What blood tests are required to differentiate between type 1 (T1DM) and type 2 (T2DM) diabetes mellitus?

Blood Testing to Differentiate Type 1 from Type 2 Diabetes Mellitus

Test for multiple islet autoantibodies (GAD, IA-2, insulin, and ZnT8) as the primary laboratory method to distinguish between type 1 and type 2 diabetes, supplemented by C-peptide measurement when autoantibody results are inconclusive. 1

Primary Diagnostic Approach: Autoantibody Testing

The American Diabetes Association recommends standardized islet autoantibody testing as the most valuable laboratory test for differentiating between T1DM and T2DM, particularly when clinical presentation is ambiguous. 2, 1 The specific autoantibodies to test include:

• Glutamic acid decarboxylase (GAD) antibodies 2
• Islet antigen 2 (IA-2/IA-2β) antibodies 2
• Insulin autoantibodies (IAA) 2
• Zinc transporter 8 (ZnT8) antibodies 2, 1

Multiple positive autoantibodies strongly indicate T1DM or latent autoimmune diabetes in adults (LADA), while their absence suggests T2DM. 2, 1 Testing for multiple autoantibodies provides the strongest differentiation between T1DM and T2DM. 1

Secondary Test: C-Peptide Measurement

C-peptide measurement assesses endogenous insulin production capacity, with lower levels typically indicating T1DM and higher levels suggesting T2DM. 2, 1 For accurate results, measure fasting C-peptide when simultaneous fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L). 1

C-peptide testing is particularly useful when:

• Autoantibody results are negative but clinical suspicion for T1DM remains 1
• Determining residual beta-cell function in established diabetes 2
• Evaluating continued need for insulin therapy 2

Clinical Algorithm for Testing

When clinical presentation is unclear, proceed with antibody testing first; if multiple autoantibodies are positive, this strongly suggests T1DM or LADA. 1 The American Diabetes Association suggests considering autoantibody testing in adults with phenotypic risk factors that overlap with T1DM, such as:

• Younger age at diagnosis 2, 1
• Unintentional weight loss 2, 1
• Ketoacidosis at presentation 2, 1
• Short time to insulin treatment 2
• Rapid progression to insulin dependence 1

For obese children and adolescents presenting with ketosis or ketoacidosis, autoantibody testing should be considered despite the atypical presentation. 1

Complementary Clinical Assessment: The AABBCC Approach

The American Diabetes Association recommends using the AABBCC clinical approach to complement laboratory testing: 2, 1

• Age: For individuals <35 years old, consider type 1 diabetes 2
• Autoimmunity: Personal or family history of autoimmune disease or polyglandular autoimmune syndromes 2
• Body habitus: BMI <25 kg/m² suggests T1DM 2
• Background: Family history of type 1 diabetes 2
• Control: Inability to achieve glycemic goals on noninsulin therapies 2
• Comorbidities: Treatment with immune checkpoint inhibitors for cancer can cause acute autoimmune type 1 diabetes 2

Important Caveats and Pitfalls

Autoantibody testing should only be performed in accredited laboratories with established quality control programs to ensure accuracy. 1 Autoantibodies may not be detectable in all T1DM patients and tend to decrease with age. 2, 1

A diagnosis of T1DM does not preclude having features classically associated with T2DM, such as insulin resistance, obesity, and other metabolic abnormalities. 2, 1 Some patients may have features of both T1DM and T2DM, requiring treatment approaches for both conditions. 1

In adults with T2DM phenotype but positive autoantibodies (LADA), insulin dependency typically develops over several years rather than immediately. 2, 1

Insulin or proinsulin testing is not recommended for routine clinical care and is primarily useful for research purposes only. 1 C-peptide measurement alone may not be clinically necessary in all cases, as response to therapy can provide useful diagnostic information. 1

Tests NOT Required for Differentiation

Standard diabetes diagnostic tests (HbA1c, fasting plasma glucose, oral glucose tolerance test) diagnose the presence of diabetes but do not differentiate between type 1 and type 2. 2 These tests establish hyperglycemia but provide no information about the underlying etiology or beta-cell function. 2