Islet Cell Antibodies
Type 1 diabetes mellitus (T1D) is an autoimmune disease that results from the cell-mediated destruction of islet beta cells. Approximately 12,000 to 15,000 children and adults annually develop T1D. The most recent Standards of Medical Care in Diabetes, supports testing for islet cell autoantibodies to facilitate the early diagnosis of T1D. Early diagnosis can reduce the rate of diabetic ketoacidosis and its associated morbidity and mortality.
The onset of T1D is preceded by the synthesis of autoantibodies to insulin and islet cell antigens. Detection of one or more islet cell autoantibodies is a strong predictor for progression to type I diabetes. The five-year cumulative risk for developing diabetes has been estimated to be 17% if seropositive for 1 antibody, 39% if seropositive for 2 antibodies, and 70% if seropositive for 3 antibodies. These autoantibodies can often be detected by age 3.
Some adults have slowly progressive T1D that has been classified as latent autoimmune diabetes of adulthood (Type 1.5 diabetes). They may be initially diagnosed as having type 2 diabetes (T2D) because of their adult onset of disease and their initial insulin independence. Testing for islet cell autoantibodies is helpful in distinguishing T1D from T2D in these patients.
Presently, four autoantibodies to islet cell antigens have been discovered: insulin, insulinoma associated 2 antigen, glutamic acid decarboxylase 65 (GAD65) and Zinc cation efflux transporter 8 (ZnT8). Individual sensitivities of these autoantibodies for diagnosis of type 1diabetes are 91% for GAD65 antibody, 74% for IA-2 antibody, and 49% for insulin antibody. Together, the combined sensitivity increases to 96%, with a specificity of 98%.
The American Diabetes Association (ADA), the Juvenile Diabetes Research Foundation, and the Endocrine Society published a joint statement in 2015 that describes the distinct role that islet autoantibodies play in each stage of T1D. Stage 1 is characterized as testing positive for multiple islet cell autoantibodies but remaining euglycemic. Stage 2 occurs when a person with multiple autoantibodies begins to become dysglycemic but remains asymptomatic. Once a person develops the classic symptoms of diabetes, they are in stage 3.
Detection of insulin antibodies in a patient who has never been treated with insulin is consistent with predisposition to T1D. Detection of insulin antibodies is not as informative in patients who have already received insulin therapy because antibody can arise secondary to treatment. Reference range is 0- 0.02 nmol/L.
IA-2 is a tyrosine phosphatase in neuroendocrine tissues. Autoantibodies to IA-2 usually appear later than autoantibodies to insulin and GAD, and are highly associated with expression of multiple anti-islet autoantibodies and progression to diabetes. Reference range for IA2 autoantibody is 0 - 0.02 nmol/L.
Glutamic acid decarboxylase (GAD) is an enzyme involved in the synthesis of the neurotransmitter, gamma-aminobutyric acid (GABA). GAD65 antibody is the most frequently detected pancreatic islet antibody. and is useful to assess predisposition to T1D and distinguish between patients with T1D and T2D.GAD65 autoantibody also serves as a marker of predisposition to other autoimmune disease that occur with T1D such as Graves' disease, Hashimoto's thyroiditis, hypothyroidism, pernicious anemia, premature ovarian failure, Addison's disease and vitiligo. Reference range is 0- =0.02 nmol/L.
GAD65 antibodies are not specific for T1D and may be present in patients with a variety of autoimmune neurologic disorders including stiff-man syndrome, neuromyelitis optica, myasthenia gravis, Lambert-Eaton syndrome and dysautonomia.
ZnT8 has also been identified as a type 1 diabetes autoantigen. Sixty to 80 percent of patients with newly diagnosed T1D have ZnT8 autoantibodies. In addition, 26 percent of subjects with antibody negative (insulin, GAD, IA-2 and ICA) type 1 diabetes have ZnT8 autoantibodies. In children followed from birth to the development of diabetes, ZnT8 autoantibodies appear later than insulin autoantibodies. ZnT8 autoantibody is typically lost very early after the onset of diabetes. This test is not widely available for clinical use.
Nearly 90% of people diagnosed with T1D do not have a family member with T1D and do not recognize the disease’s symptoms until they become ill. For this reason, ADA’s Standards of Medical Care in Diabetes now recommend that relatives of individuals with T1D have yearly monitoring for islet cell autoantibodies through a clinical research trial such as TrialNet,. Individuals who test positive are eligible for clinical research trials aimed at preventing the onset of T1D.
References
American Diabetes A. (2) classification and diagnosis of diabetes. Diabetes Care 2015;38 Suppl:S8–S16.
Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: A scientific statement of jdrf, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015;38:1964–74
Nambam B, Aggarwal S, Jain A. Latent autoimmune diabetes in adults: A distinct but heterogeneous clinical entity. World J Diabetes. 2010 Sep 15;1(4):111-5).
Schlosser M, Mueller PW, Torn C, et al. Participating L. Diabetes antibody standardization program: Evaluation of assays for insulin autoantibodies. Diabetologia 2010;53:2611–20.
