What labs are used to determine type 1 diabetes in a patient?

Laboratory Tests to Determine Type 1 Diabetes

Start with plasma glucose measurement to diagnose diabetes, then confirm type 1 etiology with islet autoantibody testing (GAD, IA-2, ZnT8, and IAA if not yet on insulin), supplemented by C-peptide measurement when needed to assess beta-cell function. 1, 2

Initial Glycemic Testing to Diagnose Diabetes

The first step is establishing that diabetes exists using any of these criteria 1, 2:

• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in patients with classic symptoms (polyuria, polydipsia, weight loss) is sufficient for diagnosis 1, 2
• Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) after 8 hours of no caloric intake 1
• 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during 75g oral glucose tolerance test 1
• HbA1c ≥6.5% (48 mmol/mol) using NGSP-certified laboratory method 1

Critical pitfall: In acute-onset type 1 diabetes with classic symptoms, plasma glucose is preferred over HbA1c because conditions affecting red blood cell turnover can interfere with A1C accuracy 1, 2. Approximately one-third of type 1 diabetes patients present with diabetic ketoacidosis, making immediate plasma glucose measurement essential 2.

Confirmation Requirements

• Diagnosis requires two abnormal test results either from the same sample (e.g., both A1C and FPG elevated) or from two separate samples obtained without delay 3, 2
• If a patient has classic symptoms plus random glucose ≥200 mg/dL, this single test is diagnostic and no confirmation is needed 1, 2

Autoantibody Testing to Confirm Type 1 Etiology

Once diabetes is diagnosed, confirm autoimmune etiology with a panel of islet autoantibodies 3, 4, 1:

Primary Autoantibody Panel

Start with GAD (glutamic acid decarboxylase) antibodies as the first-line test, as this is the most frequently positive marker in type 1 diabetes (~80% positive in Japanese cohorts) 4, 5. If GAD is negative, proceed to:

• IA-2 (insulinoma-associated antigen-2) antibodies (~60% positive) 4, 5
• ZnT8 (zinc transporter 8) antibodies where available (~50% positive) 3, 4, 5
• Insulin autoantibodies (IAA) only if the patient has not yet been treated with insulin, as exogenous insulin renders this test unreliable 4, 1

Interpretation of Autoantibody Results

• Two or more positive autoantibodies indicate 70% risk of progression to insulin dependence within 10 years and confirm autoimmune type 1 diabetes 4, 2
• Single positive autoantibody carries lower predictive value (15% risk within 10 years) and may be seen in 1-2% of healthy individuals 4
• All antibodies negative: 5-10% of adults with true type 1 diabetes are antibody-negative, so negative results in a patient under 35 years with classic type 1 features (lean, acute onset, ketoacidosis) should not change the diagnosis 4

Important caveat: Autoantibody testing must be performed in an accredited laboratory with established quality control programs 4. The American Diabetes Association recommends this testing specifically when there is phenotypic overlap between type 1 and type 2 diabetes 4.

C-Peptide Testing to Assess Beta-Cell Function

C-peptide measurement is indicated when 4, 1:

• The patient is already on insulin therapy and you need to assess residual beta-cell function 4
• Autoantibodies are negative but clinical suspicion for type 1 diabetes remains high 4
• Classification remains uncertain after >3 years of disease duration 4

C-Peptide Testing Protocol

• Obtain a random (non-fasting) sample within 5 hours of eating with concurrent glucose measurement 4
• Interpretation 4:
  • <200 pmol/L (<0.6 ng/mL) indicates type 1 diabetes
  • 200-600 pmol/L (0.6-1.8 ng/mL) is indeterminate
  • >600 pmol/L (>1.8 ng/mL) indicates type 2 diabetes

Critical pitfall: Low or undetectable C-peptide levels indicate diminished beta-cell function characteristic of type 1 diabetes, but 51% of antibody-negative patients still required insulin within 3 years, demonstrating that antibody negativity does not predict preserved beta-cell function 4, 1.

Age-Specific Considerations

• Children <6 months: Skip autoantibody testing and proceed directly to genetic testing for neonatal diabetes 4
• Antibody-negative youth with modest hyperglycemia (HbA1c <7.5%) and one parent with diabetes: Consider MODY (maturity-onset diabetes of the young), which accounts for 1.2-4% of pediatric diabetes 4
• Overweight/obese adolescents: Measure both islet autoantibodies and C-peptide to distinguish type 1 from type 2 diabetes 1
• Adults >35 years with negative antibodies: Make clinical decision based on phenotype; consider C-peptide testing after >3 years if classification remains uncertain 4

Screening for Associated Autoimmune Conditions

After confirming type 1 diabetes, screen for additional autoimmune conditions 2:

• Thyroid antibodies: Anti-thyroid peroxidase and anti-thyroglobulin antibodies (prevalence ~20% at diagnosis in children, particularly common in girls) 2, 5
• Celiac disease: IgA tissue transglutaminase (tTG) antibodies 2

Patients with anti-thyroid antibodies are 18 times more likely to develop thyroid disease than those without, making yearly screening after age 12 years essential 5.

Common Pitfalls to Avoid

• Do not assume negative antibodies exclude type 1 diabetes in young, lean patients with acute onset, as 5-10% of type 1 diabetes is antibody-negative 4
• Do not use HbA1c alone in patients with conditions affecting red blood cell turnover (sickle cell disease, pregnancy, hemodialysis, recent blood loss, transfusion, erythropoietin therapy) 1
• Do not delay processing glucose samples: Samples must be spun and separated immediately to avoid falsely low glucose concentrations due to glycolysis 3, 1
• Do not ignore stress hyperglycemia in children with acute illness, as this can cause elevated glucose levels that do not necessarily indicate diabetes 1
• Do not test IAA after insulin therapy has started, as exogenous insulin renders the test unreliable 4