Until recently, type 1 diabetes was often diagnosed when beta cell function was critically lost, and taking insulin was needed for people to survive. In many instances, people would only find out they had the disease in the emergency room when they showed up with diabetic ketoacidosis. Kevan Herold, MD, discusses indications to test for early stages of type 1 diabetes and treatment to delay progression of the disease.

Q: What is the current classification system for type 1 diabetes, and why have health care professionals and patients become interested in this classification in the last few years?

A: We know that type 1 diabetes develops over a period of years. We know from the natural history that there's a continuous loss of beta cell function, and a continuous loss of insulin-producing beta cells over the course of the disease. However, metabolic and immunologic markers can be used to describe the progressing of the disease. This has led to the concept of “stages.”

• In stage 1, the disease process begins when autoantibodies appear, and glucose tolerance, if you test it, is normal.
• In stage 2, glucose tolerance becomes impaired, as measured with a glucose tolerance test. We know that when there is some impairment in glucose tolerance, the likelihood of developing stage 3, or clinical diabetes, is about 75% in 5 years. 
• In stage 3, patients develop clinical type 1 diabetes, meaning that they have signs and symptoms of the disease. Patients may come to the emergency room, sometimes with diabetic ketoacidosis.

The interest in classifying type 1 diabetes is growing for a few reasons.

• First, patients with prediabetes do not have symptoms and would not be identified without testing for autoantibodies, glucose tolerance, or both.
• Second, many people who develop type 1 diabetes, who are often children, present with diabetic ketoacidosis. We know that testing for the earlier stages of the disease can reduce the rates of diabetic ketoacidosis.
• Third, we now have a way to delay stage 3 of the disease using a medicine called teplizumab. This medicine was tested by TrialNet in the TN10 trial, which enrolled participants with stage 2 type 1 diabetes. The TN10 trial showed that participants taking teplizumab had a 2-year delay in developing stage 3 of the disease, on average, but some participants had a much longer delay.

Q: What criteria can health care professionals use to select patients at high risk for type 1 diabetes who should be tested for early stages of the disease?

A: The field changed when teplizumab was approved by the U.S. Food and Drug Administration (FDA). In years past, I would've said that testing should probably be limited to anyone who has a relative with type 1 diabetes. In addition to this group, I would now include people who have other autoimmune diseases, such as thyroid disease, and celiac disease, because there are several shared genetic determinants of celiac disease and type 1 diabetes. My opinion is that in the future, now that we have something we can do about the disease, we might even think about very broadly expanding the screening, including individuals without affected relatives.

I would test people when they’re at a fairly young age, because you want to delay the disease at a time when it would have great clinical significance. The current recommendations are that you begin testing in children when they are around 2 to 3 years of age, and test again when they are about 5 to 7. If you had to pick one time, I guess you could test as children are going into grade school.

But there is another peak in the incidence of type 1 diabetes later in adolescence. So, we think about testing children primarily, but you may pick up other cases by testing later, even in early adolescence.

Q: Which tests should health care professionals order and how often?

A: The tests are commercially available, and any primary health care professional can order them. A clinical lab can measure four autoantibodies to test for type 1 diabetes. These autoantibodies are

• insulin autoantibody (IAA)
• glutamic acid decarboxylase autoantibody (GADA)
• tyrosine phosphatase autoantibody (IA2A)
• zinc transporter autoantibody (ZnT8A)

When a patient tests positive for two or more of these autoantibodies, we know that the immune response that causes type 1 diabetes has been initiated. We classify a patient who tests positive for two autoantibodies as having stage 1 type 1 diabetes. Those who have only one positive autoantibody do not have a significantly greater risk of progressing to clinical disease compared to those who do not. It is when two or more autoantibodies are present that we say that the pathologic process has begun. When the disease progresses and some abnormal metabolic response to glucose can be detected, we classify the disease as stage 2 type 1 diabetes. If the disease progresses further, metabolic control cannot be maintained, and patients are diagnosed with stage 3 type 1 diabetes.

