ISLET CELL AUTOIMMUNITY
Considerable research over the past few decades has identified circulating autoantibodies directed against a variety of pancreatic islet cell antigens (ICA) in patients with type 1 diabetes and their first-degree relatives.
The autoimmune destruction of the insulin-producing pancreatic beta cells generally occurs over a period of time leading to the eventual onset of overt diabetes mellitus. During this extended pre-clinical phase, the characteristic circulation of antibodies against a variety of islet cell antigens including glutamic acid decarboxylase (GAD65), ZnT8 (a member of the large cation efflux family), IA-2 (a tyrosine phosphatase-like protein), and insulin provides early indicators of autoimmune disease activity.
Glutamic Acid Decarboxylase (GAD65) Antibodies
First detected in the serum of patients suffering from the rare neurological disorder, Stiff-Man Syndrome, antibodies to the islet cell antigen glutamic acid decarboxylase (GAD) have been found in 70-90% of prediabetic and Type 1 diabetic patients (including approximately 7-10% of adult onset diabetics with Type 1 diabetes), and have been shown to be the most sensitive single marker for identifying persons at risk of developing diabetes. Antibodies to GAD65 are generally more prevalent in older children and late-onset Type 1 diabetics, and in some patients, have been detected as many as ten years prior to the onset of clinical disease.
Zinc-Transporter Antibody (ZnT8Ab) ELISA
The most recent major islet autoantigen described is the cation efflux transporter Zinc Transporter 8 (ZnT8). Autoantibodies to ZnT8 (ZnT8Ab) have been detected in approximately 60-80% of patients at type 1 diabetes onset and are more prevalent in children than in adults. Autoantibodies to ZnT8 have been found in type 1 diabetes patients previously classified as autoantibody-negative, and when ZnT8Ab measurement is combined with the measurement of GADAb, IA-2Ab and IAA, the rate of detection of autoimmunity at diagnosis may increase.
The tyrosine phosphatase-like protein known as IA-2 is an important target of autoantibodies associated with the development of IDDM. Measurement of these immunologic markers has been shown to be of considerable value in assisting the attending clinician with the diagnosis of patients with diabetes. Antibodies to IA-2 are found in approximately 50-75% of Type 1 diabetes patients at and prior to disease onset, are generally more prevalent in younger onset patients and are usually associated with rapid progression to overt disease.
The presence of autoantibodies to insulin, the only beta-cell specific autoantigen thus far identified, is evidence of ongoing destruction of islet cells. Autoantibodies to insulin (IAA) are found predominantly, though not exclusively, in young children (<5 years) developing Type 1 diabetes. In insulin-naive (untreated) patients, the prevalence of autoantibodies to insulin is almost 100% in very young individuals and almost absent in patients with adult onset of Type 1 diabetes. (It should be noted that insulin autoantibodies are indistinguishable from insulin antibodies that commonly develop with insulin therapy).