What are the primary antibodies associated with type 1 diabetes?

Primary Antibodies Associated with Type 1 Diabetes

The five primary antibodies associated with type 1 diabetes are: insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADA/GAD65), islet antigen-2 antibodies (IA-2A and IA-2β), zinc transporter 8 antibodies (ZnT8A), and islet cell antibodies (ICA). 1

Core Autoantibody Panel

The American Diabetes Association recommends standardized testing for four specific autoantibodies when classifying diabetes in adults with phenotypic overlap between type 1 and type 2 diabetes 1:

• GADA (Glutamic Acid Decarboxylase Antibodies): Present in 70-80% of newly diagnosed type 1 diabetes patients and should be tested first as the primary marker 2, 3
• IA-2A (Islet Antigen-2 Antibodies): Detected in 50-60% of type 1 diabetes patients and indicates rapid progression risk 2, 3
• ZnT8A (Zinc Transporter 8 Antibodies): Found in approximately 50% of patients and serves as a surrogate marker of β-cell destruction 3, 4
• IAA (Insulin Autoantibodies): Present in 30-40% of type 1 diabetes patients, particularly in children, but only valid before insulin therapy begins 2, 3

Additional Historical Marker

• ICA (Islet Cell Antibodies): Detected by indirect immunofluorescence on frozen pancreas sections, this test has been largely replaced by the quantitative assays listed above 1

Clinical Testing Strategy

Standardized islet autoantibody testing should be performed in accredited laboratories with established quality control programs when there is diagnostic uncertainty 1. Testing is specifically recommended when patients present with:

• Younger age at diagnosis 1
• Unintentional weight loss 1
• Ketoacidosis 1
• Short time to insulin treatment requirement 1

Risk Stratification Based on Antibody Number

The number of positive autoantibodies directly correlates with diabetes risk and progression:

• Single persistent autoantibody: 15% risk of diabetes within 10 years 3
• Two or more autoantibodies (Stage 1): 44% risk at 5 years with normoglycemia 1, 3
• Multiple autoantibodies with dysglycemia (Stage 2): 60% risk by 2 years and 75% risk within 5 years 1, 3

Having multiple confirmed islet autoantibodies warrants referral to a specialized center for evaluation and consideration of clinical trials or approved therapies like teplizumab to delay disease progression 1, 2.

Testing Algorithm

The recommended sequential approach is 2, 3:

1. Start with GADA as the first-line test (most common marker)
2. Add IA-2A and ZnT8A if GADA is negative or to assess progression risk
3. Consider IAA testing only before insulin therapy begins, as insulin treatment induces insulin antibodies that confound results 1, 2

Important Caveats

• IAA testing loses validity after insulin initiation: Even human insulin therapy induces antibodies that cannot be distinguished from autoimmune IAA 1, 2
• IA-2A and ZnT8A indicate aggressive disease: Positivity for these antibodies suggests high risk for rapid progression regardless of age 2, 4
• GADA can occur in non-diabetic autoimmune conditions: GADA positivity alone may not necessarily reflect insulitis and can be seen in other autoimmune diseases 4
• Autoantibodies may become absent in Stage 3: By the time overt diabetes develops, some patients may no longer test positive for autoantibodies 1

Screening Recommendations

Screening for islet autoantibodies is recommended in 1:

• First-degree relatives of individuals with type 1 diabetes (who have approximately 5% lifetime risk, which is 15-fold higher than the general population) 1, 2
• Individuals with known elevated genetic risk based on HLA typing 1

However, 1-2% of healthy individuals may have a single autoantibody and remain at low risk of developing diabetes 1.