TYPE 1 DIABETES TRIALNET FROM EARLY DETECTION TO POSSIBLE PREVENTION

by Marie McCarren

IF someone in your family has Type 1 diabetes, you may wonder if others in your family will develop it as well. It is known that a family history of Type 1 diabetes raises the risk for other family members. For example, the chance that a brother or sister of someone with Type 1 diabetes will also develop it is 3% to 4%, and the chance that one of his parents will is about 2%. If a mother has Type 1 diabetes, her child has a 3% to 4% chance of developing it; when a father has Type 1 diabetes, his child has about a 6% chance of developing it. In contrast, in a family with no history of Type 1 diabetes, the chance that a child will develop it is less than 1 %.

It is now possible, however, to go beyond the overall statistics in assessing someone's risk of developing Type 1 diabetes. You can find out more precisely what the risk is for each person in your family by getting a free blood test through Type 1 Diabetes TrialNet, a network of researchers supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation International, and the American Diabetes Association. The results can show whether someone has a higher-than-average risk of developing Type 1 diabetes. The blood test takes advantage of the fact that Type 1 diabetes takes years to develop.

Development of diabetes

It often seems as though Type 1 diabetes develops over the course of weeks. But if you or your child has Type 1 diabetes, you may be able to remember subtle signs from well before the diagnosis. Maybe your son had been eating more and sleeping a lot for a couple of months, but you blamed it on a growth spurt. Maybe your daughter had the flu several months before and never seemed to completely recover from it.

The classic signs and symptoms of Type 1 diabetes-frequent urination, fatigue, eating more but losing weight-all come from not enough insulin and high blood glucose levels, and are usually what prompt a person to seek medical help. However, you can find out that diabetes is probably going to develop well before there are any symptoms. TrialNet researchers can detect an increased risk up to 10 years before blood glucose levels are high. They do this by testing for evidence of autoimmune activity.

Normally, your immune system attacks foreign invaders, such as harmful bacteria and viruses. In an autoimmune disease, however, someone's immune system mistakenly attacks the body's own cells. Type 1 diabetes is an autoimmune disease in which the immune system attacks and slowly destroys the insulin-producing beta cells of the pancreas. This might go on for years. At first, after just some of the beta cells are killed off, the others respond by working harder, and blood glucose levels stay in the normal range.

Over the years, though, more beta cells are destroyed. The beta cells that are left can produce enough insulin to keep blood glucose levels in the normal range much of the time, but there are too few beta cells to produce the burst of insulin (called a bolus) that's needed after meals. This stage is called glucose intolerance. Because blood glucose levels aren't high all the time, the person probably doesn't have symptoms of diabetes.

The autoimmune attack continued. When the person is finally diagnosed, he has probably lost over 80% of his beta cells.

To carry out the immune system's attack, white blood cells produce antibodies against certain proteins associated with beta cells. These are called autoantibodies because they act against part of a person's own body. It is possible to get tested for autoantibodies associate with Type 1 diabetes; this blood test is part of the screening process for Triolet's Natural History Study. People can be tested if they meet either of the following criteria:

�?They are 1-45 years old and have a brother, sister, child, or parent with Type 1 diabetes.

�?They are 1-20 years old and have a cousin, aunt, uncle, niece, nephew, half sibling, or grandparents with Type 1 diabetes.

Most of the people who take the test-96% to 97%-do not have the auto-antibodies. If you're one of this group, you'll get a letter of notification four to six weeks after the blood test that points out that being negative for auto-antibodies is not a guarantee that you will never develop diabetes, but it's a sign that you are not currently at increased risk. People under 18 will be retested every year.

Monitoring and prevention

If you're one of the 3% to 4% who do have autoantibodies, you can choose to have further testing done. With these results, Triolet will estimate your risk of developing Type 1 diabetes within the next five years as less than 25%, greater than 25%, or greater than 50%.

If you reach this point, there are two choices within Triolet. You can opt for close monitoring, or you can see if you are eligible for a prevention study, which includes dose monitoring.

Close monitoring. If you choose to take part in the Natural History Study, you will be tested every six months to see if you're developing diabetes. This involves an oral glucose tolerance test: First, you'll fast overnight. When you get to the study site the next day, you'll drink a very sweet drink. Triolet staff will then take several blood samples over the next two hours. The results will show whether your panaceas is able to produce enough insulin to deal with the sugar from the drink.

By testing you every six months, Triolet will probably detect diabetes before you show any symptoms (if you develop diabetes at all), after which you can start insulin treatment immediately. If you know someone who was very ill at diagnosis, perhaps with diabetic ketoacidosis, you know the value of early diagnosis and treatment. Prevention study. You may be able to join TrialNet's Oral Insulin Study if the test results from the Natural History Study show that you have insulin autoantibodies. The Oral Insulin Study is enrolling volunteers right now.

