Diabetes and Clinical Trials

What will the future bring?

Researchers continue to look for the cause or causes of diabetes and ways to manage, prevent, or cure the disorder. Scientists are searching for genes that may be involved in type 1 or type 2 diabetes. Some genetic markers for type 1 diabetes have been identified, and it is now possible to screen relatives of people with type 1 diabetes to determine whether they are at risk.

Type 1 Diabetes

A number of Federally-funded research studies and clinical trials are under way. Studies focus on the prevention and causes of type 1 diabetes as well as experimental treatments such as islet transplantation.

The Environmental Determinants of Diabetes in the Young Consortium

The main mission of The Environmental Determinants of Diabetes in the Young (TEDDY) consortium, an international group of clinical centers, is to identify infectious agents, dietary factors, or other environmental factors (including psychosocial events) that trigger type 1 diabetes in those who are genetically susceptible.

In addition, the consortium aims to:

TEDDY is funded by the NIDDK, the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Child Health and Human Development (NICHD), the National Institute of Environmental Health Sciences, the CDC, the JDRF, and the ADA. For more information, see www.niddk.nih.gov/patient/TEDDY/TEDDY.htm.

Type 1 Diabetes TrialNet

Type 1 Diabetes TrialNet is a network of experts and facilities dedicated to developing new approaches to the understanding, prevention, and treatment of type 1 diabetes. Clinical centers are located in the United States, Canada, Europe, and Australia.

TrialNet studies are focusing on:

For more information, see www.DiabetesTrialNet.org or call 1–800–HALT–DM1 (1–800–425–8361).

In many ways, the TrialNet studies build on the advances and insights gained from earlier research in type 1 diabetes. For example, researchers learned a great deal about how to predict type 1 diabetes in at-risk people from the Diabetes Prevention Trial—Type 1 (DPT–1). This study showed that people at risk of developing type 1 diabetes can be identified. The DPT-1 researchers discovered ways to identify two populations at risk of developing type 1 diabetes within 5 years: those at high risk (with at least a 50 percent chance) and those with an intermediate risk (having a 25 to 50 percent risk). Then researchers explored possible ways of preventing type 1 diabetes in both groups. TrialNet will identify people at risk who may be eligible for clinical trials. In addition, TrialNet will conduct trials to save beta cell function in those with new onset type 1 diabetes.

TrialNet is funded by the NIDDK, NICHD, and NIAID. JDRF and ADA also support this effort.

The Immune Tolerance Network

TrialNet works closely with the Immune Tolerance Network, another international, collaborative consortium. Its goal is to find safe and effective ways to induce long-term immune tolerance—prevention of an unwanted immune response by the body. For example, type 1 diabetes might be prevented if scientists could learn how to prevent the immune system from mistakenly attacking the insulin-producing cells in the pancreas.

Effective immune tolerance could possibly:

• prevent the body’s rejection of organ or tissue transplants
• prevent or treat autoimmune diseases
• prevent or treat allergies and asthma

Islet Transplantation

Researchers are working on a way for people with type 1 diabetes to live without daily insulin injections. In an experimental procedure called islet transplantation, islets are taken from a donor pancreas and transferred into a person with type 1 diabetes. Once implanted, the beta cells in these islets begin to make and release insulin.

Scientists have made many advances in islet transplantation in recent years. Since reporting their findings in the June 2000 issue of the New England Journal of Medicine, researchers at the University of Alberta in Edmonton, Alberta, Canada, have continued to use a procedure called the Edmonton protocol to transplant pancreatic islets into people with type 1 diabetes. Before use of the Edmonton protocol, during the 1990s, less than 10 percent of islet cell transplant recipients were able to control blood glucose levels for more than 1 year without insulin injections.

The Collaborative Islet Transplant Registry (CITR), funded by NIDDK, was created in 2001. CITR’s mission is to expedite progress and promote safety in islet transplantation by collecting, analyzing, and communicating data on islet transplantation. The CITR will study islet transplantation alone as well as islet transplantation following kidney transplant.

