MEDICINE / DIABETES : Researchers Find Cause, Treatment for Disease in Mice

In a development with significant implications for the prevention of diabetes in humans, UCLA and Stanford researchers have independently determined the cause of the disease in mice and developed effective techniques to prevent it.

The two teams report today in the British journal Nature that the disease results when the immune systems of the mice launch an attack on a pancreatic protein called GAD, destroying the pancreas and preventing its release of life-sustaining insulin.

Evidence indicates that this same mechanism is at work in the estimated 1 million Americans who have insulin-dependent diabetes.

“This is the kind of work that has breakthrough potential,” said Dr. James R. Gavin III, president of the American Diabetes Assn. “The implications for human disease are really quite striking. . . . It’s the kind of news we in diabetes research have been waiting for.”

The finding is particularly hopeful because the researchers have been able to prevent the onset of diabetes in the animals by feeding them precise quantities of GAD, a process known as oral tolerization.

The National Institutes of Health is already planning a clinical trial of the approach in humans, but it is not likely to start for two to three years, according to Joan Harmon, executive director of the Diabetes Research Program at NIH. Researchers are optimistic because of recent successes in using oral tolerization to treat arthritis and multiple sclerosis.

Insulin is used to regulate the use and storage of sugars in the bloodstream. In its absence, diabetics develop excessive thirst and urination and can lapse into a coma that is fatal unless they receive treatment.

The immediate symptoms of diabetes can be controlled by injection of insulin, but most diabetics eventually develop a variety of complications, including nerve damage and blindness, that result from poor control of blood-sugar levels.

Researchers have known for some time that insulin-dependent diabetes, also known as Type 1 diabetes, is caused by an autoimmune attack on the pancreas, but it has not been clear what triggers the attack and what components of the pancreas are attacked. The new research provides the first clear-cut description of the process.

Dr. Daniel Kaufman and his colleagues at UCLA and the University of Florida and, independently, Dr. Hugh McDevitt and his colleagues at Stanford, study non-obese diabetic, or NOD, mice that spontaneously develop a form of diabetes remarkably similar to Type 1 diabetes in humans.

By studying the identity of immune cells produced during the mice’s first few weeks of life, both teams were able to show that the disease begins when the cells attack an enzyme called glutamic acid decarboxylase. GAD plays key signaling roles in the brain and the pancreas but is not present elsewhere in the body.

The blood-brain barrier, which shields the brain from foreign substances in the bloodstream, protects the brain from attack, but the pancreas is devastated.

“The attack on GAD is like the first spark that starts a bonfire of autoimmune responses” against the pancreas, said Dr. Paul Lehmann of UCLA. Within weeks, the immune system attacks many other components of the pancreas as well, leading to widespread destruction.

Why the attack occurs is still a matter of conjecture, however. Clearly, genetic susceptibility plays an important role, explaining why diabetes often runs in families.

Many researchers believe that a viral infection may be the catalyst that triggers the autoimmune attack. UCLA biologist Allan J. Tobin has shown, for example, that one protein in a family of respiratory viruses called Coxsackie viruses bears a strong resemblance to GAD. Immune cells primed to attack the virus may then go on to attack the pancreas.

Both groups of researchers further showed that feeding infant mice GAD before diabetes develops can prevent its onset. This widely recognized oral tolerization phenomenon occurs as part of the digestive process so that the body does not develop an immune response against foreign proteins in food.

Researchers have previously shown that high levels of antibodies for GAD are present in humans who have recently developed Type 1 diabetes. The presence of such antibodies in otherwise healthy individuals is also being studied as a way to predict the onset of the disease.

These studies suggest that the human form of the disease is very similar to that in mice. If that is the case, then oral tolerization should be effective in preventing the onset of the disease in humans too.