The presence of insulin auto-antibodies means your immune system is reacting to your own insulin. There is some evidence that if a person eats the same protein his immune system is attacking, the immune system will stop its attack. This is called aral tolerization.

In the Oral Insulin Study, half the participants will take capsules of insulin crystals. (Insulin taken by mouth does not lower blood glucose.) Half the participants will take capsules that look the same but do not contain insulin; this inactive substance is called a placebo (see "Design of TrialNet Studies" on this page). Researchers will determin whether, over time, there is a difference between the groups in how many people develop diabetes.

DESIGN OF TRIALNET STUDIES

TrialNet's prevention and early intervention studies are placebo controlled, randomized, and double -masked. This means that only some of the people in each study will get the drug being tested; these participants are in the treatment group. The other participants will get capsules, injections, or infusions that look like what the treatment group is getting, but which have no active drug in them. This is called getting a placebo. The people who receive placebos are in the control group. When the study ends, the researchers will determine whether there were any differences between the two groups in the progression of diabetes.

You can't choose your group; a computer chooses it for you randomly. This is what it means to say that a study is "randomized." "Double-masked" means that while the study is going on, neither you nor the medical professionals you are working with will know if you're in the treatment group or the control group. After the study ends, TrialNet will tell you which group you were in.

Treating recently diagnosed diabetes

At diagnosis, a person with Type 1 diabetes still has some beta cells left, which are making a small amount of insulin; how much insulin is different for each person. For example, a person with diabatic ketoacidosis at diagnosis probably has fewer beta cells left than a person who was not as sick. However, in either case, the immune system will keep attacking any beta cells that remain. A year after diagnosis, most people with Type 1 diabetes have lost essentially all of their beta cells and are making no insulin.

Researchers are exploring the possibility that shortly after diagnoses, a person could receive a treatment that would stop the immune system's attack. The person would still need to use injected insulin, but the remaining beta cells would be a great help. Beta cells keep track of blood glucose levels: When blood glucose is high, they release insulin; when blood glucose is low, they don't. So for a person with some remaining beta cells, injected insulin would still be necessary to do most of the work of lowering blood glucose, but the remaining beta cells could do the fine-tuning of blood glucose control. This could make it easier to maintain near-normal blood glucose levels, and a person might also have fewer episodes of hypoglycemia (low blood glucose).

TrialNet is recruiting volunteers for two studies examining treatments that may protect remaining beta cells. Both of these studies are for people who have been diagnose with Type 1 diabetes for less than three months.

One study examines a drug used to treat another autoimmune disease. Abatacept is a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, and it works by interrupting one of the steps in the autoimmune attack. In this study, two-thirds of the participants will get abatacept and one-third will get placebo infusions.

The other study examines whether injections of a protein associated with diabetes can slow the immune system's attack. Many people who are newly diagnosed with Type 1 diabetes have autoantibodies to a protein called glutamic acid decarboxylase (GAD). There is evidence that if the body is exposed again and again to GAD, the immune system will learn to tolerate it, and the autoimmune attack on beta cells will lessen. This is called peptide-induced tolerance (a peptide is a short piece of protein).

In this study, TrialNet will compared the progression of diabetes in people who get three injections of GAD with its progress in those who receive placebo injections.

Getting tested for risk of diabetes

To find out how to get your family members tested to determine their risk of Type 1 diabetes, and to find out about TrialNet studies that you or they might be able to join, visit the TrialNet Web site at www.diabetestrialnet.org or call (800) 425-8361.

For a diabetes-risk screening test, you'll be asked to visit a TriallNet center, of which there are currently more than 150. If there isn't one near you, TrialNet staff will help you make arrangements to have your blood drawn at your doctor's office or at a local lab.

If your child is going to a diabetes camp this summer, call the camp and ask if TrialNet staff will be there on the drop-off or pick-up day. If so, you can get several family members screened at once. A screening takes about 15 minutes.

TYPE 1 DIABETES TRIALNET FROM EARLY DETECTION

TO POSSIBLE PREVENTION

by Marie McCarren

IF someone in your family has Type 1 diabetes, you may wonder if others in your family will develop it as well. It is known that a family history of Type 1 diabetes raises the risk for other family members. For example, the chance that a brother or sister of someone

with Type 1 diabetes will also develop it is 3% to 4%, and the chance that one of his parents will is about 2%. If a mother has Type 1 diabetes, her child has a 3% to 4% chance of developing it; when a father has Type 1 diabetes, his child has about a 6% chance of developing it. In contrast, in a family with no history of Type 1 diabetes, the chance that a child will develop it is less than 1 %.

