How should I measure and interpret fasting insulin levels?

Fasting Insulin Measurement and Interpretation

When to Measure Fasting Insulin

Fasting insulin levels are NOT routinely recommended for diabetes diagnosis or screening. The 2023 American Diabetes Association/American Association for Clinical Chemistry guidelines make no recommendation for measuring insulin levels in the diagnosis or management of diabetes mellitus 1. Instead, fasting plasma glucose, HbA1c, or oral glucose tolerance testing should be used for diabetes screening and diagnosis 1.

Specific Clinical Scenarios Where Fasting Insulin May Be Useful

• Suspected insulinoma or endogenous hyperinsulinism: Measure insulin during documented hypoglycemia (glucose <55 mg/dL) after a supervised fast, with concomitant C-peptide measurement 1, 2, 3
• Polycystic ovary syndrome (PCOS) evaluation: Fasting insulin or fasting glucose/insulin ratio may help identify hyperinsulinemia in women with hyperandrogenism 4
• Research settings for insulin resistance assessment: Fasting insulin can be used to calculate surrogate markers like HOMA-IR, though this is not recommended for routine clinical practice 5, 6

How to Measure Fasting Insulin Properly

Sample Collection Requirements

• Draw blood after an overnight fast of at least 8 hours, ideally in the morning 1
• Use venous plasma samples collected in tubes with appropriate glycolytic inhibitors (granulated citrate buffer preferred over sodium fluoride alone) 1
• Process samples promptly: Place in ice-water slurry immediately and centrifuge within 15-30 minutes to prevent glycolysis 1
• Measure in an accredited laboratory when used for diagnostic purposes 1

Critical Pre-Analytical Considerations

• Discontinue proton pump inhibitors at least 1 week before testing if evaluating for gastrinoma, as these medications spuriously elevate gastrin and can interfere with interpretation 1
• Ensure patient is off medications that affect insulin secretion (sulfonylureas, meglitinides) when assessing for endogenous hyperinsulinism
• Use insulin-specific assays (immunoradiometric assays without proinsulin cross-reactivity) rather than older RIA methods that cross-react with proinsulin 3

Interpreting Fasting Insulin Levels

For Suspected Insulinoma/Endogenous Hyperinsulinism

The diagnosis requires demonstrating inappropriate insulin secretion during documented hypoglycemia, NOT elevated fasting insulin in isolation. 1

• Insulin level >3 mcIU/mL (usually >6 mcIU/mL) when glucose <40-45 mg/dL indicates inappropriate insulin secretion 1
• Insulin-to-glucose ratio ≥0.3 at the time of hypoglycemia supports the diagnosis 1
• C-peptide must be elevated (>0.6 ng/mL) concomitantly to confirm endogenous insulin production 1, 2, 3
• Measure proinsulin levels (should be >35 pmol/L) when using insulin-specific assays, as some insulinomas produce predominantly proinsulin 3

Critical Pitfall: Assay-Dependent Thresholds

When using modern insulin-specific assays without proinsulin cross-reactivity, insulin levels may be <6 mcIU/mL or even <3 mcIU/mL during hypoglycemia in patients with small insulinomas 3. **Always measure C-peptide and/or proinsulin concomitantly**—elevated C-peptide (>0.6 ng/mL) confirms endogenous hyperinsulinism even when insulin appears "normal" 3.

For Insulin Resistance Assessment (Research Context Only)

• No established clinical cutoffs exist for fasting insulin to diagnose insulin resistance in routine practice 5, 6
• Fasting insulin >16.8 mcIU/mL has been used in research to identify hyperinsulinemia in PCOS populations 4
• Fasting glucose/insulin ratio ≤4.5 may indicate hyperinsulinemia (ratio >4.5 suggests normoinsulinemia) 4
• HOMA-IR calculation (fasting insulin × fasting glucose / 405) correlates with insulin resistance but lacks standardized diagnostic thresholds for clinical use 5, 6

Non-Fasting Insulin Measurements

Non-fasting insulin measurements are NOT validated for clinical diagnosis but show moderate correlation with fasting values (r=0.45 for HOMA-IR) and may be acceptable for epidemiological research 5. For clinical decision-making, always obtain properly collected fasting samples.

Common Pitfalls to Avoid

• Never use fasting insulin alone to diagnose diabetes or prediabetes—this is not guideline-recommended and lacks validated thresholds 1
• Never interpret insulin levels without simultaneous glucose measurement—the insulin level must be evaluated in the context of the concurrent glucose concentration 1, 3
• Never diagnose insulinoma based on elevated fasting insulin in the absence of documented hypoglycemia—asymptomatic hyperinsulinemia has many causes 1
• Never rely on insulin measurements alone when C-peptide should be measured—C-peptide is mandatory when using insulin-specific assays to confirm endogenous hyperinsulinism 3
• Never forget to check for factitious hypoglycemia—measure C-peptide and screen urine for sulfonylureas to exclude exogenous insulin administration 1