What tests differentiate between type 1 (T1D) and type 2 (T2D) diabetes?

Tests to Differentiate Type 1 vs Type 2 Diabetes

C-peptide measurement is the most valuable laboratory test to differentiate between type 1 and type 2 diabetes in ambiguous cases, particularly in individuals who have a type 2 phenotype but present with ketoacidosis. 1

Primary Diagnostic Tests

C-peptide Testing

• When to use: In ambiguous cases where clinical presentation doesn't clearly indicate type 1 or type 2 diabetes
• Interpretation:
  • Low C-peptide (<200 pmol/L or <0.6 ng/mL): Suggests type 1 diabetes
  • Intermediate C-peptide (200-600 pmol/L or 0.6-1.8 ng/mL): Indeterminate
  • High C-peptide (>600 pmol/L or >1.8 ng/mL): Suggests type 2 diabetes 1
• Testing conditions: Measure fasting C-peptide when simultaneous fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L) 1
• Timing considerations: Do not test C-peptide within 2 weeks of a hyperglycemic emergency 1

Islet Autoantibody Testing

• Primary antibodies to test:
  • Glutamic acid decarboxylase (GAD) antibodies (first-line)
  • If GAD negative, test for islet tyrosine phosphatase 2 (IA-2) and/or zinc transporter 8 (ZnT8) antibodies 1
  • In patients not yet treated with insulin, insulin autoantibodies may also be useful
• Interpretation:
  • Positive autoantibodies: Strongly suggests type 1 diabetes
  • Negative autoantibodies: Does not rule out type 1 diabetes (5-10% of type 1 patients are antibody-negative) 1

Diagnostic Algorithm

1. Start with clinical assessment:

   • Age at diagnosis (<35 years suggests type 1)
   • Body habitus (normal/low BMI suggests type 1)
   • Presence of DKA at diagnosis (suggests type 1)
   • Severity of symptoms (rapid onset suggests type 1)

2. Test for islet autoantibodies (GAD, IA-2, ZnT8)

   • If positive → Type 1 diabetes
   • If negative → Proceed to step 3

3. Assess age:

   • If <35 years: Evaluate for features of monogenic diabetes
     • If features present → Test C-peptide
     • If no features → Likely type 1 diabetes (despite negative antibodies)
   • If >35 years: Proceed to step 4

4. Evaluate clinical features of type 2 diabetes:

   • If present → Likely type 2 diabetes
   • If absent → Measure C-peptide (after >3 years duration)
     • <200 pmol/L → Type 1 diabetes
     • 200-600 pmol/L → Indeterminate (likely type 1)

     • 600 pmol/L → Type 2 diabetes 1

Important Considerations

• C-peptide limitations: Measurement is only indicated in patients receiving insulin treatment 1
• Random C-peptide: A random sample (with concurrent glucose) within 5 hours of eating can replace a formal C-peptide stimulation test for classification purposes 1
• Antibody testing caveats: 5-10% of people with type 1 diabetes do not have detectable autoantibodies 1
• Misdiagnosis risk: Classification is not always straightforward at presentation, and misdiagnosis is common 1
• Latent Autoimmune Diabetes in Adults (LADA): Consider in adults with slow progression, positive autoantibodies but initial presentation similar to type 2 diabetes 2

When Standard Tests Are Inconclusive

• Response to drug therapy can provide useful information when laboratory tests are inconclusive 1
• Consider the possibility of monogenic diabetes (MODY) in patients with atypical features, especially with strong family history and mild hyperglycemia 1
• In patients with features of both type 1 and type 2 diabetes, classification should be based on the predominant clinical picture and treatment needs 3

Remember that proper differentiation between diabetes types is crucial for determining appropriate therapy and management strategies, ultimately affecting morbidity, mortality, and quality of life outcomes.