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

Diabetes Mellitus: Diagnostic Criteria and Management

Diagnostic Criteria

Diabetes is diagnosed when any one of the following criteria is met: fasting plasma glucose ≥126 mg/dL (7.0 mmol/L), 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test, HbA1c ≥6.5% (using an NGSP-certified assay), or random plasma glucose ≥200 mg/dL with classic hyperglycemic symptoms. 1, 2

Specific Diagnostic Thresholds

• Fasting Plasma Glucose (FPG): ≥126 mg/dL after at least 8 hours of fasting 1, 2
• 2-Hour Plasma Glucose (OGTT): ≥200 mg/dL during 75-g oral glucose tolerance test 1, 2
• HbA1c: ≥6.5% (48 mmol/mol) using NGSP-certified and DCCT-standardized assay 1, 2
• Random Plasma Glucose: ≥200 mg/dL with classic symptoms (polyuria, polydipsia, unexplained weight loss) 1, 2

Critical Testing Requirements

In the absence of unequivocal hyperglycemia or hyperglycemic crisis, diagnosis requires two abnormal test results from the same sample or in two separate test samples. 1 A single test showing diabetic-range values is sufficient only when accompanied by classic symptoms, HbA1c ≥6.5%, or documented diabetic retinopathy. 1

Important Testing Caveats

• The HbA1c test must be performed using an NGSP-certified method standardized to the DCCT assay 1, 2
• In conditions that alter the relationship between HbA1c and glycemia—including sickle cell disease, pregnancy (second and third trimesters), glucose-6-phosphate dehydrogenase deficiency, HIV, hemodialysis, recent blood loss or transfusion, or erythropoietin therapy—only plasma glucose criteria should be used for diagnosis 1
• Marked discordance between measured HbA1c and plasma glucose levels should raise suspicion of HbA1c assay interference due to hemoglobin variants 1

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Classification: Type 1 vs Type 2 Diabetes

Type 1 Diabetes Mellitus

Type 1 diabetes is caused by autoimmune destruction of pancreatic β-cells, rendering the pancreas unable to synthesize and secrete insulin. 1 It accounts for approximately 5-15% of diabetes cases in developed countries. 1

Staging of Type 1 Diabetes

Type 1 diabetes progresses through three distinct stages that can be identified before clinical symptoms appear: 1, 2

• Stage 1: Multiple islet autoantibodies present with normoglycemia (FPG <100 mg/dL, 2-hour PG <140 mg/dL) 1, 2
• Stage 2: Islet autoantibodies present with dysglycemia (FPG 100-125 mg/dL or 2-hour PG 140-199 mg/dL or HbA1c 5.7-6.4% or ≥10% increase in HbA1c) 1, 2
• Stage 3: Overt hyperglycemia meeting diabetes criteria with clinical symptoms 1, 2

Diagnostic Testing for Type 1 Diabetes

The presence of two or more positive islet autoantibodies confirms type 1 diabetes and predicts progression to insulin dependence (70% within 10 years). 2, 3 A single positive autoantibody carries lower predictive value (15% risk within 10 years). 2

Key autoantibodies to test include: 3

• Glutamic acid decarboxylase (GAD65) antibodies
• Insulinoma-associated antigen-2 (IA-2) antibodies
• Insulin autoantibodies (IAA)
• Zinc transporter 8 (ZnT8) antibodies

Type 2 Diabetes Mellitus

Type 2 diabetes results from a combination of insulin resistance and inadequate insulin secretion, accounting for 85-95% of diabetes cases in developed countries. 1 Patients may have insulin levels that appear normal or elevated, but these are insufficient to compensate for insulin resistance. 1

Risk Factors for Type 2 Diabetes

Type 2 diabetes occurs more frequently in: 1

• Older individuals (age is a major risk factor)
• Individuals with obesity (BMI ≥25 kg/m²; ≥23 kg/m² for Asian Americans)
• Those with physical inactivity
• Women with prior gestational diabetes or polycystic ovary syndrome
• Individuals with hypertension or dyslipidemia
• Certain racial/ethnic groups (African American, Native American, Hispanic/Latino, Asian American)
• Those with family history in first-degree relatives

Distinguishing Type 1 from Type 2 Diabetes

When clinical presentation is ambiguous, islet autoantibody testing is the most valuable laboratory test for differentiation. 3, 4 Testing for multiple autoantibodies (GADA, IA-2A, IAA, ZnT8A) provides the strongest differentiation. 3

C-Peptide Measurement

C-peptide measurement is primarily indicated when the patient is already on insulin therapy and you need to assess residual β-cell function. 2 Interpretation: 2

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

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

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

Clinical Algorithm: AABBCC Approach

The American Diabetes Association recommends the AABBCC clinical approach to complement laboratory testing: 1, 3

• Age: For individuals <35 years old, consider type 1 diabetes
• Autoimmunity: Personal or family history of autoimmune disease
• Body habitus: BMI <25 kg/m² suggests type 1
• Background: Family history of type 1 diabetes
• Control: Level of glucose control on noninsulin therapies
• Comorbidities: Treatment with immune checkpoint inhibitors can cause acute autoimmune type 1 diabetes