There isn't 100% clear guidance on how to monitor a child with positive antibodies. I would say that if a child is found to have two positive autoantibodies, monitoring with random plasma glucose and  hemoglobin A1C should occur about every year.

If a primary health care professional finds that a patient tests positive for autoantibodies, TrialNet is interested in speaking with the family and with the primary health care professional. My number one recommendation would be to refer the patient to TrialNet.

TrialNet really appreciates collaborating with primary health care professionals because they are the closest to those who would potentially benefit from all that TrialNet is doing and has discovered. Primary health care professionals may see patients who don’t have type 1 diabetes but have a relative with the disease. Those are exactly the people who we want to reach out to for testing.

Q: What treatments are available to delay later stages of type 1 diabetes, when are these treatments indicated, and are these treatments available in primary care?

A: Teplizumab was approved by the FDA to delay type 1 diabetes from progressing from stage 2 to stage 3. Primary health care professionals have the option to prescribe teplizumab. However, they may feel more comfortable referring the patient to an endocrinologist. Health care professionals can give this medicine in outpatient settings. Many insurance companies will cover the cost for people at early stages of the disease. We're hopeful that in the future, teplizumab will be available for people at stage 3 of type 1 diabetes, because we know the medicine has benefits even after symptoms have developed and a patient is diagnosed with stage 3 type 1 diabetes.

Q: How can patients benefit from being tested for type 1 diabetes autoantibodies and receiving treatment to delay the onset of stage 3 type 1 diabetes?

A: Testing for type 1 diabetes autoantibodies and delaying the onset of stage 3 type 1 diabetes has several benefits.

• Testing provides people with information about their risk of developing type 1 diabetes. Giving people this information has been shown to reduce the rates of diabetic ketoacidosis.
• Delaying the onset of stage 3 reduces the time a patient is exposed to the high blood glucose levels that occur with type 1 diabetes, which can lead to organ complications.
• The older a patient is, when and if they develop stage 3 of the disease, the better they may be able to manage the disease, as opposed to managing it as a child or younger individual.
• Patients have time to learn lifestyle changes that might be appropriate for someone who has diabetes. These changes may include increasing physical activity and following a healthy eating plan.
• Delaying the onset of type 1 diabetes buys the patient time for more advances in the diabetes field. We don't treat diabetes today the same way we treated it 4 years ago.
• Although the way we treat diabetes today has improved, being able to delay the onset of the disease is extraordinarily valuable for the families and the patient. This is a disease that is with you 24/7, 365 days a year, every single day of your life. You must constantly pay attention to your nutrition, physical activity, and sleep.
• If a child has a sibling or parent with type 1 diabetes and tests negative for autoantibodies, this test result can be very reassuring for parents. We know that more than 90% of relatives of people with type 1 diabetes will test negative for autoantibodies.

Q: What research is being done on preventing or delaying type 1 diabetes?

A: In TrialNet, we're studying anti-thymocyte globulin (ATG) in people who are at stage 2 of type 1 diabetes. We know that this medicine works in people who are at stage 3 of the disease. We're also interested in studying some other medicines to treat people that may develop stage 3 type 1 diabetes. We encourage people who test positive for autoantibodies to contact TrialNet.

TrialNet is also interested in determining whether combinations of medicines might extend the effects of teplizumab or any other medicine. Other groups around the country are working on using stem cells to replace beta cells.

Areas of interest for future research projects include trying to identify people likely to develop other autoimmune diseases, like rheumatoid arthritis, and seeing if we can intervene before clinical presentation of the disease, as we are doing with type 1 diabetes. An important area of our interest right now is developing strategies to recruit people from understudied groups to participate in type 1 diabetes research.

Do you have any experience testing for and managing early stages of type 1 diabetes? Tell us in the comment section below.