Diagnostic Tests for Type 1 Diabetes Mellitus
Type 1 diabetes is diagnosed using standard glycemic criteria (fasting plasma glucose ≥126 mg/dL, 2-hour OGTT ≥200 mg/dL, HbA1c ≥6.5%, or random glucose ≥200 mg/dL with symptoms), followed by confirmation of autoimmune etiology through measurement of islet autoantibodies (GAD65, IA-2, insulin, ZnT8) and C-peptide levels. 1, 2
Initial Glycemic Testing
The diagnosis begins with demonstrating hyperglycemia using any of these criteria:
- Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) after at least 8 hours of no caloric intake 1, 3
- 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-gram oral glucose tolerance test (OGTT) 1, 3
- HbA1c ≥6.5% (48 mmol/mol) using an NGSP-certified method standardized to the DCCT assay 1, 3
- Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in patients with classic symptoms of hyperglycemia (polyuria, polydipsia, weight loss) or hyperglycemic crisis 1, 3, 2
Confirmation Requirements
Unless the patient presents with unequivocal hyperglycemia or hyperglycemic crisis, the diagnosis requires confirmation with a second abnormal test result. 1, 3 This can be either:
- A repeat of the initial test from a new blood sample 1, 3
- A different test performed without delay 1, 3
- Two different tests (such as HbA1c and FPG) both above diagnostic thresholds from the same sample 1, 3
Type-Specific Confirmatory Testing
Once hyperglycemia is established, type 1 diabetes is confirmed by demonstrating autoimmune destruction of beta cells through specific autoantibody testing and assessment of beta-cell function. 1, 2
Islet Autoantibody Panel
Measurement of multiple islet autoantibodies is essential for confirming the autoimmune nature of type 1 diabetes: 1, 2
- Glutamic acid decarboxylase autoantibodies (GAD65) 1, 2
- Insulin autoantibodies (IAA) 1, 2
- Tyrosine phosphatase autoantibodies (IA-2 and IA-2β) 1, 2
- Zinc transporter 8 autoantibodies (ZnT8) 1, 2
The presence of two or more autoantibodies strongly confirms type 1 diabetes and indicates stage 1 disease even before clinical hyperglycemia develops. 1 Standardized islet autoantibody tests are recommended for classification of diabetes in adults who have phenotypic features overlapping with type 1 diabetes, such as younger age at diagnosis, unintentional weight loss, ketoacidosis, or rapid progression to insulin requirement. 1
C-Peptide Measurement
C-peptide levels should be measured to assess residual beta-cell function. 2 In established type 1 diabetes, C-peptide is typically low or undetectable, reflecting the destruction of insulin-secreting beta cells. 1, 2 This distinguishes type 1 from type 2 diabetes, where C-peptide levels are normal or elevated. 3
Clinical Context and Presentation
Approximately one-third of type 1 diabetes patients present with diabetic ketoacidosis (DKA) at diagnosis, particularly children and adolescents. 2 In patients presenting with DKA or classic symptoms (polyuria, polydipsia, weight loss) plus random glucose ≥200 mg/dL, immediate diagnosis can be made without waiting for confirmatory testing, as knowing the glucose level is critical for management decisions. 1
Important Limitations and Pitfalls
HbA1c Interference
In conditions with increased red blood cell turnover (sickle cell disease, pregnancy, hemodialysis, recent blood loss, transfusion, or erythropoietin therapy), only plasma glucose criteria should be used for diagnosis. 1, 3, 2 Marked discordance between HbA1c and plasma glucose levels should raise suspicion for hemoglobin variant interference in the A1C assay. 1, 3, 2
Distinguishing from Other Diabetes Types
Autoantibody testing is particularly valuable in adults where the distinction between type 1 and type 2 diabetes may not be clinically obvious. 1 Adults with type 1 diabetes may have slower beta-cell destruction and may not present with classic symptoms seen in children. 1 Overweight or obese adolescents require autoantibody and C-peptide testing to distinguish type 1 from type 2 diabetes, as obesity is increasingly common and does not exclude type 1 diabetes. 1, 2
Antibody-negative patients should be considered for monogenic diabetes testing, as these conditions are frequently misdiagnosed as type 1 diabetes. 2
Staging of Type 1 Diabetes
Type 1 diabetes can be identified in presymptomatic stages: 1
- Stage 1: Multiple autoantibodies present with normoglycemia 1
- Stage 2: Multiple autoantibodies with dysglycemia (FPG 100-125 mg/dL, 2-hour PG 140-199 mg/dL, or HbA1c 5.7-6.4%) 1
- Stage 3: Clinical diabetes with symptoms and hyperglycemia meeting diagnostic criteria 1
Screening for presymptomatic type 1 diabetes with autoantibody panels may be offered to first-degree relatives of patients with type 1 diabetes, particularly in research settings or for consideration of clinical trials. 1