What are the diagnostic criteria and initial treatment for type 1 diabetes mellitus (DM)?

How to Diagnose Type 1 Diabetes Mellitus

In patients with classic symptoms (polyuria, polydipsia, weight loss), a single random plasma glucose ≥200 mg/dL (11.1 mmol/L) is sufficient to diagnose diabetes, and islet autoantibody testing—starting with GAD antibodies—should then be performed to confirm type 1 diabetes. 1, 2, 3

Diagnostic Approach Based on Clinical Presentation

For Symptomatic Patients (Acute Presentation)

Plasma glucose measurement takes priority over A1C in symptomatic patients. 1, 4 The diagnostic criteria are:

• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in the presence of classic symptoms (polyuria, polydipsia, weight loss, polyphagia, fatigue, blurred vision) confirms diabetes 1, 2, 4
• Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) (no caloric intake for ≥8 hours) 2
• 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during 75-g oral glucose tolerance test 2

Critical caveat: Approximately one-third of type 1 diabetes patients present with life-threatening diabetic ketoacidosis (DKA), requiring immediate treatment without waiting for confirmatory testing. 1, 4 In children and adolescents, DKA is often the first manifestation, and rates have increased dramatically over the past 20 years. 1

For Asymptomatic or Unclear Presentations

When symptoms are absent or atypical, two abnormal test results are required—either from the same sample or two separate samples performed without delay. 1, 4 For example, if A1C is 7.0% and repeat is 6.8%, diabetes is confirmed; if two different tests (A1C and fasting glucose) are both above thresholds from the same sample, diagnosis is confirmed. 1

Confirming Type 1 Diabetes Specifically

Autoantibody Testing Algorithm

The American Diabetes Association recommends islet autoantibody testing as first-line to distinguish type 1 from type 2 diabetes, particularly in adults with overlapping phenotypic features. 1, 3

Step-by-step approach:

1. Start with GAD (glutamic acid decarboxylase) antibodies as the primary test 1, 2, 3
2. If GAD is negative, proceed to test for IA-2 (islet tyrosine phosphatase 2) and/or ZnT8 (zinc transporter 8) antibodies 1, 2, 3
3. In insulin-naïve patients, insulin autoantibodies (IAA) may also be useful 3

Important: Autoantibody testing must be performed only in accredited laboratories with established quality control and proficiency testing programs. 2, 3

Clinical Features Suggesting Type 1 Diabetes (AABBCC Approach)

The 2025 ADA guidelines recommend the AABBCC mnemonic for distinguishing diabetes type: 1

• Age <35 years old
• Autoimmunity (personal or family history of autoimmune disease)
• Body habitus (BMI <25 kg/m²)
• Background (family history of type 1 diabetes)
• Control (inability to achieve glycemic goals on non-insulin therapies)
• Comorbidities (e.g., treatment with immune checkpoint inhibitors)

Additional Confirmatory Testing

C-peptide testing is useful in insulin-treated patients to assess residual β-cell function, but must not be performed within 2 weeks of a hyperglycemic emergency as results will be misleading. 2, 3 Low or undetectable C-peptide confirms advanced β-cell destruction. 1

Staging of Type 1 Diabetes

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

• Stage 1: Multiple islet autoantibodies + normoglycemia + presymptomatic 1, 2
• Stage 2: Islet autoantibodies + dysglycemia (IFG 100-125 mg/dL, IGT 140-199 mg/dL, or A1C 5.7-6.4%) + presymptomatic 1, 2
• Stage 3: Overt hyperglycemia meeting diabetes criteria + symptomatic disease 1, 2

Multiple positive autoantibodies indicate higher risk of progression to insulin dependence. 2, 3 The presence of two or more autoantibodies is an almost certain predictor of clinical diabetes. 1

Critical Pitfalls to Avoid

When NOT to Use A1C

Do not rely on A1C for diagnosis in conditions with altered red blood cell turnover: 1, 2

• Sickle cell disease
• Pregnancy (second and third trimesters)
• Glucose-6-phosphate dehydrogenase deficiency
• Hemodialysis
• Recent blood loss or transfusion
• Erythropoietin therapy
• Iron-deficient anemia
• HIV treated with certain protease inhibitors and NRTIs

In these conditions, use only plasma glucose criteria. 1

Other Important Caveats

• Point-of-care A1C assays should not be used for diagnosis unless FDA-cleared specifically for diagnostic purposes 2, 3
• 5-10% of adult-onset type 1 diabetes may be autoantibody negative, so clinical judgment remains essential 3
• Obesity does not preclude type 1 diabetes diagnosis—obesity is increasingly common and may be a risk factor for type 1 diabetes 1
• In young children with acute illness, "stress hyperglycemia" can occur—incidental hyperglycemia without classic symptoms does not necessarily indicate new-onset diabetes 2
• Plasma samples must be spun and separated immediately after collection to ensure accurate glucose measurement 1

Screening for Presymptomatic Type 1 Diabetes

Autoantibody-based screening should be offered to first-degree family members of individuals with type 1 diabetes or those with known elevated genetic risk. 1, 4 When multiple islet autoantibodies are identified, referral to a specialized center for evaluation and/or consideration of clinical trials or approved therapy to delay progression should be considered. 1

Screening in asymptomatic children without family history is currently recommended only in research settings. 2, 4