It is now possible, however, to go beyond the overall statistics in assessing someone's risk of developing Type 1 diabetes. You can find

out more precisely what the risk is for each person in your family by getting a free blood test through Type 1 Diabetes TrialNet, a network of researchers supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation International, and the American Diabetes Association. The results can show whether someone has a higher-than-average risk of developing Type 1 diabetes. The blood test takes advantage of the fact that Type 1 diabetes takes years to develop.

Development of diabetes

It often seems as though Type 1 diabetes develops over the course of weeks. But if you or your child has Type 1 diabetes, you may be able to remember subtle signs from well before the diagnosis. Maybe your son had been eating more and sleeping a lot for a couple of months, but you blamed it on a growth spurt. Maybe your daughter had had the flu several months before and never seemed to completely recover from it.

The classic signs and symptoms of Type 1 diabetes-frequent urination, fatigue, eating more but losing weight-all come from not enough insulin and high blood glucose levels, and are usually what prompt a person to seek medical help. However, you can find out that diabetes is probably going to develop well before there are any symptoms. TrialNet researchers can detect an increased risk up to 10 years before blood glucose levels are high. They do this by testing for

evidence of autoimmune activity.

Normally, your immune system attacks foreign invaders, such as harmful bacteria and viruses. In an autoimmune disease, however, someone's immune system mistakenly attacks the body's own cells. Type 1 diabetes is an autoimmune disease in which the immune system attacks and slowly destroys the insulin-producing beta cells of the pancreas. This might go on for years. At first, after just some of the beta cells are killed off, the others respond by working harder, and blood glucose levels stay in the normal range.

Over the years, though, more beta cells are destroyed. The beta cells that are left can produce enough insulin to keep blood glucose levels in the normal range much of the time, but there are too few beta cells to produce the burst of insulin (called a bolus) that's needed after meals. This stage is called glucose intolerance. Because blood glucose levels aren't high all the time, the person probably doesn't have symptoms of diabetes.

The autoimmune attack continued. When the person is finally diagnosed, he has probably lost over 80% of his beta cells.

To carry out the immune system's attack, white blood cells produce antibodies against certain proteins associated with beta cells. These are called autoantibodies because they act against part of a person's own body. It is possible to get tested for autoantibodies associate with Type 1 diabetes; this blood test is part of the screening process for TrialNet's Natural History Study. People can be tested if

they meet either of the following criteria:

�?They are 1-45 years old and have a brother, sister, child, or parent with Type 1 diabetes.

�?They are 1-20 years old and have a cousin, aunt, uncle, niece, nephew, half sibling, or grandparents with Type 1 diabetes.

Most of the people who take the test-96% to 97%-do not have the autoantibodies. If you're one of this group, you'll get a letter of notification four to six weeks after the blood test that points out that being negative for autoantibodies is not a guarantee that you will never develop diabetes, but it's a sign that you are not currently at increased risk. People under 18 will be retested every year.

Monitoring

and prevention

If you're one of the 3% to 4% who do have autoantibodies, you can choose to have further testing done. With these results, TrialNet will estimate your risk of developing Type 1 diabetes within the next five years as less than 25%, greater than 25%, or greater than 50%.

If you reach this point, there are two choices within TrialNet. You can opt for close monitoring, or you can see if you are eligible for a prevention study, which includes dose monitoring.

Close monitoring. If you choose to take part in the Natural History Study, you will be tested every six months to see if you're developing diabetes. This involves an oral glucose tolerance test: First, you'll fast overnight. When you get to the

study site the next day, you'll drink a very sweet drink. TrialNet staff will then take several blood samples over the next two hours. The results will show whether your panaceas is able to produce enough insulin to deal with the sugar from the drink.

By testing you every six months, TrialNet will probably detect diabetes before you show any symptom (if you develop diabetes at all), after which you can start insulin treatment immediately. If you know someone who was very ill at diagnosis, perhaps with diabetic ketoacidosis, you know the value of early diagnosis and treatment. Prevention study. You may be able to join TrialNet's Oral Insulin Study if the test results from the Natural History Study show that you have insulin autoantibodies. The Oral Insulin Study is enrolling volunteers right now.

The presence of insulin autoantibodies means your immune system is reacting to your own insulin. There is some evidence that if a person eats the same protein his immune system is attacking, the immune system will stop its attack. This is called aral tolerization.

In the Oral Insulin Study, half the participants will take capsules of insulin crystals. (Insulin taken by mouth does not lower blood glucose.) Half the participants will take capsules that look the same but do not contain insulin; this inactive substance is called a placebo (see "Design of TrialNet Studies" on this page). Researchers will determin whether, over time, there is a difference between the groups in how many people develop diabetes.

