What are the diagnostic criteria for type 1 diabetes mellitus, including clinical symptoms, plasma glucose thresholds, glycated hemoglobin (HbA1c), pancreatic autoantibody testing, and fasting C‑peptide levels?

Diagnosis of Type 1 Diabetes Mellitus

Type 1 diabetes is diagnosed when hyperglycemia meets standard glucose or HbA1c thresholds (identical to those for any diabetes type) AND is accompanied by evidence of β-cell autoimmunity—specifically, the presence of one or more islet autoantibodies, with glutamic acid decarboxylase (GAD) antibodies tested first, followed by IA-2 and/or ZnT8 if GAD is negative. 1

Standard Glycemic Criteria for Diabetes (Apply to All Types)

The diagnosis of diabetes requires meeting any one of the following thresholds 2, 1, 3:

• Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) after at least 8 hours of no caloric intake 2, 1
• 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-gram oral glucose tolerance test (OGTT) 2, 1
• HbA1c ≥6.5% (48 mmol/mol) measured in an NGSP-certified laboratory standardized to the DCCT assay 2, 1
• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic hyperglycemic symptoms 2, 1

Classic symptoms that accompany random hyperglycemia include polyuria, polydipsia, unexplained weight loss, polyphagia, fatigue, and blurred vision. 2, 1

Confirmation Requirements

• In the absence of unequivocal hyperglycemia (e.g., hyperglycemic crisis with clear symptoms), two abnormal test results are required to confirm diabetes. 2, 3
• These can be two repeat measurements of the same test on different days, or two different tests each exceeding their respective thresholds. 2, 3
• If a patient presents with classic symptoms or hyperglycemic crisis, a single random plasma glucose ≥200 mg/dL is sufficient for immediate diagnosis. 2

Distinguishing Type 1 from Other Diabetes Types

Once diabetes is confirmed by glycemic criteria, type 1 diabetes is distinguished by the presence of islet autoantibodies. 1

Autoantibody Testing Algorithm

1. First-line test: Glutamic acid decarboxylase (GAD) antibodies 1
2. If GAD is negative, proceed to test for:
   • Islet tyrosine phosphatase 2 (IA-2) antibodies 1
   • Zinc transporter 8 (ZnT8) antibodies 1
3. Additional autoantibodies that may be measured include insulin autoantibodies and islet cell antibodies. 2

All autoantibody testing must be performed in an accredited laboratory with established quality control. 1

Interpretation of Autoantibody Results

• Presence of one or more islet autoantibodies confirms immune-mediated (type 1A) diabetes. 1
• Multiple positive autoantibodies indicate higher risk of rapid progression to insulin dependence. 1
• 5–10% of adult-onset type 1 diabetes may be autoantibody-negative (idiopathic type 1B diabetes), which presents a diagnostic challenge. 1, 4

Staging of Type 1 Diabetes

Type 1 diabetes develops through three distinct stages 2, 1:

Stage 1: Presymptomatic with Normoglycemia

• ≥2 islet autoantibodies present 2, 1
• Normal glucose tolerance (no impaired fasting glucose or impaired glucose tolerance) 2
• No symptoms 2

Stage 2: Presymptomatic with Dysglycemia

• ≥2 islet autoantibodies present 2, 1
• Dysglycemia: Fasting plasma glucose 100–125 mg/dL (5.6–6.9 mmol/L) and/or 2-hour plasma glucose 140–199 mg/dL (7.8–11.0 mmol/L) and/or HbA1c 5.7–6.4% (39–47 mmol/mol) or ≥10% increase in HbA1c 2
• No symptoms 2

Stage 3: Symptomatic Diabetes

• Overt hyperglycemia meeting standard diagnostic criteria 2, 1
• Classic symptoms of insulin deficiency 2
• Requires immediate insulin therapy 2

C-Peptide Testing

C-peptide measurement is useful in insulin-treated patients to assess residual β-cell function, but has important limitations 1:

• Do not perform C-peptide testing within 2 weeks of a hyperglycemic emergency, as results may be misleadingly low due to glucose toxicity. 1
• Fasting C-peptide <0.3 ng/mL suggests severe insulin deficiency, though this is not a formal diagnostic criterion. 2
• C-peptide helps distinguish type 1 from type 2 diabetes in ambiguous cases, particularly in adults. 1

Special Considerations in Children and Adolescents

• For OGTT in children, use a glucose load of 1.75 g/kg body weight (maximum 75 grams). 2, 1
• The metabolic state of untreated children with type 1 diabetes can deteriorate rapidly; therefore, definitive diagnosis and insulin initiation must occur immediately to prevent diabetic ketoacidosis. 2, 1
• Incidental hyperglycemia without classic symptoms does not necessarily indicate new-onset diabetes in young children with acute illness, who may experience "stress hyperglycemia." 2, 1
• Consultation with a pediatric endocrinologist is indicated for children with incidental hyperglycemia, especially if immunological, metabolic, or genetic markers for type 1 diabetes are present. 2

Screening for Type 1 Diabetes in Asymptomatic Individuals

Screening with a panel of islet autoantibodies is currently recommended only in two settings 2, 1:

1. Research studies 2, 1
2. First-degree family members of a proband with type 1 diabetes 2, 1

Persistence of autoantibodies is a risk factor for clinical diabetes and may serve as an indication for intervention in the setting of a clinical trial. 2

Critical Pitfalls to Avoid

HbA1c Limitations

• Do not use HbA1c for diagnosis in conditions that alter red blood cell turnover: hemoglobinopathies (including sickle cell disease), pregnancy (second/third trimester), G6PD deficiency, hemodialysis, recent blood loss or transfusion, and erythropoietin therapy. 3
• Point-of-care HbA1c assays should not be used for diagnosis unless FDA-cleared specifically for diagnostic purposes. 1, 3
• In these situations, use plasma glucose criteria alone. 3

Sample Handling

• Plasma glucose samples must be centrifuged and separated immediately after collection to avoid glycolysis, which produces falsely low results. 2, 3

Fulminant Type 1 Diabetes

• A rare subtype of idiopathic type 1 diabetes presents with remarkably abrupt onset (symptoms <1 week), **extremely high plasma glucose** (often >700 mg/dL), low HbA1c (<8.5%), severe ketoacidosis, elevated pancreatic enzymes, and absence of all diabetes-related autoantibodies. 4
• This fulminant presentation requires immediate insulin therapy despite negative autoantibodies. 4

Delays in Diagnosis

• Delays in diagnosis and initiation of insulin replacement therapy must be avoided in children with suspected type 1 diabetes, as metabolic decompensation can occur within days. 2, 1