What are the diagnostic criteria and initial management strategies for type 1 and type 2 diabetes mellitus?

Diagnostic Criteria for Type 1 and Type 2 Diabetes

Diabetes is diagnosed when fasting plasma glucose (FPG) is ≥126 mg/dL, hemoglobin A1C is ≥6.5%, 2-hour plasma glucose during 75-g oral glucose tolerance test (OGTT) is ≥200 mg/dL, or random plasma glucose is ≥200 mg/dL with classic hyperglycemic symptoms. 1, 2

Confirmation Requirements

Two abnormal test results are required to confirm diabetes, either from the same test repeated on different days or two different tests performed at the same time or different time points. 1 However, a single test showing "diabetic type" hyperglycemia is sufficient if any of the following are present: 1

• Classic symptoms of hyperglycemia (polyuria, polydipsia, unintentional weight loss)
• HbA1c ≥6.5% by NGSP-certified method
• Unequivocal diabetic retinopathy

Specific Diagnostic Thresholds

Plasma Glucose Criteria

• Fasting plasma glucose: ≥126 mg/dL (7.0 mmol/L) after at least 8-hour fast 1
• 2-hour plasma glucose during 75-g OGTT: ≥200 mg/dL (11.1 mmol/L) 1
• Random plasma glucose: ≥200 mg/dL (11.1 mmol/L) with symptoms 1

HbA1c Criteria

• HbA1c: ≥6.5% (48 mmol/mol) using NGSP-certified and DCCT-standardized assay 1

Distinguishing Type 1 from Type 2 Diabetes

Primary Approach: Islet Autoantibody Testing

Start with glutamic acid decarboxylase (GAD65) antibodies as the first-line test, as this is the most frequently positive marker in autoimmune diabetes. 3, 4 If GAD is negative, proceed to test IA-2 (insulinoma-associated antigen-2) and ZnT8 (zinc transporter 8) antibodies. 3, 4 In patients not yet on insulin, insulin autoantibodies (IAA) may also be useful. 4

The presence of two or more positive islet autoantibodies confirms type 1 diabetes and predicts progression to insulin dependence (70% within 10 years). 1, 4 A single positive autoantibody carries lower predictive value (15% risk within 10 years). 4

When to Order Autoantibody Testing

Consider autoantibody testing in adults with phenotypic features that overlap between type 1 and type 2 diabetes: 1, 3, 4

• Age <35 years at diagnosis
• Lean body habitus (BMI <25 kg/m²)
• Unintentional weight loss despite diabetes diagnosis
• Ketoacidosis or ketosis at presentation (even if obese)
• Rapid progression to insulin dependence
• Short time to insulin treatment requirement
• Family history of autoimmune disease

In obese children and adolescents presenting with ketosis or ketoacidosis, autoantibody testing should be considered to exclude type 1 diabetes. 3, 4

C-Peptide Testing for Beta-Cell Function

C-peptide measurement is primarily indicated when the patient is already on insulin therapy and you need to assess residual beta-cell function. 3, 4 Obtain a random (non-fasting) sample within 5 hours of eating with concurrent glucose measurement. 4

C-peptide interpretation: 4

• <200 pmol/L (<0.6 ng/mL): indicates type 1 diabetes
• 200-600 pmol/L (0.6-1.8 ng/mL): indeterminate

• 600 pmol/L (>1.8 ng/mL): indicates type 2 diabetes

For accurate C-peptide results, measure fasting C-peptide when simultaneous fasting plasma glucose is ≤220 mg/dL (12.5 mmol/L). 3

Clinical Phenotype Assessment (AABBCC Approach)

Use the AABBCC clinical approach to complement laboratory testing: 3

Type 1 Diabetes Indicators:

• Age: <35 years at diagnosis 4
• Autoimmunity: Family history of autoimmune disease 4
• Body habitus: BMI <25 kg/m², lean 4
• Background: No family history of type 2 diabetes 4
• Control: Acute symptom onset, ketoacidosis, weight loss 4
• Comorbidities: Absence of metabolic syndrome features 4

Type 2 Diabetes Indicators:

• Age: ≥35 years at diagnosis 4
• Autoimmunity: No family history of autoimmune disease 4
• Body habitus: BMI ≥25 kg/m² (≥23 kg/m² in Asian Americans), overweight/obese 1, 4
• Background: Family history of type 2 diabetes in first-degree relatives 1, 4
• Control: Gradual symptom onset, milder hyperglycemia, no weight loss 4
• Comorbidities: Hypertension, dyslipidemia, metabolic syndrome features 1, 4

