What tests can diagnose hyperinsulinemia in an individual with risk factors for type 2 diabetes?

Testing for High Insulin Levels (Hyperinsulinemia)

To determine if someone has high insulin levels, measure fasting plasma insulin and C-peptide after an overnight fast (8-12 hours), with fasting insulin ≥12 μU/mL or C-peptide >0.6 ng/mL suggesting hyperinsulinemia in the context of normal or low glucose levels. 1, 2

Primary Testing Approach

Fasting Insulin and C-peptide Measurement

• Fasting plasma insulin should be measured after an 8-12 hour overnight fast, with levels ≥12 μU/mL considered elevated and indicative of insulin resistance or hyperinsulinemia 3
• C-peptide measurement provides a more stable marker of endogenous insulin secretion, with fasting levels >0.6 ng/mL (>0.2 nmol/L) indicating preserved or excessive insulin production 1, 2
• These tests are particularly useful when evaluating insulin resistance in patients with risk factors for type 2 diabetes, including obesity, family history, or metabolic syndrome 4

Clinical Context Matters

The interpretation of insulin levels depends critically on the concurrent glucose level:

• In hypoglycemia (glucose <55 mg/dL): Insulin ≥3 μU/mL with C-peptide ≥0.6 ng/mL indicates inappropriate hyperinsulinemia, suggesting endogenous hyperinsulinism 1, 2
• In normal fasting glucose (70-99 mg/dL): Elevated fasting insulin suggests insulin resistance, where the body compensates for decreased insulin sensitivity by producing more insulin 5, 3
• In prediabetes/diabetes: Insulin levels may appear "normal" but are actually insufficient relative to the degree of hyperglycemia, representing relative insulin deficiency 4

Indirect Assessment Methods

Calculated Indices for Insulin Resistance

When direct insulin measurement is unavailable or for screening purposes:

• HOMA-IR (Homeostasis Model Assessment): Calculated as [fasting insulin (μU/mL) × fasting glucose (mg/dL)] / 405, with values ≥2.6 suggesting insulin resistance 3
• QUICKI (Quantitative Insulin Sensitivity Check Index): Calculated as 1/[log(fasting insulin μU/mL) + log(fasting glucose mg/dL)], with values <0.33 indicating insulin resistance 3
• McAuley Index: Uses fasting insulin and triglycerides, with values <5.8 suggesting insulin resistance (this has the highest sensitivity and specificity at 0.75 and 0.91 respectively) 3

Standard Diabetes Screening Tests

For patients with risk factors, standard diabetes screening can identify the metabolic consequences of chronic hyperinsulinemia:

• Fasting plasma glucose ≥126 mg/dL diagnoses diabetes; 100-125 mg/dL indicates prediabetes (impaired fasting glucose) 6, 7
• Hemoglobin A1C ≥6.5% diagnoses diabetes; 5.7-6.4% indicates prediabetes, reflecting average glucose exposure over 2-3 months 4, 6, 7
• 2-hour oral glucose tolerance test with 75g glucose load: ≥200 mg/dL diagnoses diabetes; 140-199 mg/dL indicates prediabetes (impaired glucose tolerance) 6, 7

Advanced Testing for Specific Scenarios

Extended Fasting Tests

• Mini-fasting test: Measure glucose, insulin, and C-peptide after 12-hour overnight fast on 3 consecutive days; 100% of patients with endogenous hyperinsulinism showed insulin ≥3 μU/mL and C-peptide ≥0.6 ng/mL with symptomatic hypoglycemia 1
• 72-hour supervised fast: Gold standard for diagnosing endogenous hyperinsulinism (insulinoma, nesidioblastosis), but often unnecessary if mini-fasting test is diagnostic 1

Proinsulin Measurement

• Proinsulin >5 pmol/L with glucose <2.5 mmol/L (45 mg/dL) has 100% specificity and sensitivity for endogenous hyperinsulinism 2
• Proinsulin >22 pmol/L at fasting glucose 2.5-3.3 mmol/L (45-60 mg/dL) may diagnose hyperinsulinism in 74% of cases 2
• This is particularly useful when insulin and C-peptide results are equivocal 2

Critical Pitfalls to Avoid

Test Interpretation Errors

• Do not interpret insulin levels in isolation: Always correlate with concurrent glucose levels, as "normal" insulin with low glucose is pathologic, while elevated insulin with normal glucose indicates resistance 1, 2
• Timing matters: Insulin has a short half-life; samples must be drawn simultaneously with glucose and processed promptly to avoid falsely low values 7
• Obesity confounds results: Obese patients naturally have higher baseline insulin levels due to increased insulin resistance, so absolute cutoffs may not apply 4, 3

When NOT to Use Certain Tests

• A1C should not be used in conditions affecting red blood cell turnover: hemoglobinopathies, hemolytic anemias, pregnancy, recent blood loss/transfusion, hemodialysis, or erythropoietin therapy 4, 7
• Fasting insulin alone is insufficient for diagnosing endogenous hyperinsulinism; C-peptide and/or proinsulin provide better diagnostic accuracy 2

Screening Recommendations for At-Risk Patients

Who Should Be Tested

• All adults ≥35 years should be screened for diabetes/prediabetes (which reflects chronic hyperinsulinemia) 4
• Any age with BMI ≥25 kg/m² (≥23 kg/m² in Asian Americans) plus one additional risk factor: family history, hypertension, dyslipidemia, physical inactivity, history of gestational diabetes, or polycystic ovary syndrome 4, 6
• Repeat testing every 3 years if initial results are normal 4

Risk Factor Assessment

The American Diabetes Association risk test evaluates age, sex, family history, gestational diabetes history, hypertension, physical activity, and weight to identify high-risk individuals who warrant testing 4