Is there a lab test to distinguish between Type 1 (T1) Diabetes Mellitus (DM) and Type 2 (T2) Diabetes Mellitus (DM)?

Laboratory Tests for Distinguishing Between Type 1 and Type 2 Diabetes Mellitus

Islet autoantibody testing is the most valuable laboratory test for differentiating between Type 1 and Type 2 diabetes mellitus, particularly in cases where clinical presentation is ambiguous. 1

Primary Diagnostic Tests

Autoantibody Testing

• Testing for multiple autoantibodies provides the strongest differentiation between T1DM and T2DM 2, 1
• Specific autoantibodies to test include:
  • Glutamic acid decarboxylase (GAD) antibodies
  • Islet antigen 2 (IA-2) antibodies
  • Insulin autoantibodies (IAA)
  • Zinc transporter 8 (ZnT8) antibodies 2, 1
• Multiple positive autoantibodies strongly suggest T1DM or latent autoimmune diabetes in adults (LADA) 1
• Autoantibody testing should be performed in accredited laboratories with established quality control programs 1

C-peptide Testing

• C-peptide measurement assesses endogenous insulin production capacity 2
• Lower C-peptide levels typically indicate T1DM while higher levels suggest T2DM 2, 1
• For accurate results, measure fasting C-peptide when simultaneous fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L) 2
• C-peptide is particularly helpful in ambiguous cases, such as individuals with a type 2 phenotype who present with ketoacidosis 2

When to Use Laboratory Testing

• Laboratory testing is most valuable when clinical presentation is unclear 2
• Consider testing in these situations:
  • Adults with phenotypic risk factors that overlap with T1DM (younger age at diagnosis, unintentional weight loss, ketoacidosis, or rapid progression to insulin dependence) 2
  • Obese children/adolescents presenting with ketosis or ketoacidosis 2
  • Patients not responding as expected to initial therapy 2

Clinical Context and Limitations

• Autoantibodies may not be detectable in all T1DM patients and tend to decrease with age 1
• In adults with T2DM phenotype but positive autoantibodies (LADA), insulin dependency typically develops over several years 1
• The AABBCC clinical approach can complement laboratory testing:
  • Age (e.g., <35 years suggests T1DM)
  • Autoimmunity (personal/family history of autoimmune disease)
  • Body habitus (BMI <25 kg/m² suggests T1DM)
  • Background (family history of T1DM)
  • Control (inability to achieve glycemic goals on non-insulin therapies)
  • Comorbidities (e.g., immune checkpoint inhibitor treatment can cause T1DM) 2

Common Pitfalls and Caveats

• A diagnosis of T1DM does not preclude having features classically associated with T2DM (insulin resistance, obesity) 2
• Some patients may have features of both T1DM and T2DM, requiring treatment approaches for both conditions 2
• C-peptide measurement alone may not be clinically necessary in all cases, as response to therapy can provide useful diagnostic information 2
• Insulin or proinsulin testing is not recommended for routine clinical care and is primarily useful for research purposes 2

Algorithm for Laboratory Differentiation

1. Start with clinical assessment using AABBCC approach 2
2. If diagnosis remains unclear:
   • Order islet autoantibody panel (GAD, IA-2, IAA, ZnT8) 2, 1
   • Consider C-peptide measurement (fasting) 2
3. Interpret results:
   • Multiple positive autoantibodies → T1DM 2, 1
   • Negative autoantibodies with normal/high C-peptide → T2DM 2
   • Positive autoantibodies with normal/high C-peptide → Consider LADA 1