Staging of Type 1 Diabetes

Type 1 diabetes can be identified in presymptomatic stages using autoantibody testing: 1

• Stage 1: Multiple islet autoantibodies with normoglycemia (FPG <100 mg/dL, 2-hour PG <140 mg/dL) 1
• Stage 2: Islet autoantibodies with dysglycemia (FPG 100-125 mg/dL or 2-hour PG 140-199 mg/dL or HbA1c 5.7-6.4%) 1
• Stage 3: Overt hyperglycemia meeting diabetes criteria with clinical symptoms 1

The 5-year risk of developing symptomatic type 1 diabetes in Stage 1 is 44% overall but varies based on number, titer, and specificity of autoantibodies. 1

Important Caveats and Pitfalls

HbA1c Limitations

Do not use HbA1c for diagnosis in conditions with altered red blood cell turnover: 1

• Sickle cell disease
• Pregnancy (second and third trimesters)
• Glucose-6-phosphate dehydrogenase deficiency
• Hemodialysis
• Recent blood loss or transfusion
• Erythropoietin therapy
• Iron-deficiency anemia

In these conditions, use only plasma glucose criteria for diagnosis. 1

Marked discordance between measured HbA1c and plasma glucose levels should raise suspicion of hemoglobin variants (hemoglobinopathies). 1 For patients with hemoglobin variants but normal red blood cell turnover (such as sickle cell trait), use an HbA1c assay without interference from hemoglobin variants. 1

Antibody-Negative Type 1 Diabetes

5-10% of adults with true type 1 diabetes are antibody-negative, so negative autoantibodies in someone under 35 years with classic type 1 features does not exclude the diagnosis. 4 In patients diagnosed under 35 years with lean body habitus, acute onset, and no clinical features of type 2 diabetes, treat as type 1 diabetes despite negative antibodies. 4

51% of antibody-negative patients still required insulin within 3 years, demonstrating that antibody negativity does not predict preserved beta-cell function. 4

Type 2 Diabetes Can Present with Ketoacidosis

Diabetic ketoacidosis can occur in type 2 diabetes, particularly in ethnic minorities (African American, Hispanic/Latino) and obese patients. 1, 4 This can lead to misclassification. More than half of newly diagnosed Black patients with unprovoked ketoacidosis are obese. 4

Consider Monogenic Diabetes (MODY)

In antibody-negative youth with modest hyperglycemia (HbA1c <7.5% at diagnosis) and one parent with diabetes, consider MODY rather than type 1 diabetes. 4 MODY accounts for 1.2-4% of pediatric diabetes and is frequently misdiagnosed. 4

In children diagnosed <6 months of age, skip autoantibody testing and proceed directly to genetic testing for neonatal diabetes. 4

Laboratory Quality Requirements

Autoantibody testing should be performed only in accredited laboratories with established quality control programs and participation in proficiency testing programs. 4 HbA1c testing must be performed using a method certified by the NGSP and standardized to the DCCT assay. 1

Pre-Test Preparation

Patients should consume a mixed diet with at least 150 g of carbohydrate on the 3 days prior to OGTT. 1 Fasting and carbohydrate restriction can falsely elevate glucose levels with an oral glucose challenge. 1

Plasma glucose samples must be spun and separated immediately after they are drawn to prevent falsely low results. 1

Screening Recommendations

Type 2 Diabetes Screening in Adults

Begin screening at age 35 years for all patients, or earlier in adults of any age with BMI ≥25 kg/m² (≥23 kg/m² in Asian Americans) and one or more additional risk factors for diabetes. 1

Additional risk factors include: 1

• Physical inactivity
• First-degree relative with diabetes
• High-risk race/ethnicity (African American, Latino, Native American, Asian American, Pacific Islander)
• History of gestational diabetes or polycystic ovary syndrome
• Hypertension (≥140/90 mmHg or on therapy)
• HDL cholesterol <35 mg/dL and/or triglycerides >250 mg/dL
• History of cardiovascular disease

If tests are normal, repeat screening at minimum 3-year intervals. 1

Type 1 Diabetes Screening in At-Risk Individuals

Screening for presymptomatic type 1 diabetes may be done by detection of autoantibodies to insulin, GAD, IA-2, or ZnT8 in first-degree relatives of patients with type 1 diabetes. 1 When multiple islet autoantibodies are identified, referral to a specialized center for further evaluation and/or consideration of clinical trial or approved therapy (such as teplizumab) to potentially delay development of clinical diabetes should be considered. 1, 4