The September 2005 CITR annual report noted that with use of the Edmonton protocol, after 1 year, 58 percent of those who had transplants no longer needed to inject insulin. Of those who were still insulin-dependent 1 year after transplantation (33 percent of those followed by the registry), requirements for insulin were decreased. The average reduction in insulin requirements was 69 percent. In summary, a total of 91 percent of those with transplants showed improvement following transplantation. The success of the Edmonton protocol has been confirmed at other study sites, including the NIDDK.

The goal of islet transplantation is to infuse enough islets to control the blood glucose level without insulin injections. For an average-sized person (154 pounds), a typical transplant requires about 1 million islets, extracted from two donor pancreases. Because good control of blood glucose can slow or prevent the progression of complications associated with diabetes, such as nerve or eye damage, a successful transplant may reduce the risk of these complications. However, transplanted islets lose their ability to function over time. Also, a transplant recipient needs to take immunosuppressive drugs to stop the immune system from rejecting the transplanted islets.

These drugs have significant side effects, and their long-term effects are still unknown. Immediate side effects of immunosuppressive drugs may include mouth sores and gastrointestinal problems, such as stomach upset or diarrhea. Patients may also have increased blood cholesterol levels, decreased white blood cell counts, decreased kidney function, and increased susceptibility to bacterial and viral infections. Taking immunosuppressive drugs increases the risk of tumors and cancer as well. Researchers are trying to find safer or less toxic immunosuppressants or new approaches that will allow successful transplantation without the use of immunosuppressive drugs.

The results of the Edmonton protocol are very encouraging, but more research is needed to develop safer and more effective immunosuppression and to enhance islet survival after transplantation.

Another obstacle to widespread use of islet transplantation is the severe shortage of islets. Only about 6,000 pancreases a year become available for transplantation or for harvesting of islets. However, researchers are pursuing alternative sources, such as creating islets from other types of cells. New technologies could then be employed to grow islets in the laboratory.

Type 2 Diabetes
Diabetes Prevention Program

In 1996, NIDDK launched its Diabetes Prevention Program (DPP). The goal of this research effort was to learn how to prevent or delay type 2 diabetes in people with impaired glucose tolerance (IGT), a strong risk factor for type 2 diabetes.

The findings of the DPP, released in August 2001, showed that people at high risk for type 2 diabetes could sharply lower their chances of developing the disorder through diet and exercise. In addition, treatment with the oral diabetes drug metformin also reduced diabetes risk, though less dramatically. Metformin lowers the amount of glucose released by the liver and also fights insulin resistance, a condition in which the body doesn't use insulin properly.

Participants randomly assigned to intensive lifestyle intervention reduced their risk of getting type 2 diabetes by almost 60 percent. On average, this group maintained their physical activity at 30 minutes per day, usually with walking or other moderate intensity exercise, and lost 5 to 7 percent of their body weight. Participants randomized to treatment with metformin reduced their risk of getting type 2 diabetes by 31 percent.

Of the 3,234 participants enrolled in the DPP, 45 percent were from minority groups that suffer disproportionately from type 2 diabetes: African Americans, Hispanics/Latinos, Asian Americans and Pacific Islanders, and American Indians. The trial also recruited other groups known to be at higher risk for type 2 diabetes, including individuals aged 60 and older, women with a history of gestational diabetes, and people with a first-degree relative with type 2 diabetes. Participants are being followed to check for long-term effects of the interventions, including the effects on risk of CVD.

Type 2 Diabetes in Children and Teens

Two studies focusing on type 2 diabetes in children and teens are under way. The TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) study, a 13-site study sponsored by NIDDK, will compare treatments for type 2 diabetes in children and teens. Participants will undergo one of three treatments:

• taking one diabetes medication (metformin)
• taking two diabetes medications (metformin and rosiglitazone, another medication that fights insulin resistance)
• taking metformin and participating in an intensive lifestyle change program designed to promote weight loss by cutting calories and increasing physical activity

The main goal of the study is to determine how well each type of treatment controls blood glucose levels. The study also will evaluate how long each type of treatment is effective.

The STOPP-T2D (Studies to Treat or Prevent Pediatric Type 2 Diabetes) study, sponsored by NIDDK with support from the ADA, is exploring methods to lower risk factors for type 2 diabetes and CVD in middle-school children (grades 6 through 8) at eight sites. A 3-year program will focus on the benefits of improving nutrition, promoting physical activity, and making changes in behavior.