Testing for Type 1 Diabetes—How Useful are these Tests?

Feb 1, 2000

There are three categories of tests which help doctors in screening for type 1 diabetes, according to Stephen E. Gitelman, MD, with the Division of Endocrinology and Pediatrics at UCSF, San Francisco:

  • Metabolic tests. These include the IV glucose tolerance test, in which a patient is intravenously given glucose. The result gives an indication of the degree (if any) of a patient's beta-cell destruction.
  • Autoimmune tests. These test for GAD (glutamic acid decarboxylase) antibodies, ICA (islet cell antibodies), IAA (insulin autoantibodies) and IA-2 (tyrosine phosphatase).
  • Genetic tests. HLA (human leucocyte antigens) genotyping.

How Autoimmune Tests Work

ICA. The autoimmune destruction of the pancreatic beta cells is detected by measuring levels of ICA in a person. A positive ICA test often shows up years before type 1 and is often one of the earliest predictors/indications of the disease. In first-degree relatives of those with diabetes, about 3.5% will test positive for ICA.

"If you take a tissue sample from a normal pancreas and put the patient's serum on it, you can see if the patient's antibodies are cross-reacting with the healthy beta cells from the tissue sample," explains Gitelman. "So in someone without diabetes and with no risk, there would be no reaction. It should be negative."

But if you take it from someone newly diagnosed with diabetes and test it, Gitelman continues, 60-80% will have a significant reaction. Relatives of people with diabetes may also have similar cross-reactions.

GAD. Other autoimmune tests for autoantibodies for GAD, IAA and IA-2 do not require a pancreatic tissue sample, only blood samples from the patients. GAD is an enzyme, a protein made by the beta cells, and is important for functions in the beta and many other cells. If the beta cells are attacked, antibodies are directed against the GAD enzymes.

IAA and IA-2. Some of these antibodies are present in as many as 80_90% of people before they develop diabetes.

Developments in Autoimmune Testing

"What has happened over the past 10-20 years is that we have tried to take whole serum and break it into specific autoantibodies to see which are cross-reacting with the beta cells.," says Gitelman. "As we learn more about antigens that the immune system reacts to, we're developing a whole panel of things that we can test for. The problem is you need to study a number of patients in various states to figure out how different these autoantibodies are."

Environmental Factor

Scientists have long known of an environmental link to type 1 diabetes. Common viruses, such as the Coxsackie which cause common upper respiratory tract infections, can sometimes trigger type 1. An autoimmune cascade is activated: because a part of the virus is similar to pancreatic beta cells, the immune system is duped into thinking that its own beta cells are foreign entities and will start to attack them.

Genetics and Ethnicity

People who have certain HLA markers may have more of a genetic predisposition towards type 1. International research has shown that northern Europeans with the HLA marker of DR3 or DR4 have a higher susceptibility to type 1, although the most susceptible HLA markers may be different from country to country. Certain populations, like the Chinese, seem more protected from type 1 diabetes because they do not carry these markers. In the US, type 1 rates are highest among northern Europeans. The disease afflicts African-Americans also, but to a lesser extent.

Genetic Testing: HLA Genotyping

HLA are any of a complex of genetically determined antigens occurring on the surface of almost every human cell by which one person's cells can be distinguished from others.

"HLA are immune system molecules on cell surfaces. They identify cells to the immune system, allowing it to tell 'self' from 'non-self'," explains Richard Furlanetto, MD, Scientific Director of Juvenile Diabetes Foundation (JDF). Depending on how the HLA system presents antigens to the T-lymphocytes, it may trigger an immune response.

So when you put in a different HLA type in a person-as in organ transplants such as kidney transplants-doctors look for a close HLA match between donor and recipient.

Tests Are Becoming Better Predictors

Many parents who have one type 1 child are often worried that their other children may also develop the disease. Parents should realize that even if their other children test positive for certain antibodies it just means they are at higher risk, not necessarily that they will get the disease.

"Results of the tests, too, may vary depending on the timing of the tests", says Gitelman. "Some levels may drop off over time."

GAD antibodies, however, often persist over time. Others, like the ICAA, may drop off over time, especially after the onset of the disease when it may wane.

"Enough studies have been done on large populations to allow us to predict with increasing certainty how an individual will progress over time," says Gitelman. We know that the more antibodies you have and the higher the levels, the greater your chance of developing diabetes."

Gitelman believes researchers are moving ever closer to improving the predictability of these tests. Large trials which use these tests, known collectively as the Diabetes Prevention Trial 1 (DPT-1), are underway. "These tests may eventually become very helpful. I recommend using them now in the context of established clinical trials," says Gitelman.

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