Tests for Hyperinsulinemia
For a patient with suspected hyperinsulinemia, measure fasting plasma insulin concentration alongside simultaneous fasting plasma glucose to calculate the fasting insulin-to-glucose ratio (I/G index), with a limiting value of 0.4 (when insulin is in mIU/L and glucose in mg%) indicating hyperinsulinemia. 1
Initial Laboratory Assessment
The diagnostic workup should include:
- Fasting plasma insulin concentration with simultaneous fasting plasma glucose measurement 2, 1
- Insulin-to-glucose ratio (I/G index): The insulinogenic index with a cut-off value of 0.4 identifies hyperinsulinism 1
- Glucose-to-insulin ratio (G/I index): A limiting value of 6 (insulin in mIU/L, glucose in mg%) helps assess insulin resistance, with values below 6 suggesting insulin resistance 1
- C-peptide measurement: Both basal and during oral glucose tolerance test (OGTT), as the C-peptide to insulin ratio helps distinguish between hypersecretory hyperinsulinism versus reduced hepatic insulin clearance 1
- Normal basal C-peptide:insulin ratio is approximately 5:1
- After glucose load, the ratio decreases to approximately 2.5:1 1
Oral Glucose Tolerance Test (OGTT)
Perform a 75-gram OGTT with serial insulin and glucose measurements to evaluate dynamic insulin response 2, 1:
- Measure plasma insulin and glucose at baseline, 30 minutes, 1 hour, and 2 hours post-glucose load 1
- Post-load insulin threshold: Insulin levels >63 mIU/L at 2 hours indicate hyperinsulinemia 1
- Calculate I/G and G/I indices at multiple time points, particularly at 2 hours 1
The OGTT is particularly valuable because hyperinsulinemic responses can occur with four different glycemic curve patterns: normal curves, flat curves, impaired glucose tolerance, and diabetic curves 1
Additional Metabolic Assessment
Include these tests to evaluate associated metabolic abnormalities and underlying causes:
- Fasting lipid profile: To assess for dyslipidemia associated with insulin resistance 3
- Serum electrolytes (including calcium and magnesium) 3
- Liver function tests: To evaluate hepatic insulin clearance and fatty liver disease 3
- Thyroid-stimulating hormone: To exclude thyroid dysfunction 3
- Hemoglobin A1c: To assess glycemic control and identify pre-diabetes or diabetes 3
Specialized Testing for Specific Clinical Contexts
For Suspected Congenital Hyperinsulinism (Infants/Children)
When evaluating hyperinsulinism in pediatric patients, additional testing is required 4:
- Plasma beta-hydroxybutyrate during hypoglycemia (suppressed in hyperinsulinism) 4
- Plasma fatty acids during hypoglycemia (suppressed in hyperinsulinism) 4
- Plasma ammonia (elevated in glutamate dehydrogenase mutations) 4
- Plasma acylcarnitine profile 4
- Urine organic acids 4
- Genetic testing for genes associated with congenital hyperinsulinism (SUR-1, Kir6.2, glucokinase, glutamate dehydrogenase, SCHAD, SLC16A1) 4
- Acute insulin response (AIR) tests for phenotypic characterization 4
Advanced Research Methods (Not for Routine Clinical Use)
While the hyperinsulinemic-euglycemic clamp and frequently sampled intravenous glucose tolerance test are considered "gold standard" methods for measuring insulin sensitivity, they are impractical for routine clinical practice and should be reserved for research settings 2
Clinical Pitfalls to Avoid
- Do not rely solely on fasting insulin levels: A single fasting insulin measurement without glucose context provides limited diagnostic value 2, 1
- Distinguish hyperinsulinemia from insulin resistance: High fasting insulin can predict type 2 diabetes independent of insulin resistance, representing a distinct pathogenic mechanism 5
- Consider timing of measurements: Fasting measurements may miss postprandial hyperinsulinemia, making OGTT essential for comprehensive assessment 1
- Account for hepatic clearance: The C-peptide to insulin ratio helps identify whether hyperinsulinemia results from hypersecretion versus reduced hepatic extraction 1