The NIH-funded studies seek to slow or stop the immune system's attack on insulin-producing cells in two groups of people: those newly diagnosed with type 1 diabetes and those at risk for developing it.
"It would be a tremendous step forward if insulin-producing cells can be shielded from further destruction by immune cells," said Elias A. Zerhouni, M.D., NIH Director. "We stand to learn a great deal from these promising studies, which are exploiting the knowledge gained from earlier research in immunology, endocrinology, and the biology of type 1 diabetes."
Type 1 diabetes is an autoimmune disease that accounts for 5 to 10 percent of diagnosed diabetes cases in the United States -- up to a million people. It arises when a person's own immune system destroys beta cells in the pancreas. Beta cells sense blood glucose and produce the hormone insulin, which regulates glucose and converts it to energy. Formerly called juvenile onset diabetes, type 1 diabetes usually develops in children and young adults. People with this form of diabetes typically need three or more insulin injections a day or treatment with an insulin pump, as well as careful monitoring of blood glucose and attention to diet and exercise, to properly control their blood glucose.
The immune destruction of beta cells begins well before a person develops the symptoms of diabetes and continues long after the disease is diagnosed. During the "honeymoon phase," the months after diabetes is diagnosed, most patients still have a reservoir of functioning beta cells that, with the help of insulin injections, makes it easier to control blood glucose. If the honeymoon period can be extended, researchers hope that more patients would be able to tightly control their blood glucose. Well controlled glucose is critical to preventing or delaying serious damage to the eyes, nerves, kidneys, heart, and blood vessels.
STUDIES FOR NEWLY DIAGNOSED PATIENTS Researchers participating in Type 1 Diabetes TrialNet are now conducting two studies that seek to safely preserve insulin production in people diagnosed with type 1 diabetes in the previous 3 months. "The more beta cells a person has, the easier it is to control diabetes and prevent complications," said TrialNet chair Jay Skyler, M.D., of the University of Miami. "With these studies, we hope to stop the immune system's attack on these cells and keep the disease from getting worse."
A number of studies have already shed light on how a subgroup of T cells, the "warrior" cells of the immune system, seek out and attack insulin-producing cells. B cells, another group of immune cells that were initially seen as idle bystanders, are now thought to raise the alarm by presenting antigens to T cells, urging them to take action.
This new insight is now being tested in a clinical study that seeks to "turn off" the alert by reducing the number of circulating B cells. In this study, researchers are testing the use of Rituximab, a monoclonal antibody that binds to a receptor on the surface of B cells and destroys them. Rituximab, approved by the Food and Drug Administration to treat B cell non-Hodgkin's lymphomas, has also been used with minimal toxicity to treat autoimmune diseases, such as chronic idiopathic thrombocytopenia, myasthenia gravis, and rheumatoid arthritis.
In another TrialNet study, patients are randomly assigned to one of three groups receiving mycophenolate mofetil (MMF) alone; MMF plus daclizumab (DZB); or placebo. Both MMF and DZB, which slow immune cell activity, have been approved by the Food and Drug Administration to prevent organ rejection after an organ transplant.
Both the new Rituximab trial and the ongoing MMF/DZB trial are recruiting patients with type 1 diabetes diagnosed within the previous three months. In each study, patients are randomly assigned to receive the experimental treatment or placebo. Participants will be closely monitored for any possible side effects of the drugs.
STUDY FOR NEWBORNS AT RISK FOR TYPE 1 DIABETES Some studies show that the immune destruction of beta cells is linked to an inflammatory process triggered by specific cytokines, molecules that regulate communication among immune cells. TrialNet researchers hope to quell this inflammation and prevent the development of autoantibodies with docosahexaenoic acid (DHA), an omega-3 fatty acid that may have anti-inflammatory benefits. "Nutritional Intervention to Prevent Type 1 Diabetes (NIP)" is a pilot study of DHA being conducted in babies less than 5 months old who have immediate family members with type 1 diabetes. The "NIP" study is also screening pregnant mothers in their third trimester whose babies are at risk for type 1 diabetes, either because the mother has type 1 diabetes herself or other immediate relatives have the disease.
NATURAL HISTORY STUDY TrialNet researchers are also probing the causes of type 1 diabetes by examining the immune and metabolic events that precede the onset of diabetes symptoms. They are screening two groups of relatives of those with type 1 diabetes: first-degree relatives ages 1 to 45 and second-degree relatives ages 1 to 20. Screening involves a simple blood test for the autoantibodies that appear in at-risk people years before diabetes develops. The presence of autoantibodies to GAD, IA-2, and insulin point to a greater risk for developing type 1 diabetes. For a person with high-risk genes who has all three antibodies, the risk of developing diabetes in the next 5 years is greater than 50 percent.
After enrolling in the study, participants will be closely monitored for diabetes development and may be eligible to participate in studies that try to arrest the disease.
Type 1 diabetes is caused by a combination of genetic and environmental factors. About 18 regions of the genome have been linked to type 1 diabetes risk. The most well studied region is IDDM1, which contains the human leukocyte antigen (HLA) genes that encode immune response proteins. Specific variations in these genes predispose a person to the disease, but having them does not guarantee that someone will develop the disease. One or more external co-factors, such as a viral infection or component of the diet, appear to trigger immune cells' misguided attack on beta cells in genetically susceptible people. Researchers are working to identify all the genes and environmental triggers that contribute to the risk of developing type 1 diabetes, and they have already learned a great deal about assessing an individual's level of risk.
The studies are funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases within the NIH. The ADA and the Juvenile Diabetes Research Foundation International (JDRF) also support the initiative.