T1D and Autoantibodies: Here’s What You Need to Know

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Tests for islet autoantibodies—molecules made by your own immune system that attack insulin producing cells—are being used in a few different ways. For example, services such as TrialNet screen family members of those with T1D to determine if they are also at risk for developing diabetes.

Here at Glu, we wanted to write a good overview of autoantibodies. However, I found a lack of readily accessible information regarding autoantibodies on the internet. The general consensus seems to be that, yes, autoantibodies represent early signs of T1D. Have more of them means that odds of developing T1D are higher. Getting tested may be a good idea for some people.

But the easily understandable information kind of just stops there. Sure, there are many scholarly articles with titles such as Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes.” Important research, but not exactly a basic descriptive article. Some other resources are very much dumbed-down and inaccurate. For example, I found some materials that stated that “autoantibodies mean that the immune system is turned on.” Really? Which autoantibodies? And, in reality—the immune system is always active to some degree; it doesn’t simply turn on and off!

What if you want to know a little bit more than “autoantibodies are bad,” but a little bit less than “Masked and Overt Autoantibodies Specific to the DPD Epitope of 65-kDa Glutamate Decarboxylase (GAD65-DPD) Are Associated with Preserved β-Cell Functional Reserve in Ketosis-Prone Diabetes”?

Why don’t we have any middle-of-the-road, “I’m not a scientist, but I am pretty darn knowledgeable about type 1 and want a comprehensive overview?” What exactly are autoantibodies? What do they do? How will autoantibody testing impact the future of T1D research and treatment?

What Are Autoantibodies?

Let’s start with antibodies. Antibodies are proteins, produced by the body’s immune system, that detect harmful substances, also called antigens, such as bacteria and viruses to protect the body. Once the antibody targets its antigen and attaches to it, other immune system cells attack and destroy the antigen. Each type of antibody is specific to the antigen it targets. Autoantibodies are antibodies that target one’s own healthy tissue. The immune system fails to distinguish between the body’s own tissues and external matter (Taplin et al., 2008).

AntibodyAntigen

In the case of type 1 diabetes, these autoantibodies attack different pancreatic cells and affect the pancreas’ normal function. There are currently five different autoantibodies that are commonly found in those who already have type 1 diabetes (see table below). 90% of people with diabetes have at least 2 of these autoantibodies. Researchers are still searching for new autoantibodies that are correlated with T1D (Gorus et al., 2013). This is because understanding the exact immune system mechanisms that cause the body to destroy its own insulin-producing cells may be crucial to curing or preventing the disease.

In an undiagnosed person, no particular autoantibody is more strongly associated with developing T1D than another; however, the number of autoantibodies is a strong predictor of developing the disease. That is, someone who tests positive for multiple autoantibodies is more likely to be diagnosed with T1D down the road (Taplin & Barker, 2008). New autoantibodies can develop at any time; therefore, if a young child tests negative, they may still develop autoantibodies later on.

The appearance of autoantibodies can pre-date development of T1D by years or even decades (Wenzlau et al., 2013). Testing for these molecules could lead to earlier diagnoses of T1D, and could help avoid episodes of DKA and subsequent hospital stays.

 

Type of autoantibody Abbrev. What does it “attack”/target? What percentage of people with T1D have these antibodies?
Islet Cell Autoantibodies ICA These autoantibodies target islet cells (include alpha, beta, delta, PP, and epsilon cells) Found in 80% of people at diagnosis
Insulin Autoantibodies IAA • These autoantibodies target insulin itself*

• Are usually the first autoantibodies detected in young children

• 50% of people at diagnosis

• Less common in those diagnosed after adolescence

Glutamic Acid Decarboxylase Autoantibodies GADA • Targets a form of glutamic acid decarboxylase, an enzyme that synthesizes an inhibitory neurotransmitter (GABA) in the brain*

• These autoantibodies are also seen in other autoimmune disease, such as myasthenia gravis

 

• 70% of all people with T1D

• More common in those diagnosed after adolescence**

Insulinoma-associated-protein-2 Autoantibodies IA-2A Targets a specific protein that is found in insulin-releasing cells** About 60% of people at diagnosis
Zinc-transporter 8 Autoantibodies ZnT8A • Targets zinc transporters found only in beta cells

• seems to appear later in the disease process**

• may also be related to other autoimmune diseases, such as thyroid disease^^

Found in up to 80% of people at diagnosis, but only 26% of people who test positive for other autoantibodies who later develop T1D^

*Pihoker et al., 2005
**Gorus et al., 2013
^Yang et al., 2010
^^Rogowicz-Frontczak et al., 2014

Who Can Be Tested for Islet Autoantibodies?

