Laboratory Tests for Hypoglycemic Episodes in Non-Diabetic Patients
For non-diabetic patients experiencing hypoglycemic episodes, a comprehensive laboratory workup should include serum insulin, C-peptide, and proinsulin levels at the time of hypoglycemia, along with plasma glucose measurement to establish the diagnosis and determine the etiology. 1
Initial Laboratory Evaluation During Hypoglycemia
When a patient presents with hypoglycemia (blood glucose <70 mg/dL), the following tests should be ordered immediately:
Critical Samples (Draw During Hypoglycemia)
- Plasma glucose (to confirm hypoglycemia)
- Serum insulin
- C-peptide levels
- Proinsulin levels
- Beta-hydroxybutyrate (to assess for ketosis)
- Insulin antibodies
- Sulfonylurea and meglitinide screen
These tests should ideally be collected during the hypoglycemic episode before treatment is administered, as they provide crucial diagnostic information about the cause of hypoglycemia 1, 2.
Additional Baseline Laboratory Tests
- Complete blood count
- Comprehensive metabolic panel (including liver and kidney function)
- Thyroid function tests
- Morning cortisol level
- Adrenocorticotropic hormone (ACTH) level
- Growth hormone level
- IGF-1 (Insulin-like growth factor 1)
Blood Sampling Considerations
The method of blood sampling is critical for accurate results:
- For critically ill patients: Draw blood samples from an arterial line or venous line, as capillary samples are inaccurate 3
- For stable patients: Venous samples are preferred, but capillary samples may be used if necessary 3
Diagnostic Algorithm Based on Laboratory Results
Pattern 1: Elevated Insulin with Suppressed C-peptide
- Suggests exogenous insulin administration
- Rule out surreptitious insulin use or accidental administration
Pattern 2: Elevated Insulin with Elevated C-peptide
- Suggests endogenous hyperinsulinism
- Consider:
- Insulinoma
- Nesidioblastosis (as seen in case reports) 4
- Sulfonylurea or meglitinide use
- Autoimmune hypoglycemia
Pattern 3: Low Insulin and C-peptide
- Consider:
- Adrenal insufficiency
- Hepatic failure
- Renal failure
- Severe malnutrition
- Non-islet cell tumors
Follow-Up Testing Based on Initial Results
Imaging studies: If insulinoma is suspected (elevated insulin and C-peptide during hypoglycemia), order:
- Abdominal CT or MRI
- Endoscopic ultrasound
72-hour fasting test: Gold standard for diagnosing insulinoma if initial results are inconclusive
Cortisol stimulation test: If adrenal insufficiency is suspected
Common Pitfalls to Avoid
Failing to obtain samples during hypoglycemia: Laboratory values may normalize after glucose administration, making diagnosis difficult 1
Relying solely on fingerstick glucose measurements: These can be inaccurate, especially in critically ill patients 3
Not considering medication effects: Many non-diabetes medications can cause hypoglycemia and should be reviewed
Overlooking rare causes: Non-diabetic hypoglycemia can result from insulinoma, adrenal insufficiency, or other endocrine disorders that require specific testing 2, 5
Delayed diagnosis: Persistent hypoglycemia can lead to neurocognitive dysfunction and increased mortality if not properly identified and treated 6
Mortality Risk Considerations
Hypoglycemia severity correlates directly with mortality risk, with moderate hypoglycemia (41-70 mg/dL) having a 28.5% mortality rate and severe hypoglycemia (≤40 mg/dL) having a 35.4% mortality rate 1. This underscores the importance of prompt and accurate diagnosis.
By following this structured approach to laboratory testing, clinicians can efficiently diagnose the cause of hypoglycemia in non-diabetic patients and initiate appropriate treatment to prevent recurrent episodes and reduce morbidity and mortality.