In a patient with hypoglycemia and a normal plasma insulin level, what are the appropriate next diagnostic steps?

Diagnostic Approach to Hypoglycemia with Normal Insulin Levels

When a patient presents with documented hypoglycemia but normal plasma insulin levels, the critical first step is to determine the timing of hypoglycemia episodes and then measure C-peptide, proinsulin, and screen for sulfonylureas during the next hypoglycemic event to distinguish between endogenous and exogenous causes. 1

Immediate Diagnostic Algorithm

Step 1: Classify the Timing Pattern

The timing of hypoglycemia fundamentally changes your differential diagnosis:

• Fasting hypoglycemia (occurring after 8+ hours without food) suggests insulinoma, though this is extremely rare 1
• Postprandial hypoglycemia (1-3 hours after eating) suggests late dumping syndrome in patients with prior gastric, esophageal, or bariatric surgery 1
• Random/unpredictable hypoglycemia raises concern for factitious hypoglycemia from exogenous insulin or sulfonylureas 1

Step 2: Order the Critical Laboratory Panel During Hypoglycemia

You must obtain simultaneous measurements when glucose is <70 mg/dL (<3.9 mmol/L): 1

• Plasma glucose (to confirm hypoglycemia)
• Insulin level (may be "normal" but inappropriately elevated for the glucose level)
• C-peptide (distinguishes endogenous from exogenous insulin)
• Proinsulin (elevated proinsulin-to-insulin ratio strongly suggests insulinoma) 1
• Sulfonylurea screen (to exclude factitious hypoglycemia) 1

Step 3: Interpret the C-Peptide Result

This is the pivotal decision point:

• Elevated or inappropriately normal C-peptide = endogenous insulin production → proceed to supervised fast for insulinoma workup 1
• Suppressed or undetectable C-peptide with elevated insulin = factitious hypoglycemia from exogenous insulin injection 1, 2
• Elevated C-peptide with positive sulfonylurea screen = surreptitious sulfonylurea use 1

The Supervised 48-72 Hour Fast

If fasting hypoglycemia occurs or insulinoma is suspected based on inappropriately elevated C-peptide, admit the patient for a supervised fast—this is the gold standard diagnostic test. 1, 3

Protocol Details:

• Monitor plasma glucose every 4-6 hours initially, then hourly when glucose approaches 60 mg/dL 3
• When glucose falls below 55 mg/dL, immediately draw: glucose, insulin, C-peptide, proinsulin, and sulfonylurea screen 1
• Continue fast up to 72 hours or until Whipple's triad is documented 3
• Insulinoma is confirmed by: inappropriately elevated insulin (>3 μU/mL) and C-peptide (>0.6 ng/mL) during documented hypoglycemia, with increased proinsulin-to-insulin ratio 1, 3

Special Considerations for Post-Surgical Patients

If the patient has prior gastric, esophageal, or bariatric surgery and experiences postprandial hypoglycemia:

• This represents late dumping syndrome from rapid glucose absorption followed by excessive insulin secretion 1
• A mixed-meal test may be more diagnostic than a supervised fast in these cases 3
• Measure glucose, insulin, and C-peptide at baseline, then every 30 minutes for 3-5 hours after a standardized meal 3

Critical Pitfalls to Avoid

Do not assume "normal" insulin levels exclude hyperinsulinemic hypoglycemia—insulin levels that are detectable or in the "normal range" during hypoglycemia are actually inappropriately elevated and pathologic. 4 In true hypoglycemia, insulin should be suppressed to near-zero levels.

Always measure C-peptide—this is essential to distinguish endogenous insulin production (insulinoma, sulfonylurea use) from exogenous insulin administration (factitious hypoglycemia). 1, 2 Elevated insulin with suppressed C-peptide is pathognomonic for factitious hypoglycemia from injected insulin. 1

Screen for sulfonylureas—surreptitious use of oral hypoglycemic agents can present identically to insulinoma (elevated insulin and C-peptide) but requires completely different management. 1

Rare Causes to Consider

• Insulin autoimmune syndrome (IAS): Check for insulin antibodies if the patient has high insulin levels with detectable C-peptide but no evidence of insulinoma; this can occur with certain medications containing sulfhydryl compounds or, rarely, from insulin antibodies induced by prior exogenous insulin use 2
• IGF-II-producing tumors: Very rare pancreatic islet cell tumors can produce IGF-II causing hypoglycemia with normal insulin levels; consider measuring IGF-II if other workup is negative 4
• Postprandial insulinoma: Extremely rare insulinomas present only with postprandial hypoglycemia; if clinical suspicion is high despite negative fasting studies, perform a mixed-meal test 5

When to Refer

Once you have biochemically confirmed hyperinsulinemic hypoglycemia with elevated C-peptide and excluded factitious causes, refer to endocrinology for tumor localization with endoscopic ultrasound, CT/MRI, and octreotide scanning. 3 GLP-1 receptor imaging is a promising new technique for localizing very small insulinomas. 3