First-degree relatives of someone who currently has the disease are eligible for testing through TrialNet, a research program run by a global network of clinical research centers. These tests can help family members determine if they are at risk of developing the disease. Those who test positive for one or more autoantibodies participate in follow-up testing over time, including glucose tolerance tests and screening for additional autoantibodies. In some cases, counseling should also be considered to help that person cope with the possibility that they could develop T1D.

Autoantibody tests can also be ordered by a doctor who may suspect a patient diagnosed with type 2 diabetes actually has type 1 diabetes. For example, a patient diagnosed later in life but is not responding to oral type 2 diabetes medications may actually have early stage type 1 diabetes.

Is Autoantibody Testing Necessary/Useful?

So, people can get tested for autoantibodies; but does that mean that they should? Like many medical tests, this could be a deeply personal area with various implications. To further understand different perspectives on diagnostic tests, I turned to the Glu community. In a recent Question of the Day, the majority of respondents on Glu said, in the comment section, that being tested is a personal decision, and should be made only by the person who would be tested. However, parents may sometimes take control of this decision, especially if their child is very young. This can be an incredibly difficult decision. Testing positive for autoantibodies could be extremely distressing for many people; several commenters described feelings of “waiting for the other shoe to drop” after a test came back positive. Being on high alert for symptoms could prevent severe hyperglycemia and DKA, but it could also have a negative impact on one’s day-to-day life.

Glu Question of the Day, August 11, 2014

Glu Question of the Day, August 11, 2014

How Could Autoantibody Testing Be Used in the Future?

Currently, testing is only recommended for those who have immediate family members with T1D, or when a diagnosis of diabetes is unclear. However, because diabetes is not 100% hereditary—that is, we have not identified a specific gene that people with T1D pass to their offspring that causes the disease—many people without family history do develop it. Therefore, these people would not benefit from current autoantibody testing. Screening the entire population presents two problems. One, many people carry one autoantibody and never develop T1D, and this could cause them to unnecessarily worry. Two, screening everyone would be incredibly expensive and yield so few new diagnoses (remember, only .5% of the US population has T1D), with many “false negatives” (that is, people may be tested who have not yet developed autoantibodies, but will later in life). Using autoantibodies in the future in combination with other immune markers, genetic testing, and epidemiological statistics may have a bigger impact on early disease diagnosis in general. Additionally, identifying all autoantibodies that are involved in the complex immune functions that destroy insulin-producing cells and ultimately cause T1D may bring scientists closer to understanding how to prevent and cure the disease.

Have you or your family members been tested for autoantibodies? What was the experience like?

To learn more about TrialNet’s Pathway to Prevention program, please click here.

Danielle Gianferante–GluDanielle

References

Gorus, F. K., Balti, E. V., Vermeulen, I., Demeester, S., Van Dalem, A., Costa, O., … & Weets, I. (2013). Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost‐effective and age‐independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients. Clinical & Experimental Immunology171(1), 82-90.

Pihoker, C., Gilliam, L. K., Hampe, C. S., & Lernmark, Å. (2005). Autoantibodies in diabetes. Diabetes54(suppl 2), S52-S61.

Rogowicz-Frontczak, A., Zozulińska-Ziółkiewicz, D., Litwinowicz, M., Niedźwiecki, P., Wyka, K., & Wierusz-Wysocka, B. (2014). Are zinc transporter type 8 antibodies a marker of autoimmune thyroiditis in non-obese adults with new-onset diabetes? European Journal of Endocrinology170(4), 651-658.

Taplin, C. E., & Barker, J. M. (2008). Autoantibodies in type 1 diabetes.Autoimmunity41(1), 11-18.

Wenzlau, J. M., & Hutton, J. C. (2013). Novel diabetes autoantibodies and prediction of type 1 diabetes. Current Diabetes Reports13(5), 10.1007/s11892–013–0405–9.

Yang, L., Luo, S., Huang, G., Peng, J., Li, X., Yan, X., … & Zhou, Z. (2010). The diagnostic value of zinc transporter 8 autoantibody (ZnT8A) for type 1 diabetes in Chinese. Diabetes/metabolism research and reviews26(7), 579-584.

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