Blood Tests for Non-Diabetic Hypoglycemia
The complete hypoglycemic blood panel must include simultaneous measurement of glucose, insulin, C-peptide, proinsulin, insulin antibodies, and screening for oral hypoglycemic agents during a documented hypoglycemic episode. 1, 2, 3
Critical Timing and Documentation
Blood samples must be obtained during symptomatic hypoglycemia (when glucose is documented <70 mg/dL) to have diagnostic value, as patients are typically normoglycemic between episodes. 4, 2, 3
The diagnosis requires establishing Whipple's triad: documented low blood glucose, neuroglycopenic symptoms (confusion, altered mental status, seizures), and resolution of symptoms when glucose normalizes. 4, 3
If the patient is asymptomatic at presentation, provocation testing is necessary—either a supervised 72-hour fast for fasting hypoglycemia or a mixed meal test for postprandial symptoms. 2, 3
Essential Laboratory Panel Components
During documented hypoglycemia (<70 mg/dL), obtain:
Laboratory glucose measurement (not just fingerstick) to confirm true hypoglycemia 4, 2
Insulin level to detect inappropriate hyperinsulinemia 5, 2, 3
C-peptide to distinguish endogenous insulin production from exogenous insulin administration (C-peptide is suppressed with exogenous insulin but elevated with insulinoma or sulfonylurea use) 5, 2, 3
Proinsulin because an elevated proinsulin-to-insulin ratio strongly suggests insulinoma 5, 2
Beta-hydroxybutyrate to classify the hypoglycemia as ketotic versus non-ketotic 4, 3
Insulin antibodies to detect insulin autoimmune syndrome 2, 3
Plasma and urine screening for sulfonylureas and other oral hypoglycemic agents to rule out factitious hypoglycemia 2, 3
Diagnostic Classification Based on Results
The blood panel results will classify hypoglycemia into three categories that direct further investigation: 4
Non-ketotic hyperinsulinemia (elevated insulin, elevated C-peptide, suppressed beta-hydroxybutyrate): suggests insulinoma, sulfonylurea use, or insulin autoimmune syndrome
Non-ketotic hypoinsulinemia (low insulin, low C-peptide, suppressed beta-hydroxybutyrate): suggests non-islet cell tumor producing IGF-II
Ketotic hypoinsulinemia (low insulin, low C-peptide, elevated beta-hydroxybutyrate): suggests hormone deficiency (cortisol, growth hormone) or critical illness
Key Diagnostic Patterns
For insulinoma diagnosis: Inappropriately elevated plasma insulin concentrations despite low glucose, plus an increased proinsulin-to-insulin ratio during fasting hypoglycemia strongly indicates islet cell tumor. 5
For factitious hypoglycemia: Elevated insulin with suppressed C-peptide indicates exogenous insulin administration, while elevated insulin with elevated C-peptide plus positive sulfonylurea screen indicates oral agent ingestion. 5, 2
Common Pitfalls to Avoid
Do not rely on fingerstick glucose alone—many healthy individuals have glucose readings in the 50-60 mg/dL range on continuous monitoring without symptoms, which does not constitute pathologic hypoglycemia. 4
Do not obtain blood tests when the patient is asymptomatic and normoglycemic—these results are meaningless for diagnosis and will mislabel healthy individuals as hypoglycemic. 4, 2
Do not diagnose hypoglycemia without confirming Whipple's triad—symptoms must correlate with documented low glucose and resolve with glucose correction. 4, 3
In critically ill hospitalized patients, hypoglycemia may occur from severe illness itself and does not require extensive investigation unless another specific cause is suspected. 4, 6