Important caveat: A diagnosis of type 1 diabetes does not preclude having features classically associated with type 2 diabetes, such as insulin resistance or obesity. 3 Some patients may have features of both conditions requiring treatment approaches for both. 3

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Screening Recommendations

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, 2

Additional risk factors warranting earlier screening include: 2

• 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
• Physical inactivity

If tests are normal, repeat screening at minimum 3-year intervals. 2

Children and Adolescents

Screening for type 2 diabetes should be considered in children and adolescents with overweight or obesity and additional risk factors. 1 The dramatic increase in type 2 diabetes incidence in children, especially in racial and ethnic minority populations, necessitates risk-based screening. 1

Presymptomatic Type 1 Diabetes Screening

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. 2 This allows identification of individuals in Stages 1 and 2 before clinical symptoms develop. 1

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Management Strategies

Type 1 Diabetes Management

Type 1 diabetes requires insulin replacement therapy from diagnosis due to absolute insulin deficiency. 1 Patients need comprehensive education regarding:

• Insulin injection technique and storage
• Blood glucose monitoring
• Recognition and treatment of hypoglycemia
• "Sick day" management rules
• Ketone monitoring 1

Type 2 Diabetes Management

Glycemic Targets

The HbA1c goal for most nonpregnant adults with type 2 diabetes is <7%. 4 However, targets should be adjusted based on individual factors:

• More stringent goals (<6.5%) may be appropriate for: 4

  • Short duration of diabetes
  • Type 2 diabetes treated with lifestyle or metformin only
  • Long life expectancy
  • No cardiovascular disease

• Less stringent goals (<8%) may be appropriate for: 4

  • History of severe hypoglycemia
  • Limited life expectancy
  • Advanced microvascular or macrovascular complications
  • Extensive comorbid conditions

Initial Management Approach

Nutrition therapy and physical activity are fundamental components of diabetes management and should be initiated at diagnosis. 4 Moderate-to-vigorous exercise that makes the individual breathe hard and perspire is recommended. 4

Metformin is the preferred initial pharmacologic agent for most patients with type 2 diabetes. 1, 4 It has high glucose-lowering effectiveness (expected HbA1c reduction 1.0-1.5%), does not cause hypoglycemia when used alone, and is generally well-tolerated. 1

Escalation of Therapy

If the HbA1c level is 9% or greater at diagnosis, consider initial dual-regimen combination therapy to more quickly achieve glycemic control. 4

When blood glucose levels are ≥300-350 mg/dL or HbA1c levels are 10-12%, especially with symptoms, consider starting with insulin therapy. 4

Insulin Therapy in Type 2 Diabetes

Due to progressive β-cell dysfunction, insulin replacement is frequently required in type 2 diabetes. 1 The principle is creating as normal a glycemic profile as possible without unacceptable weight gain or hypoglycemia. 1

Initial insulin therapy typically consists of basal insulin alone added to existing oral agents. 1 Options include:

• Intermediate-acting (NPH insulin)
• Long-acting (insulin glargine or insulin detemir)

Long-acting analogs are associated with modestly less overnight hypoglycemia and possibly slightly less weight gain (insulin detemir) compared to NPH, but are more expensive. 1

Some patients will require prandial insulin therapy with rapid-acting insulin analogs (insulin lispro, insulin aspart, or insulin glulisine) dosed just before meals. 1 These provide better postprandial glucose control than regular human insulin. 1

Blood Glucose Monitoring

Self-monitoring of blood glucose (SMBG) is recommended for all patients using insulin therapy. 4 For patients not using insulin, the optimal frequency is not established but should be determined based on individual needs and goals. 4 For patients using oral agents with low risk of hypoglycemia and with HbA1c in target range, less frequent monitoring may be appropriate. 4

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Common Pitfalls and How to Avoid Them

• Misdiagnosis between type 1 and type 2 diabetes occurs in approximately 40% of adults with new type 1 diabetes. 1 Always consider autoantibody testing in adults <35 years old, those with unintentional weight loss, ketoacidosis at presentation, or rapid progression to insulin dependence. 3

• Relying solely on HbA1c for diagnosis can miss cases. 1 There is substantial overlap in HbA1c distribution between normal, prediabetes, and mild diabetes. HbA1c >6.5% suggests diabetes, but HbA1c <6.5% should not be taken as evidence against diabetes. 1

• Using only fasting plasma glucose for screening will miss many cases. 1 The 2-hour OGTT value diagnoses more people with diabetes than FPG alone, particularly in populations where postprandial hyperglycemia predominates. 1

• Autoantibodies may not be detectable in all type 1 diabetes patients and tend to decrease with age. 3 Negative autoantibodies do not exclude type 1 diabetes, especially in long-standing disease.

• C-peptide measurement alone may not be clinically necessary in all cases. 3 Response to therapy can provide useful diagnostic information without additional testing costs.