What are the methods for diagnosing diabetes?

Diagnosis of Diabetes Mellitus

The diagnosis of diabetes mellitus is established through four primary methods: fasting plasma glucose ≥126 mg/dL (7.0 mmol/L), 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT), hemoglobin A1C ≥6.5% (48 mmol/mol), or random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia. 1, 2

Diagnostic Criteria

Primary Diagnostic Tests

• Fasting Plasma Glucose (FPG): ≥126 mg/dL (7.0 mmol/L), with fasting defined as no caloric intake for at least 8 hours 1, 2
• 2-hour Plasma Glucose: ≥200 mg/dL (11.1 mmol/L) during OGTT using 75g of anhydrous glucose 1
• Hemoglobin A1C: ≥6.5% (48 mmol/mol), performed in a laboratory using a method certified by the National Glycohemoglobin Standardization Program (NGSP) 1, 2
• Random Plasma Glucose: ≥200 mg/dL (11.1 mmol/L) in patients with classic symptoms of hyperglycemia (polyuria, polydipsia, unexplained weight loss) or hyperglycemic crisis 1

Confirmation Requirements

• In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples 1, 2
• When using two separate test samples, the second test should be performed without delay 1
• If two different tests (such as A1C and FPG) are both above diagnostic thresholds, this confirms the diagnosis 1, 2
• For discordant results from two different tests, the test result above the diagnostic threshold should be repeated 1

Categories of Increased Risk for Diabetes (Prediabetes)

• Impaired Fasting Glucose (IFG): FPG 100-125 mg/dL (5.6-6.9 mmol/L) 3, 4
• Impaired Glucose Tolerance (IGT): 2-hour PG during OGTT 140-199 mg/dL (7.8-11.0 mmol/L) 3, 4
• A1C: 5.7-6.4% (39-47 mmol/mol) 3

Special Considerations and Limitations

A1C Testing Limitations

• A1C should not be used for diagnosis in conditions with increased 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
  • HIV treated with certain drugs
  • Iron-deficient anemia 1, 3

Test Variability Considerations

• FPG has a 12-15% day-to-day variance 1
• Marked discordance between A1C and plasma glucose levels should raise suspicion of hemoglobin variants interfering with the A1C assay 1, 3
• Plasma glucose samples should be spun and separated immediately after collection to prevent preanalytic variability 1

Specific Diabetes Types

Type 1 Diabetes

• Characterized by autoimmune destruction of pancreatic β-cells 1
• Diagnostic markers include:
  • Islet cell autoantibodies
  • Autoantibodies to GAD (GAD65)
  • Autoantibodies to insulin
  • Autoantibodies to tyrosine phosphatases IA-2 and IA-2β
  • Autoantibodies to zinc transporter 8 (ZnT8) 1, 2
• Often presents with diabetic ketoacidosis (DKA) 1

Type 2 Diabetes

• Accounts for 90-95% of all diabetes cases 1
• Often associated with metabolic syndrome and obesity 2
• Typically has normal or elevated C-peptide levels 2

Gestational Diabetes Mellitus (GDM)

• Diagnosed using either one-step or two-step strategy at 24-28 weeks of gestation 1
• One-step strategy: 75-g OGTT with diagnostic thresholds of:
  • Fasting: ≥92 mg/dL (5.1 mmol/L)
  • 1-hour: ≥180 mg/dL (10.0 mmol/L)
  • 2-hour: ≥153 mg/dL (8.5 mmol/L) 1
• Two-step strategy:
  • Step 1: 50-g glucose load test (non-fasting) with 1-hour plasma glucose measurement
  • Step 2: If ≥130,135, or 140 mg/dL (7.2,7.5, or 7.8 mmol/L), proceed to 100-g OGTT 1

Practical Approach to Diagnosis

1. Assess risk factors: family history, BMI >25 kg/m², sedentary lifestyle, hypertension, dyslipidemia, history of gestational diabetes, polycystic ovary syndrome 1, 4
2. Begin with FPG and A1C tests in patients with risk factors 2, 3
3. If either test is positive, confirm with a repeat of the same test or a different test 1, 2
4. In cases of discordance or high clinical suspicion with negative initial tests, perform an OGTT 2, 3
5. For patients with classic symptoms and random glucose ≥200 mg/dL, additional testing is not required 1

Screening Recommendations

• Screen patients with sustained blood pressure >135/80 mm Hg 1
• Screen patients with hypertension or hyperlipidemia 1
• Consider screening high-risk ethnic groups: Black, Latin American, Native American, and Asian-Pacific Islander populations 4