Diagnostic Approach for Hyperinsulinemic Hypoglycemia
The diagnosis of hyperinsulinemic hypoglycemia requires documenting inappropriately elevated insulin levels during a hypoglycemic episode (glucose <54 mg/dL), with the supervised 72-hour fast being the gold standard test, though proinsulin >5 pmol/L with glucose <2.5 mmol/L (45 mg/dL) provides 100% diagnostic specificity and sensitivity for endogenous hyperinsulinism. 1
Critical First Step: Distinguish Timing of Hypoglycemia
The timing of hypoglycemic episodes immediately narrows your differential diagnosis:
- Fasting hypoglycemia (not provoked by meals) suggests insulinoma, which is extremely rare 2
- Postprandial hypoglycemia (1-3 hours after eating) suggests late dumping syndrome in patients with prior gastric/bariatric surgery 2
- Random hypoglycemia may indicate factitious hypoglycemia from exogenous insulin or sulfonylureas 2
The Supervised Fast: Gold Standard Diagnostic Test
When to perform: If fasting hypoglycemia occurs or insulinoma is suspected, a supervised 48-72 hour fast in a hospital setting is indicated 2
What to measure during hypoglycemia:
- Simultaneous plasma glucose, insulin, C-peptide, and proinsulin levels 2, 3, 1
- Sulfonylurea screen to exclude factitious hypoglycemia 2
Diagnostic thresholds during documented hypoglycemia (glucose <54 mg/dL):
- Proinsulin >5 pmol/L provides 100% sensitivity and specificity for endogenous hyperinsulinism 1
- C-peptide >0.2 nmol/L confirms endogenous insulin production (rules out exogenous insulin) 1
- Insulin levels are less reliable—can be <21 pmol/L in 8-35% of insulinoma patients 1
Distinguishing Insulinoma from Other Causes
Insulinoma characteristics:
- C-peptide <9.6 ng/mL has 97.3% sensitivity for insulinoma 3
- Insulin <75 μU/mL has 93.4% sensitivity for insulinoma 3
- Increased proinsulin-to-insulin ratio strongly suggests insulinoma 2
Autoimmune hypoglycemia characteristics:
- Markedly elevated insulin (median 324.6 μU/mL) and C-peptide (median 14.25 ng/mL) 3
- More common in females (91%) 3
- Test for insulin antibodies 4
Factitious hypoglycemia from exogenous insulin:
- Inappropriately low C-peptide levels during hyperinsulinemic hypoglycemia 2
- Elevated insulin with suppressed C-peptide is pathognomonic 2
Important Caveat: The 72-Hour Fast Can Be Normal
Critical pitfall: A normal 72-hour fast does not exclude insulinoma 5. Some insulinomas present with:
- Normal fasting glucose after 72 hours 5
- Glucose-stimulated hypoglycemia during oral glucose tolerance test 5
- Postprandial hypoglycemia only 6
If clinical suspicion remains high despite normal fasting test, consider prolonged oral glucose tolerance test 5.
Localization Studies (After Biochemical Diagnosis)
Imaging sensitivity for insulinoma:
- Angiography with Doppman test: 100% 3
- Endoscopic ultrasound (EUS): 88% 3
- MRI: 86% 3
- CT scan: 82% 3
- Nuclear imaging: 52% 3
Selective intra-arterial calcium infusion reveals high insulin levels in the region of the insulinoma 6.
Post-Gastric Surgery Hypoglycemia (Late Dumping)
For patients with prior esophageal, gastric, or bariatric surgery presenting with postprandial hypoglycemia 1-3 hours after eating:
- This represents reactive hypoglycemia from rapid glucose absorption followed by excessive insulin secretion 2
- Diagnosis is clinical based on timing and surgical history 2
- No need for prolonged fasting test 2
Monitoring During Diagnostic Workup
Factory-calibrated continuous glucose monitoring (CGM) is useful for:
- Detecting asymptomatic hypoglycemia 6
- Documenting hypoglycemia unawareness 6
- Monitoring response to medical treatment (e.g., diazoxide) 6
Common Diagnostic Pitfalls to Avoid
- Do not rely solely on insulin levels—they have poor sensitivity (can be normal in 8-35% of insulinomas) 1
- Do not stop evaluation after normal 72-hour fast if clinical suspicion remains high 5
- Do not forget to measure C-peptide—essential to distinguish endogenous from exogenous insulin 2
- Do not miss surreptitious sulfonylurea use—always screen for oral hypoglycemic agents 2