a fourfold jump.

"We didn't start out with any preconceived notion about budget," says Kahn, who is also the Mary K. Iacocca Professor of Medicine at Harvard Medical School. "The question was not what we could do if we had four times as much money, but what could we accomplish over the next 10 years to solve problems involving the genetics of the disease and its complication, development of new treatments, and reducing risks of getting diabetes. Once we agreed on goals, we developed a research plan and then calculated how much would be needed to reach our goals."

"We now have a clear scientific plan of how to deal with a disease that affects 16 million people," adds Douglas Melton, a Harvard professor of molecular and cellular biology and a member of the DRWG. "We need more support because the percentage of federal funds for diabetes has gone down steadily as a proportion of the total budget since 1984."

Death Rates Rising

While the death rate and incidence of most cancers and of heart disease have been on the decrease, deaths from diabetes have increased 30 percent over the past 20 years. Kahn cites an aging population, soaring rates of obesity, sedentary lifestyles, a growth of minority populations, and inadequate treatment as main reasons.

More people are living longer and gaining more weight. About half of all Americans are overweight and one-third are obese. Blacks, Hispanics, Native Americans, and Asians experience higher rates of diabetes and its complications, such as blindness and kidney failure, than whites. Nobody knows why.

"The treatments we use manage the disease and control blood sugar levels, but they don't stop the progress of the disease," Kahn points out. "Life expectancy for diabetics averages 10 to 15 years less than for the general population."

There are two forms of the disease, both growing at a rate of between 700,000 and 750,000 new cases a year. Type 1, or insulin dependent diabetes, is purely genetic and commonly appears suddenly between ages 10 and 16. New cases have tripled in the United States in the past 50 years. Type 2, or non-insulin dependent diabetes, usually occurs gradually in people older than 40. Today, the U.S. population includes some 1 million Type 1 and 15 million Type 2 people.

Together, they are the leading cause of kidney failure, blindness in adults, and limb amputations, as well as major risk factors for heart disease, strokes, and birth defects. The DRWG estimates that diabetes costs the nation about $105 billion annually, including more than one out of every ten healthcare dollars.

Diabetes Prevention

In Type 1 diabetes, immune defenses go awry and cause the body to attack insulin-producing cells in the pancreas. Insulin comprises the main hormone that controls the storage of glucose (blood sugar) in the body. "If blood sugar remains low for a long time, it can cause seizures and permanent brain damage," Kahn notes. On the other hand, high levels of blood sugar adversely affect small blood vessels, leading to blindness, kidney damage, and destruction of nerves.

Researchers know much of what they need to know about genes that predispose people to Type 1 or Type 2 diabetes. The DRWG proposes a nationally coordinated research program to find all the genes and the key proteins that these genes are responsible for producing.

"If we could determine which genes put people at high risk, there's a good chance that we could slow down or even prevent development of both types of the disease," Kahn says.

An effort aimed at Type 1 and called the Diabetes Prevention Trial is now underway at more than 20 different medical centers in the country. One surprising tactic under study would give high-risk people small amounts of insulin as a potential vaccine.

In experiments done at Joslin Diabetes Center, Richard Jackson, assistant professor of medicine, and his team gave siblings of diabetics low doses of insulin, and that seemed to delay onset of the disease.

Another group of Harvard researchers, working at Brigham and Women's Hospital in Boston, plans to give the insulin orally. The idea is to "teach" the body that the hormone is part of "self" and not a foreign substance that should be attacked by the immune system.

The DRWG wants more money for this kind of effort and for research on transplantation of insulin-producing beta cells into the pancreas. The biggest obstacle on this course is getting enough cells. "About 35,000 new cases of Type 1 occur each year, but donor organs number around 3,000 a year," Kahn points out. "And that doesn't include one million people who already have the disease."

This shortage is pushing research in two directions, trying to stimulate growth of beta cells in donated human organs, and using pancreas cells from other animals, such as pigs.

Douglas Melton is leading a team that works on determining how the pancreas is made during development in the womb. "If we can copy this process in the laboratory, we may be able to grow human pancreas cells that can be used as transplants," Melton says.

New Drugs

Not knowing the genes involved in Type 2 is a major hindrance to research aimed at identifying those at highest risk and at prevention. The disease is more complex than Type 1 because Type 2 genes only predispose people to diabetes; actually getting it requires environmental triggers, such as diet, lack of exercise and, perhaps, other unknown factors.

Another national effort, dubbed Diabetes Prevention Program (DPP), is under way to meet these and other challenges of Type 2. "So far, it appears as if prevention will entail a combination of drugs and lifestyle changes," Kahn comments. "DPP is now testing the result of diet and exercise while taking metformin, a drug that improves liver metabolism." Glucose is stored in the liver until the body signals that it needs more sugar.

Under the DRWG plan, additional funds would go to understanding cell signaling and regulation, disturbances of which lead to Type 2 and its complications. Such research complements new information about the genetics of diabetes and can identify targets for new treatments. For example, George King, a professor of medicine at Harvard Medical School, found that high levels of glucose activate a substance called protein kinease C (PKC). This has led to development and testing of a new drug to block the effects of PKC on the eyes, kidneys, and nerves.

Faulty cell signaling also underpins insulin resistance, wherein the body does not make enough insulin and thereby compromises its ability to provide energy to tissues and organs.

Obesity worsens insulin resistance, one reason why it's a major risk factor for developing the disease. More than 60 percent of black, Mexican American, and Native American women are overweight and between 33 and 37 percent are obese, according to the DRWG report. Also, obesity in children and adolescents is increasing at an alarming rate.

DRWG also wants to fund more studies of hormones that suppress or stimulate appetite, such as leptin and melanin concentrating hormone. Determining how these hormones work in the body could lead to drugs that might help control weight.

Kahn also notes that researchers are "extremely excited" about uncoupling proteins (UCPs), major controllers of energy utilization in the body. "The hope is to develop a drug that will burn up energy even when a person doesn't do anything." Kahn says. "You take a pill and you're body thinks you're jogging while you're sitting still. We could call it 'jogamine.'"

These are only highlights of the 138-page DRWG plan. It covers many more aspects of research into genetics, immunology, cell signaling, obesity, and the complications of diabetes. It also proposes a national network dedicated to testing new drugs and other treatments.

"The cost of implementing the plan, a fourfold budget increase to $1.6 billion in five years, sounds like a lot," admits Kahn. "But it is consistent with the human and economic impact of diabetes on the United States and with levels of research funding for other major diseases."