Autoantibody Testing for T1D

The Really Short Version
If you have been diagnosed with diabetes (fasting blood sugar greater than 125 mg/dl) and suspect you may have Type 1 diabetes/LADA, testing for glutamic acid decarboxylase autoantibodies (GAD), islet cell cytoplasmic autoantibodies (ICA), insulinoma-associated 2 autoantibodies (IA-2), and zinc transporter 8 autoantibodies (ZnT8) is warranted. It is important to get the full suite of autoantibody tests, not just GAD[1].  If a single islet autoantibody or multiple islet autoantibodies are detected, the diagnosis of Type 1 autoimmune diabetes is confirmed[2]. The c-peptide test is also useful for showing how much endogenous insulin your body is producing. The appropriate medical treatment for a person who has autoimmune diabetes is exogenous insulin.

From the Medical Laboratory Observer, “When the clinician cannot clearly differentiate Type 1 diabetes from Type 2 diabetes based upon clinical features, islet autoantibody testing is warranted because the correct diagnosis affects the selection of therapy, the patient’s prognosis, and the need for testing for associated autoimmune diseases” [i.e., autoimmune hypothyroidism (Hashimoto’s Disease) and celiac disease].  The American Association of Clinical Endocrinologists, in AACE's Clinical Practice Guidelines for Diabetes Mellitus, now recommends that Type 1 diabetes be confirmed by the presence of autoantibodies (GAD, IA-2, IAA, and ZnT8).

The Longer Version for Science Geeks and Information Junkies

Type 1 diabetes results from a deficiency of insulin caused by autoimmune destruction of the pancreatic beta cells.  Autoantibodies are important markers of islet autoimmunity, however, the actual destruction of the beta cells results from a cell-mediated autoimmune response.

In a study published in 1974, researchers first identified pancreatic islet cell autoantibodies (ICAs) in Type 1 diabetic patients who had multi-endocrine deficiencies associated with organ-specific autoimmunity; this study established Type 1 diabetes as an autoimmune disease. Although it is widely believed that Type 1 diabetes is a childhood disease, that is a myth not backed by science, and in fact the majority of new-onset Type 1 diabetes is seen in adults[3]. Onset in adults may be rapid or slow, with the slow onset called latent autoimmune diabetes in adults or LADA.  Adults with slowly progressive Type 1 diabetes are frequently misdiagnosed as having Type 2 diabetes, an altogether different disease, which can result in serious health consequences, including rapid onset of diabetic complications and potentially death. In multiple scientific studies documented worldwide over more than three decades (with the first study published in 1977[4]), about 10% or more of people diagnosed with “Type 2” diabetes are autoantibody positive, have been misdiagnosed, and in fact have Type 1 autoimmune diabetes (those 10% typically have a lower BMI than the true Type 2s). In the U.S. alone, that represents millions of people who have been misdiagnosed; simply because a medical doctor says a person has Type 2 diabetes does not mean the person truly has Type 2 diabetes. I believe it is important to get a correct diagnosis for the disease you have, which increases the likelihood that you will get the best and most appropriate medical treatment. Autoantibody testing can be very important especially for the person with adult-onset Type 1 diabetes: the treatment for Type 1 diabetes is exogenous insulin, and if you have Type 1 diabetes but are misdiagnosed by a doctor and given the standard initial treatment for Type 2 diabetes (not exogenous insulin), you risk hastening beta cell destruction, hastening the onset of diabetic complications, and risk death from diabetic ketoacidosis. Autoantibody testing is not an exact or perfect science, but autoantibody testing can be extremely useful.

The presence of autoantibodies can be used to distinguish between autoimmune diabetes (Type 1a diabetes) and non-autoimmune diabetes (Type 2 diabetes and monogenic diabetes (aka MODY)); the American Association of Clinical Endocrinologists (AACE) now recommends testing for autoantibodies for diagnosing Type 1 diabetes[5].  Autoantibodies are not present in Type 2 diabetes; if autoantibodies are present, the person has Type 1a diabetes (according to the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, “Although the specific etiologies of [Type 2] diabetes are not known, autoimmune destruction of beta cells does not occur.”) The full suite of autoantibodies include GAD, ICA, IA-2, IAA, and ZnT8, and those antibodies are detected in 94% of new-onset cases of Type 1 diabetes (IAA can only be tested if exogenous insulin has not yet been used, and ZnT8 is a relatively new test that may not be widely available[6]).  Your doctor can order the autoantibody tests, and in some U.S. states a patient can order the tests (ARUP Laboratories (www.aruplab.com) in Utah performs the full suite of autoantibody tests including ZnT8). The correct treatment for Type 1a diabetes, at whatever age it is diagnosed, is exogenous insulin (preferably intensive insulin therapy) initiated as early as possible, to control glucose levels, prevent further destruction of residual beta cells, reduce the possibility of diabetic complications, and prevent death from diabetic ketoacidosis (DKA)[7]. A person who is autoantibody positive should not be treated as if he/she has Type 2 diabetes. In the Diabetes Control and Complications Trial (DCCT), all subjects with adult-onset Type 1 diabetes had some residual beta cell function (Bernard Zinman MD, DCCT). Those adults who were assigned to the intensive insulin therapy group were slower to lose residual beta cell function than the conventional therapy group (risk reduction 57%).

