Autoantibodies for Type 1 Diabetes Detection
The four primary autoantibodies used to detect type 1 diabetes are GADA (glutamic acid decarboxylase antibodies), IA-2A (insulinoma-associated antigen 2 antibodies), ZnT8A (zinc transporter 8 antibodies), and IAA (insulin autoantibodies). 1
Core Autoantibody Panel
The standard autoantibody panel for type 1 diabetes detection includes:
- GADA (GAD65 antibodies): Antibodies against glutamic acid decarboxylase, one of the most commonly detected markers 1
- IA-2A: Antibodies against insulinoma-associated antigen 2 (also called protein phosphatase-like IA-2), a tyrosine phosphatase 1
- ZnT8A: Antibodies against zinc transporter 8, which exists in three variants and is present in approximately 58-80% of new-onset type 1 diabetes patients 2, 3
- IAA: Antibodies against native insulin (not insulin used for treatment) 1
Clinical Testing Strategy
For adults with uncertain diabetes classification, start with standardized islet autoantibody testing in an accredited laboratory with established quality control programs. 1
When to Test
Test for autoantibodies in adults when there is phenotypic overlap between type 1 and type 2 diabetes, specifically when patients present with: 1
- Younger age at diagnosis
- Unintentional weight loss
- Ketoacidosis
- Short time to insulin treatment requirement
Autoantibody testing is NOT recommended for routine diabetes diagnosis but rather for classification when the diabetes type is uncertain. 1
Risk Stratification Based on Autoantibody Number
The number of positive autoantibodies directly predicts diabetes risk: 1
- Single autoantibody: 15% risk of developing type 1 diabetes within 10 years
- Two or more autoantibodies: 70% risk of developing type 1 diabetes within 10 years
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
Screening Recommendations
Screening for islet autoantibodies should be offered to first-degree relatives of individuals with type 1 diabetes or those with known elevated genetic risk, preferably in research settings. 1
The rationale: 1
- First-degree relatives have approximately 5% risk of developing type 1 diabetes (15-fold higher than general population)
- General population screening is not recommended due to low prevalence (1-2% of healthy individuals may have a single autoantibody with low diabetes risk)
Analytical Considerations and Quality Control
All autoantibody testing must be performed in accredited laboratories with established quality control programs and participation in proficiency testing programs. 1
Recommended Testing Methods
- GADA, IA-2A, and ZnT8A: Standardized radiobinding assays using coupled in vitro transcription translation or commercially available ELISA/chemiluminescence assays 1
- IAA: Radioisotopic method calculating displaceable insulin radioligand binding after addition of excess nonradiolabeled insulin 1
Critical Caveat for IAA Testing
IAA testing is only valid before insulin therapy begins, as insulin antibodies develop following any insulin treatment, even with human insulin. 1 This makes IAA unreliable for classification once treatment has started.
Practical Testing Algorithm
For cost-effectiveness and efficiency, particularly in first-degree relatives: 4
Screen for IA-2A and ZnT8A first - This identifies 78% of rapid progressors (those who will develop diabetes within 5 years) and is more cost-effective than testing all four antibodies 4
If IA-2A and/or ZnT8A are positive: High risk for rapid progression regardless of age 4
If both negative but clinical suspicion remains: Add GADA and IAA testing 1
If multiple antibodies detected: Perform oral glucose tolerance test to stage disease (Stage 1: normoglycemia, Stage 2: dysglycemia, Stage 3: overt diabetes) 1
Sensitivity of Combined Testing
Testing for all four autoantibodies (GADA, IA-2A, ZnT8A, IAA) detects autoimmunity in approximately 94% of patients with clinically diagnosed type 1 diabetes at disease onset. 2
Adding ZnT8A to the traditional three-antibody panel (GADA, IA-2A, IAA): 3
- Increases detection of patients with ≥2 antibodies from 78% to 87% in those under age 15
- Increases detection from 51% to 63% in those aged 15-39 years
- Identifies 13.5% of patients who are negative for GADA and IA-2A 3, 5
Age-Related Considerations
IA-2A and ZnT8A positivity predicts rapid progression to diabetes independent of age, while GADA and IAA alone show decreased progression rates with increasing age. 4
ZnT8A and IA-2A prevalence is higher in younger patients and those with lower BMI, making them particularly useful markers in pediatric populations. 3, 5