What are the diagnostic approaches and treatment options for insulin resistance?

Diagnosing Insulin Resistance

Diagnose insulin resistance using fasting plasma glucose (100-125 mg/dL), fasting insulin levels (>15 mU/L), or hemoglobin A1C (5.7-6.4%), with BMI ≥25 kg/m² (≥23 kg/m² in Asian Americans) and additional risk factors triggering the need for testing. 1, 2

Risk Assessment: Who Should Be Tested

Begin by identifying patients at risk through the following criteria:

• Obesity markers: BMI ≥25 kg/m² (or ≥23 kg/m² for Asian Americans) 1, 2
• Family history: First-degree relative with type 2 diabetes 1, 3
• Racial/ethnic predisposition: American Indian, African American, Hispanic/Latino, or Asian/Pacific Islander ancestry 1, 2
• Physical signs: Acanthosis nigricans (velvety hyperpigmentation in axillary/flexural areas), central/visceral adiposity, or skin tags 1, 4
• Associated conditions: Hypertension, dyslipidemia, polycystic ovary syndrome, or history of gestational diabetes 1, 2, 3
• Lifestyle factors: Physical inactivity 2, 5

Diagnostic Testing Algorithm

First-Line Laboratory Tests (Choose One or More):

1. Fasting Plasma Glucose (FPG)

• Impaired fasting glucose: 100-125 mg/dL indicates insulin resistance 1, 2
• Requires 8-hour fast 6
• Most practical initial screening test 1

2. Fasting Insulin Levels

• Normal: <15 mU/L 1
• Borderline high: 15-20 mU/L 1
• High (diagnostic): >20 mU/L 1, 7
• Directly suggests insulin resistance when elevated 1

3. Hemoglobin A1C

• Prediabetes range: 5.7-6.4% indicates insulin resistance 1, 2
• Does not require fasting 2
• Risk increases disproportionately at higher end of range 2

4. Oral Glucose Tolerance Test (OGTT)

• Impaired glucose tolerance: 2-hour glucose 140-199 mg/dL after 75g glucose load 1, 2
• More sensitive than fasting glucose alone but more time-intensive 8

Alternative Validated Approaches:

HOMA-IR (Homeostasis Model Assessment)

• Calculate from fasting glucose and insulin 7
• Diagnostic cutoffs: HOMA-IR >4.65 (corresponding to fasting insulin >20.7 μU/mL) or HOMA-IR >3.60 if BMI >27.5 kg/m² (corresponding to fasting insulin >16.3 μU/mL) 7
• Sensitivity 84.9%, specificity 78.7% 7

Simple Clinical Decision Rule (No Laboratory Tests)

• Diagnose insulin resistance if BMI >28.9 kg/m² alone 7
• This approach has 78.7% sensitivity and 79.6% specificity 7

Comprehensive Clinical Evaluation

Physical Examination Focus:

• Acanthosis nigricans: Look specifically in neck, axillae, and groin 1, 4
• Central obesity: Measure waist circumference and assess abdominal fat distribution 1, 5
• Lipodystrophy: Carefully examine for fat loss patterns, particularly in patients with significant dyslipidemia and fatty liver 4
• Blood pressure: Document hypertension as associated finding 1

Additional Laboratory Assessment:

• Lipid profile: Check for dyslipidemia (HDL <35 mg/dL, triglycerides >250 mg/dL) 2, 1
• C-peptide measurement: Consider when differentiating endogenous insulin production from exogenous administration 1
• Simultaneous elevation of insulin and C-peptide confirms endogenous hyperinsulinism suggesting insulin resistance 1

Interpreting Results

Definitive Diagnosis:

• Presence of impaired fasting glucose (100-125 mg/dL) OR impaired glucose tolerance (2-hour OGTT 140-199 mg/dL) indicates prediabetes and likely insulin resistance 1
• Elevated fasting insulin (>15 mU/L) directly confirms insulin resistance 1
• A1C 5.7-6.4% suggests prediabetes with underlying insulin resistance 1, 2

Risk Stratification:

• Patients with A1C >6.0% are at very high risk and require aggressive intervention 2
• Risk is continuous across the prediabetes range, becoming disproportionately greater at higher values 2

Critical Pitfalls to Avoid

Testing Conditions:

• Always perform testing in fasting state (minimum 8 hours) to avoid postprandial variations 1, 6
• Do not use stress hyperglycemia during acute illness for diagnosis—this temporarily mimics insulin resistance 1

Interpretation Errors:

• Normal glucose does not exclude insulin resistance: Hyperinsulinemia can exist with euglycemia (termed "euglycemic dysmetabolism") 5
• Isolated elevated C-peptide without hypoglycemia generally reflects insulin resistance rather than pathological hyperinsulinism 1
• Document medications affecting glucose metabolism (corticosteroids, thiazides, beta-blockers) when interpreting results 1

A1C Limitations:

• Conditions affecting A1C accuracy include hemoglobinopathies, anemia, and recent blood transfusion 6
• Use alternative tests (FPG or OGTT) in these situations 6

Population-Specific Considerations:

• Asian Americans have increased diabetes risk at lower BMI thresholds (≥23 kg/m² vs ≥25 kg/m²) 2, 6
• African Americans may have equivalent diabetes risk at BMI 26 kg/m² compared to BMI 30 kg/m² in non-Hispanic whites 2

Treatment Approach After Diagnosis

Once insulin resistance is confirmed:

Lifestyle Interventions (First-Line):

• Weight loss to achieve healthy body weight 2, 3
• 30 minutes of accumulated moderate-intensity physical activity daily 3
• Increased dietary fiber intake 3

Pharmacotherapy:

• Metformin is the preferred insulin sensitizer when lifestyle modifications are insufficient 4
• Pharmacotherapy is not currently recommended for isolated insulin resistance without diabetes 3
• In severe insulin resistance with lipodystrophy, leptin replacement may be indicated 4

The hyperinsulinemic euglycemic clamp remains the gold standard for research purposes but is impractical for routine clinical use 9, 8. The diagnostic approach outlined above using fasting glucose, insulin levels, A1C, and clinical assessment provides accurate, reproducible identification of insulin-resistant patients suitable for clinical practice 1, 7.