DESIGN OF TRIALNET STUDIES

TrialNet's prevention and early intervention studies are placebo controlled, randomized, and double-masked. This means that only some of the people in each study will get the drug being tested; these participants are in the treatment group. The other participants will get capsules, injections, or infusions that look like what the treatment group is getting, but which have no active drug in them. This is called getting a placebo. The people who receive placebos are in the control group. When the study ends, the researchers will determine whether there were any differences between the two groups in the progression of diabetes.

You can't choose your group; a computer chooses it for you randomly. This is what it means to say that a study is "randomized." "Double-masked" means that while the study is going on, neither you nor the medical professionals you are working with will know if you're in the treatment group or the control group. After the study ends, TrialNet will tell you which group you were in.

Treating recently

diagnosed diabetes

At diagnosis, a person with Type 1 diabetes still has some beta cells left, which are making a small amount of insulin; how much

insulin is different for each person. For example, a person with diabatic ketoacidosis at diagnosis probably has fewer beta cells left than a person who was not as sick. However, in either case, the immune system will keep attacking any beta cells that remain. A year after diagnosis, most people with Type 1 diabetes have lost essentially all of their beta cells and are making no insulin.

Researchers are exploring the possibility that shortly after diagnoses, a person could receive a treatment that would stop the immune system's attack. The person would still need to use injected insulin, but the remaining beta cells would be a great help. Beta cells keep track of blood glucose levels: When blood glucose is high, they release insulin; when blood glucose is low, they don't. So for a person with some remaining beta cells, injected insulin would still be necessary to do most of the work of lowering blood glucose, but the remaining beta cells could do the fine-tuning of blood glucose control. This could make it easier to maintain near-normal blood glucose levels, and a person might also have fewer episodes of hypoglycemia (low blood glucose).

TrialNet is recruiting volunteers for two studies examining treatments that may protect remaining beta cells. Both of these studies are for people who have been diagnose with Type 1 diabetes for less than three months.

One study examines a drug used to treat another autoimmune disease. Abatacept is a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, and it works by interrupting one of the steps in the autoimmune attack. In this study, two-thirds of the participants will get abatacept and one-third will get placebo infusions.

The other study examines whether injections of a protein associated with diabetes can slow the immune system's attack. Many people who are newly diagnosed with Type 1 diabetes have autoantibodies to a protein called glutamic acid decarboxylase (GAD). There is evidence that if the body is exposed again and again to GAD, the immune system will learn to tolerate it, and the autoimmune attack on beta cells will lessen. This is called peptide-induced tolerance (a peptide is a short piece of protein).

In this study, TrialNet will compared the progression of diabetes in people who get three injections of GAD with its progress in those who receive placebo injections.

Getting tested for risk of diabetes

To find out how to get your family members tested to determine their risk of Type 1 diabetes, and to find out about TrialNet studies that you or they might be able to join, visit the TrialNet Web site at www.diabetestrialnet.org or call (800) 425-8361.

For a diabetes-risk screening test, you'll be asked to visit a TriallNet center, of which there are currently more than 150. If there isn't one near you, TrialNet staff will help you make arrangements to have your blood drawn at your doctor’s's office or at a local lab.

If your child is going to a diabetes camp this summer, call the camp and ask if TrialNet staff will be there on the drop-off or pick-up day. If so, you can get several family members screened at once. A screening takes about 15 minutes.

With both the personal benefits and the wider promise that TriallNet offers, it is likely to be time well spent.

BENEFITS OF JOINING TRIALNET

Natural History Study

�?You will learn whether you or your family members are at increased risk for Type 1 diabetes.

�?If you are at risk, you can choose to be tested for the earliest signs of diabetes by TrialNet staff every six months. This way, you can start insulin therapy as soon as your blood glucose levels are out of the normal range, before they get high enough to cause symptoms.

�?You will be helping scientists learn more about the development of Type 1 diabetes.

Prevention and Early Intervention Studies

�?TrialNet can't promise you any direct benefit from joining one of these studies, other than continued dose monitoring. You may be randomly assigned to the placebo group. If you are assigned to the treatment group, the experimental treatment may not work, or you may be at a stage of diabetes where it cannot help.

�?You will be helping scientists learn more about how to prevent Type 1 diabetes.

 

Marie McCarren is the author of Guide to Insulin & Type 2 Diabetes and A Field Guide to Type 2 Diabetes (both published by the American Diabetes Association). She writes the participant handbooks for Type 1 Diabetes TrialNet studies.

This column is edited by Jean Betschart lWemer, a Pediatric Nurse Practitioner at the Children 's Hospital of Pittsburgh.