Although a small percentage of people without diabetes will test positive for one or more autoantibodies, no long-term studies have been performed to show that those people do not later develop Type 1 diabetes. In fact, the Type 1 Diabetes TrialNet Study (www.diabetestrialnet.org) has recruited relatives of people with Type 1 diabetes, performed autoantibody testing on those individuals, and is able to use positive autoantibody results in non-diabetic relatives to predict the risk that those individuals will develop Type 1 diabetes in the future. Finally, I advocate autoantibody testing on people already diagnosed with diabetes (fasting blood sugar greater than 125 mg/dl or A1c of 6.5 or greater) not non-diabetics; in those people diagnosed with diabetes, a positive autoantibody test indicates the person has Type 1 autoimmune diabetes.

Additional Information and Resources

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus provides the following information; I have bolded some information that is particularly pertinent to those with adult-onset autoimmune diabetes:

• In [Type 1] diabetes, the rate of beta cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual beta cell function sufficient to prevent ketoacidosis for many years; such individuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide.
• Autoimmune destruction of beta cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Although patients are rarely obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis. These patients are also prone to other autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. [End of Expert Committee information.]

Finally, detailed information about each of the autoantibody tests is included in “Type 1 Diabetes Autoantibodies: Prediction and Diagnosis of Autoimmune Diabetes” (Clinical Laboratory News, October 2010, Volume 36, Number 10).  "The Clinical Application of Islet Autoantibody Testing for the Diagnosis of Autoimmune Diabetes" (William E. Winter and David Pittman, 18 October 2013, Medical Laboratory Observer) also provides excellent information on autoantibody testing.

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[1] I recommend that people get the full suite of autoantibody tests because if just GADA is tested, about 10% of adults with Type 1 autoimmune diabetes will not be detected and remain misdiagnosed. For example, a recent ActionLADA (www.actionlada.org) study found that of 598 autoantibody positive adult subjects, 90.5% were GADA positive, with a small percentage (9.5%) only positive for IA-2A and/or ZnT8A (zinc transporter). And of those 598 autoantibody positive adults, 24.1% had two or more autoantibodies present. “Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype” (DIABETES CARE, VOLUME 36, APRIL 2013).

[2] Winter and Pittman, Medical Laboratory Observer, 18 October 2013. The Clinical Application of Islet Autoantibody Testing for the Diagnosis of Autoimmune Diabetes.

[3] It has been documented for about 80 years that new-onset Type 1 diabetes is more commonly seen in adults, not children. In 1934, Dr. Elliot Joslin noted that the incidence of diabetes in lean individuals was relatively constant in each decade of life, but that diabetes in the obese was related to older age. A book published in 1958 (“How to Live With Diabetes” by Henry Dolger, M.D. and Bernard Seeman) states that “[Type 1] diabetes is almost three times more frequent among young adults than among youngsters.” Today, with autoantibody testing, the same statement is proven true. A 2008 book, “Type 1 Diabetes in Adults: Principles and Practice” (Informa Healthcare, 2008) says that adult-onset autoimmune diabetes is two to three times more common than classic childhood onset autoimmune diabetes (p. 27). The authors of “Should There be Concern About Autoimmune Diabetes in Adults? Current Evidence and Controversies” (Curr Diab Rep (2016) 16:82) state that the most common form of autoimmune diabetes is adult-onset Type 1 diabetes ( including both rapid onset and LADA).  A recent Medscape article (Miriam E. Tucker, 20 September 2016, “Half of All Type 1 Diabetes Develops after 30 Years of Age”) that used genetic data found that half of all Type 1 diabetes develops after 30 years of age (note that the researchers did not include subjects over the age of 60, so more than half of Type 1 diabetes develops after age 30).

[4] Irvine WJ, Gray RS, McCallum CJ, Duncan LJP: Clinical and pathogenic significance of pancreatic-islet-cell antibodies in diabetics treated with oral hypoglycaemic agents. Lancet1 :1025–1027,1977.

[5] American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan.  ENDOCRINE PRACTICE Vol 21 No. 4 April 2015.

[6] “Zinc Transporter 8 Antibodies Complement GAD and IA-2 Antibodies in the Identification and Characterization of Adult-Onset Autoimmune Diabetes” (DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010).

[7] There is sometimes debate about the timing and importance of initiation of insulin therapy in people with adult-onset autoimmune diabetes. LADA is defined as not requiring insulin for 6 months, but this is based on physicians’ clinical judgment not disease process and seems specious as Frederick Allen, before the discovery and first use of insulin on a patient with diabetes in 1922, kept Type 1 diabetics (many of them children) alive often for five years or more on a starvation (low carb) diet. Some scientists state that early insulin use has no advantages; yet patients with Type 1 report great relief in getting a correct diagnosis and insulin therapy because they feel so much better. Several published studies have shown that the misdiagnosed (Type 1s misdiagnosed as having Type 2 and not treated with insulin) have a much more rapid onset of diabetic complications. The authors of The Type 1 Diabetes Sourcebook (ADA/JDRF 2013) state, “starting insulin is the mainstay of therapy” for adults who present acutely with Type 1 diabetes as well as those presenting more indolently.  Regarding adult-onset Type 1 diabetes, The Type 1 Diabetes Sourcebook also says, “for those with early T1D, expert opinion recommends either low doses of basal insulin to prevent DKA or prandial insulin to prevent postprandial hyperglycemia.” I would say if you have rapid onset Type 1 diabetes, you should initiate intensive insulin therapy as soon as possible. If you have slow-onset Type 1 diabetes, it is possible that exercise and a low carb diet can keep you in control for some time. Just be sure that you are not avoiding insulin therapy due to fear.