Autoantibody Testing for Type 1.5 Diabetes (LADA)
Start with glutamic acid decarboxylase (GAD) antibodies as your primary test, and if negative, proceed to IA-2 and ZnT8 antibodies to confirm or exclude LADA. 1, 2, 3
Primary Testing Algorithm
First-Line Test
- GAD antibodies should be measured first, as they are present in 70-80% of LADA cases and represent the most frequently positive marker 2, 4, 3
- GAD positivity alone has a positive predictive value of 92% for requiring insulin within 3 years in adults aged 15-34 years 1
Second-Line Tests (If GAD Negative)
- IA-2 (insulinoma-associated antigen-2) antibodies should be tested next, as they are detected in 50-60% of type 1 diabetes patients and indicate rapid progression risk 1, 2, 4
- ZnT8 (zinc transporter 8) antibodies should also be included where available, as they are found in approximately 50% of patients and serve as a surrogate marker of beta-cell destruction 1, 2, 4
Conditional Test
- Insulin autoantibodies (IAA) should only be measured if the patient has not yet started insulin therapy, as the test becomes invalid once exogenous insulin is administered 1, 2, 3
- IAA can improve LADA diagnosis rate by 2.39% when combined with GAD and IA-2 testing 5
Supporting Metabolic Tests
C-Peptide Measurement
- C-peptide testing is primarily indicated when the patient is already on insulin therapy to assess residual beta-cell function 1, 2, 3
- Obtain a random (non-fasting) sample within 5 hours of eating with concurrent glucose measurement 2
- Interpretation: <200 pmol/L (<0.6 ng/mL) indicates significant beta-cell loss consistent with type 1 diabetes; 200-600 pmol/L (0.6-1.8 ng/mL) is indeterminate and consistent with LADA in the appropriate clinical context; >600 pmol/L (>1.8 ng/mL) suggests type 2 diabetes with preserved beta-cell function 1, 2, 3
Critical pitfall: A low-normal C-peptide (e.g., 1.3 ng/mL) should not be used to exclude LADA—autoantibody testing must still be performed, as demonstrated in cases where patients with "normal" C-peptide had positive GAD antibodies >250 IU/mL 6
When to Order These Tests
Test for LADA when adults present with any of the following features 2, 3:
- Age <35 years at diagnosis with features that could be either type 1 or type 2 diabetes
- Unintentional weight loss despite diabetes diagnosis
- Lean body habitus (BMI <25 kg/m²) at presentation
- Ketoacidosis or ketosis in an obese patient
- Rapid progression to insulin dependence despite initial non-insulin therapy
- Personal or family history of autoimmune diseases
Risk Stratification Based on Results
Single Positive Autoantibody
Multiple Positive Autoantibodies
- Two or more positive autoantibodies indicate 70% risk of diabetes progression within 10 years, with 44% risk at 5 years 4, 3
- Multiple autoantibodies with dysglycemia carry 60% risk by 2 years and 75% risk within 5 years of requiring insulin 1, 3
- The combination frequency of three antibodies (GAD, IA-2, IAA) is 10.47%, which is higher than any single antibody testing 5
Important Caveats
Antibody-Negative Cases
- 5-10% of true autoimmune diabetes cases are antibody-negative, so negative antibodies in a lean, young adult with acute onset do not exclude LADA 1, 2, 3
- In patients diagnosed under 35 years with no clinical features of type 2 diabetes or monogenic diabetes, negative antibodies should not alter the presumptive diagnosis of type 1 diabetes 2
Tests NOT Recommended
- HLA typing (HLA-DR-DQ) is not recommended for routine clinical diagnosis or classification of LADA, as it can only increase or decrease probability but is not diagnostic 3
- Genetic risk scores and SNP typing have no value for diagnosis or management of LADA in clinical practice 3
Specificity Concerns
- In adults without clinical features of type 1 diabetes, a single positive antibody will likely represent a false-positive result due to imperfect test specificity in low-prevalence populations 7
- Islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes 7