Which laboratory tests should be ordered to confirm a diagnosis of type 1 diabetes?

Laboratory Testing to Diagnose Type 1 Diabetes

Order plasma glucose (fasting ≥126 mg/dL or random ≥200 mg/dL with symptoms) to establish hyperglycemia, then measure islet autoantibodies—starting with GAD antibodies—to confirm autoimmune etiology. 1, 2

Initial Diagnostic Tests

Plasma Glucose Measurement

• Measure venous plasma glucose in a certified laboratory—never use point-of-care glucose meters for diagnosis—with a random plasma glucose ≥200 mg/dL (11.1 mmol/L) being diagnostic when classic symptoms (polyuria, polydipsia, weight loss) are present. 3, 1
• If symptoms are absent or atypical, obtain a fasting plasma glucose (≥126 mg/dL or 7.0 mmol/L) and confirm with repeat testing on a separate day using the same test. 3, 4
• HbA1c ≥6.5% measured by an NGSP-certified laboratory method can also diagnose diabetes, though plasma glucose is preferred in symptomatic presentations. 3, 1

Ketone Assessment

• Check urine ketones or serum beta-hydroxybutyrate at presentation, as approximately one-third of type 1 diabetes patients present with diabetic ketoacidosis. 1, 5

Autoantibody Testing to Confirm Type 1 Etiology

When to Order Autoantibodies

• Order islet autoantibodies when there is phenotypic uncertainty—specifically in overweight/obese patients, adults >35 years, or anyone with features overlapping type 1 and type 2 diabetes. 3, 2
• In children and lean young adults (<35 years) with acute onset, ketosis, and classic symptoms, autoantibody testing is not required for diagnosis but can be performed to confirm autoimmune etiology and enable disease staging. 3, 2

Autoantibody Panel Selection

• Start with GAD (glutamic acid decarboxylase) antibodies as the first-line test, since this is the most frequently positive marker in both children and adults with type 1 diabetes. 2
• If GAD is negative but clinical suspicion remains high, proceed to IA-2 (insulinoma-associated antigen-2) and ZnT8 (zinc transporter 8) antibodies. 3, 2
• Add insulin autoantibodies (IAA) only in patients not yet treated with exogenous insulin, as insulin therapy renders IAA testing unreliable. 2
• The presence of two or more positive autoantibodies confirms autoimmune type 1 diabetes and predicts 70% risk of progression to insulin dependence within 10 years. 2

Laboratory Quality Requirements

• Ensure autoantibody testing is performed only in accredited laboratories with established quality-control programs and participation in proficiency testing. 3, 2

C-Peptide Testing (Selective Use)

• C-peptide is primarily indicated when the patient is already on insulin therapy and you need to assess residual beta-cell function to distinguish type 1 from insulin-treated type 2 diabetes. 2
• Obtain a random (non-fasting) C-peptide within 5 hours of eating with concurrent glucose measurement; fasting C-peptide <0.6 ng/mL (<200 pmol/L) confirms severe insulin deficiency consistent with type 1 diabetes. 2, 6
• C-peptide is not needed for initial diagnosis in treatment-naïve patients with classic type 1 presentation. 2

Additional Screening at Diagnosis

• Screen for associated autoimmune conditions soon after type 1 diabetes diagnosis by measuring antithyroid peroxidase and antithyroglobulin antibodies for autoimmune thyroid disease. 1
• Measure IgA tissue transglutaminase (tTG) antibodies to screen for celiac disease, which is more common in type 1 diabetes. 1

Common Pitfalls to Avoid

• Do not use HbA1c alone in patients with suspected hemoglobin variants or conditions affecting red blood cell turnover; laboratories should be aware of potential interferences depending on the assay method used. 3
• Do not routinely order genetic markers (HLA typing, single nucleotide polymorphisms) for diagnosis or management of typical type 1 diabetes; reserve genetic testing for neonatal diabetes (<6 months of age) or suspected monogenic diabetes (MODY). 3
• Do not assume negative autoantibodies exclude type 1 diabetes in young, lean patients with acute onset and ketosis, as 5–10% of true type 1 diabetes is antibody-negative. 2
• Do not delay insulin therapy while awaiting autoantibody results in patients with hyperglycemia and ketosis; treat clinically suspected type 1 diabetes immediately. 1

Diagnostic Algorithm Summary

1. Confirm hyperglycemia: Random plasma glucose ≥200 mg/dL with symptoms (no repeat needed) OR fasting plasma glucose ≥126 mg/dL confirmed on repeat testing. 3, 1, 4
2. Assess for ketosis: Urine or serum ketones at presentation. 1, 5
3. Order autoantibodies if phenotype is uncertain: Start with GAD; add IA-2, ZnT8, and IAA (if not on insulin) as needed. 3, 2
4. Screen for associated autoimmune conditions: Thyroid antibodies and celiac serology. 1
5. Reserve C-peptide for patients already on insulin when diabetes type remains unclear. 2