What is the typical diagnostic approach for Latent Autoimmune Diabetes in Adults (LADA) in an adult patient?

How Diabetes 1.5 (LADA) Gets Diagnosed

Latent Autoimmune Diabetes in Adults (LADA) is diagnosed by demonstrating the presence of islet autoantibodies—particularly GAD antibodies—in an adult who initially presents with apparent type 2 diabetes but has clinical features suggesting autoimmune etiology. 1, 2

Clinical Triggers for Testing

You should order autoantibody testing when adults present with diabetes and have any of these phenotypic features that overlap between type 1 and type 2 diabetes: 1, 2

• Age <35 years at diagnosis (though LADA can occur at any adult age) 2
• Unintentional weight loss despite diabetes diagnosis 1, 2
• Lean body habitus (BMI <25 kg/m²) 2
• Ketoacidosis or ketosis in an obese patient 1, 2
• Rapid progression to insulin requirement (within months to 1-2 years) 2
• Acute symptom onset rather than gradual 2
• Family history of autoimmune disease 2

A critical pitfall: Do not assume obesity excludes LADA—many LADA patients present with type 2 phenotype including overweight and insulin resistance, particularly in Western countries. 1, 3

Diagnostic Testing Algorithm

Step 1: Start with GAD Antibodies

Order glutamic acid decarboxylase (GAD) antibodies first, as this is the most frequently positive marker in LADA, present in 70-80% of cases. 2, 4 GAD positivity alone has a 92% positive predictive value for requiring insulin within 3 years in adults aged 15-34 years. 4

Step 2: If GAD is Negative, Test IA-2 and ZnT8

If GAD antibodies are negative but clinical suspicion remains high, proceed to: 1, 2, 4

• IA-2 (insulinoma-associated antigen-2) antibodies - detected in 50-60% of type 1 diabetes patients 4
• ZnT8 (zinc transporter 8) antibodies where available - found in approximately 50% of patients 4

Adding ZnT8 to GAD and IA-2 testing increases diagnostic sensitivity for LADA. 2

Step 3: Consider C-Peptide for Ambiguous Cases

C-peptide testing is primarily indicated when the patient is already on insulin therapy and you need to assess residual beta-cell function. 2, 4 However, it can also help in antibody-negative cases with low-normal values suggesting autoimmune etiology. 5

Obtain a random (non-fasting) sample within 5 hours of eating with concurrent glucose measurement. 2, 4 Interpretation: 2, 4

• <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): Indeterminate; consistent with LADA in appropriate clinical context
• >600 pmol/L (>1.8 ng/mL): Suggests type 2 diabetes with preserved beta-cell function

Important caveat: A technically "normal" C-peptide that is low-normal (e.g., 1.3 ng/mL in a range of 0.8-5.2 ng/mL) should prompt autoantibody testing, as this may represent early LADA with declining beta-cell function. 5

Interpreting Results

Multiple Positive Autoantibodies

Multiple positive autoantibodies indicate 70% risk of progression to insulin dependence within 10 years, with 44% risk at 5 years. 4 This provides the strongest diagnostic certainty for LADA. 2

Single Positive Autoantibody

A single positive autoantibody carries only 15% risk of progression within 10 years and may represent a false-positive result, particularly in patients without clinical features of autoimmune diabetes. 4, 6

Critical warning: In adults without clinical features of type 1 diabetes, a single positive antibody is likely to represent a false-positive result due to imperfect test specificity in low-prevalence populations. 6 This is why clinical context is paramount—do not order antibody testing in patients who lack phenotypic features suggesting autoimmune diabetes. 6

Antibody-Negative Cases

5-10% of true autoimmune diabetes cases are antibody-negative, so negative antibodies in a lean, young adult with acute onset and rapid progression do not exclude LADA. 2, 4 In such cases, treat based on clinical phenotype and monitor for progression. 2

Laboratory Quality Requirements

Ensure autoantibody testing is performed only in an accredited laboratory with established quality control programs and participation in proficiency testing programs. 2 Standardized islet autoantibody tests are specifically recommended for classification. 1

What NOT to Order

• HLA typing (HLA-DR-DQ) is not recommended for routine clinical diagnosis of LADA, as it can only increase or decrease probability but is not diagnostic 4
• Genetic risk scores and SNP typing have no value for diagnosis or management of LADA in clinical practice 4
• Insulin autoantibodies (IAA) should only be tested in patients not yet treated with insulin, as exogenous insulin renders this test unreliable 2

Confirming the Diagnosis

The diagnosis of LADA requires meeting all three criteria: 7

1. Adult age at onset of diabetes
2. Presence of circulating islet autoantibodies (distinguishes from type 2 diabetes)
3. Insulin independence at diagnosis (distinguishes from classic type 1 diabetes)

Once autoantibodies are confirmed positive in the appropriate clinical context, the diagnosis of LADA is established, and treatment should shift from typical type 2 diabetes management toward earlier insulin therapy to preserve remaining beta-cell function. 5, 3