What labs should be ordered to differentiate between type 1 and type 2 diabetes?

Laboratory Tests to Differentiate Type 1 from Type 2 Diabetes

The most effective laboratory approach to differentiate between type 1 and type 2 diabetes is to measure islet autoantibodies, with glutamic acid decarboxylase (GAD) antibodies as the primary test, followed by additional autoantibody testing and C-peptide measurement when indicated. 1, 2

Primary Laboratory Tests

Autoantibody Testing

• First-line test: Glutamic acid decarboxylase (GAD) antibodies 2
• If GAD negative and type 1 diabetes still suspected: Test for:
  • Islet tyrosine phosphatase 2 (IA-2) antibodies
  • Zinc transporter 8 (ZnT8) antibodies
  • Insulin autoantibodies (IAA) - particularly useful in patients not yet treated with insulin 1, 2

C-peptide Testing

• Random C-peptide with concurrent glucose (within 5 hours of eating) 1
  • <200 pmol/L (<0.6 ng/mL): Consistent with type 1 diabetes
  • 200-600 pmol/L (0.6-1.8 ng/mL): Indeterminate (may be type 1 or MODY)

  • 600 pmol/L (>1.8 ng/mL): Consistent with type 2 diabetes

Interpretation Guidelines

Autoantibody Results

• Positive for one or more autoantibodies: Strongly suggests type 1 diabetes or Latent Autoimmune Diabetes in Adults (LADA) 2
• Multiple positive autoantibodies: Higher risk of progression to insulin dependence 1
• Negative autoantibodies: Does not completely rule out type 1 diabetes, as 5-10% of type 1 diabetes patients are autoantibody-negative 1

C-peptide Interpretation

• Important timing considerations:
  • Do not test C-peptide within 2 weeks of a hyperglycemic emergency
  • For insulin-treated patients, measure C-peptide prior to insulin discontinuation
  • If concurrent glucose is <4 mmol/L (<70 mg/dL) or patient may have been fasting, consider repeating the test 1

Clinical Context for Laboratory Interpretation

When interpreting laboratory results, consider these clinical factors that may influence the diagnosis:

• Age: Type 1 diabetes is more common in younger patients but can occur at any age 1
• Body habitus: BMI <25 kg/m² suggests type 1 diabetes, but obesity does not rule it out 2
• Presentation: Rapid onset, unintentional weight loss, and ketoacidosis favor type 1 diabetes 1
• Response to treatment: Inability to achieve glycemic goals on non-insulin therapies suggests type 1 diabetes 1

Common Pitfalls to Avoid

• Relying solely on clinical presentation: Up to 40% of adults with type 1 diabetes are initially misdiagnosed as having type 2 diabetes 1
• Assuming obesity rules out type 1 diabetes: Obesity is increasingly common in the general population and does not exclude type 1 diabetes 2
• Testing C-peptide too early: C-peptide levels may be falsely normal during the "honeymoon phase" of type 1 diabetes 1
• Overlooking LADA: Approximately 5-10% of adults with type 2 diabetes phenotype have autoantibodies and will eventually require insulin (LADA) 2, 3

Testing Algorithm

1. Initial presentation with diabetes:

   • Test for GAD antibodies in all adults with clinical features that overlap with type 1 diabetes
   • If GAD negative but type 1 diabetes still suspected, test for IA-2 and ZnT8 antibodies

2. If autoantibody testing is positive:

   • Diagnosis is type 1 diabetes or LADA
   • Consider early insulin therapy

3. If autoantibody testing is negative:

   • In patients <35 years old with no features of type 2 diabetes: Still consider type 1 diabetes
   • In patients ≥35 years old: Measure C-peptide after ≥3 years duration to assess insulin secretion capacity

4. C-peptide results:

   • <200 pmol/L: Type 1 diabetes
   • 200-600 pmol/L: Indeterminate (consider type 1 diabetes or MODY)

   • 600 pmol/L: Type 2 diabetes

By following this systematic approach to laboratory testing, clinicians can more accurately differentiate between type 1 and type 2 diabetes, leading to appropriate treatment decisions that will improve patient outcomes.