What tests are used to diagnose type 1 diabetes?

Tests to Diagnose Type 1 Diabetes

The diagnosis of type 1 diabetes requires demonstrating hyperglycemia using standard glycemic criteria, followed by confirmation of autoimmune beta-cell destruction through islet autoantibody testing. 1

Glycemic Testing for Diabetes Diagnosis

The initial step is to confirm diabetes using any one of the following plasma glucose criteria 1, 2:

• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms (polyuria, polydipsia, unexplained weight loss, polyphagia, fatigue, blurred vision) – this single test is sufficient for immediate diagnosis 1, 2
• Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) after at least 8 hours without caloric intake 1, 2
• 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-gram oral glucose tolerance test 1, 2
• HbA1c ≥6.5% (48 mmol/mol) performed in an NGSP-certified laboratory 1

Two abnormal test results are required for confirmation unless the patient presents with unequivocal hyperglycemia, classic symptoms, or hyperglycemic crisis. 1, 2 The two results can be repeat measurements of the same test on different days or two different tests, each exceeding its threshold. 2 The second test should be performed without delay. 3

Critical Testing Pitfalls

• Do not use HbA1c in conditions with altered red blood cell turnover: sickle cell disease, pregnancy (second/third trimesters), glucose-6-phosphate dehydrogenase deficiency, hemodialysis, recent blood loss or transfusion, or erythropoietin therapy – use only plasma glucose criteria in these situations 1
• Point-of-care HbA1c assays should not be used for diagnosis unless FDA-cleared specifically for diagnostic purposes 2, 4
• Plasma glucose specimens must be centrifuged and separated immediately after collection to prevent falsely low values from glycolysis 2

Autoantibody Testing to Confirm Type 1 Diabetes

Once diabetes is confirmed by glycemic criteria, measure islet autoantibodies to distinguish type 1 from other diabetes types. 1

Testing Algorithm

Step 1: Measure glutamic acid decarboxylase (GAD) antibodies as the primary test – this is positive in approximately 80% of type 1 diabetes cases 1, 2, 5

Step 2: If GAD is negative, follow with islet antigen 2 (IA-2) and/or zinc transporter 8 (ZnT8) antibodies 1, 2

Step 3: Consider insulin autoantibodies (IAA) in patients who have not yet received insulin therapy 2

The presence of two or more positive autoantibodies strongly confirms type 1 diabetes and indicates stage 1 disease even before clinical hyperglycemia develops. 1, 3 However, 5-10% of adult-onset type 1 diabetes cases are autoantibody-negative, so negative results do not completely exclude the diagnosis. 2, 5

Autoantibody Testing Standards

• Tests must be performed only in an accredited laboratory with established quality control 2
• 90-95% of people with type 1 diabetes have at least one autoantibody when diagnosed 5, 6
• Autoantibodies can become undetectable over time in established type 1 diabetes, potentially leading to false-negative results 2

C-Peptide Testing for Ambiguous Cases

When the clinical picture is unclear in adults already on insulin, C-peptide testing helps differentiate type 1 from type 2 diabetes: 2

• C-peptide <0.3 ng/mL (<200 pmol/L) suggests severe insulin deficiency consistent with type 1 diabetes 2
• C-peptide >0.6 ng/mL (>600 pmol/L) indicates preserved beta-cell function, effectively ruling out type 1 diabetes 2
• Values between 0.3-0.6 ng/mL (200-600 pmol/L) are indeterminate 2

Critical C-peptide pitfalls:

• Do not measure within 2 weeks of a hyperglycemic emergency (DKA or hyperosmolar state) as results will be falsely low 2, 4
• If concurrent glucose is <70 mg/dL or the patient was fasting, repeat the test 2
• A random C-peptide drawn within 5 hours after a meal can substitute for formal stimulation testing 2

Screening for Presymptomatic Type 1 Diabetes

Autoantibody screening in asymptomatic individuals is recommended only for: 1, 4

• First-degree relatives of people with type 1 diabetes
• Research study participants

The presence of multiple confirmed islet autoantibodies predicts progression to clinical diabetes and should prompt referral to a specialized center for evaluation and consideration of clinical trials or approved therapy (such as teplizumab) to delay disease development. 1

Three-Stage Classification System

Type 1 diabetes develops through distinct stages 1, 3:

• Stage 1: Two or more islet autoantibodies with normoglycemia (no impaired fasting glucose or glucose tolerance), presymptomatic
• Stage 2: Two or more islet autoantibodies with dysglycemia (fasting glucose 100-125 mg/dL, 2-hour OGTT 140-199 mg/dL, or HbA1c 5.7-6.4%), presymptomatic
• Stage 3: Symptomatic disease with overt hyperglycemia meeting standard diagnostic criteria

Pediatric Testing Considerations

• For oral glucose tolerance testing in children, use 1.75 g/kg body weight glucose load (maximum 75 g) 2, 4
• Classic symptoms with random glucose ≥200 mg/dL confirm diabetes without repeat testing 2
• Incidental hyperglycemia in acutely ill children often reflects stress hyperglycemia rather than new-onset diabetes 2, 4
• The metabolic state of untreated children with type 1 diabetes can deteriorate rapidly – make a definitive diagnosis immediately to avoid delays in treatment 2
• Approximately one-third of patients with type 1 diabetes present with life-threatening diabetic ketoacidosis 4

Additional Testing After Diagnosis

Screen for associated autoimmune conditions soon after diagnosis 4, 3:

• Thyroid antibodies: antithyroid peroxidase and antithyroglobulin
• Celiac disease: IgA tissue transglutaminase (tTG) antibodies with total serum IgA level

Patients with type 1 diabetes are at increased risk for Hashimoto thyroiditis, Graves disease, celiac disease, Addison disease, vitiligo, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. 1, 3

Common Diagnostic Pitfalls

• Do not assume obesity excludes type 1 diabetes – obesity is increasingly common and may coexist with type 1 disease 1, 2, 3
• Do not rely solely on age – nearly half of type 1 diabetes cases are diagnosed in adulthood, with a median age of diagnosis of 24 years in the US 2, 5
• Recognize that a small subset of patients have "idiopathic type 1 diabetes" with permanent insulin deficiency and DKA risk but no detectable autoimmunity, more common in individuals of African or Asian ancestry 1, 3