What is the differential diagnosis for a patient with hyperinsulinemia and elevated C (connecting) peptide levels, with a normal Hemoglobin A1c (HbA1c)?

Differential Diagnosis for Hyperinsulinemia with Elevated C-Peptide and Normal HbA1c

The most likely diagnosis is insulinoma, which classically presents with elevated insulin (>6 mcIU/mL), elevated C-peptide (>0.2 nmol/L or approximately >0.6 ng/mL), and hypoglycemia, though your patient's normal HbA1c suggests they are not experiencing chronic hypoglycemia. 1

Primary Differential Considerations

1. Insulinoma (Most Likely)

• Insulin levels >6 mcIU/mL with C-peptide >0.2 nmol/L (approximately >0.6 ng/mL) during hypoglycemia are diagnostic of endogenous hyperinsulinism. 1
• Your patient's insulin of 29 mcIU/mL and C-peptide of 5.4 ng/mL are markedly elevated, consistent with autonomous insulin secretion 1
• The normal HbA1c suggests episodic rather than continuous hypoglycemia, which is typical for insulinoma 1
• Key diagnostic step: Perform a supervised 48-72 hour fast with serial measurements of glucose, insulin, and C-peptide. 1 Insulinoma is confirmed when plasma glucose drops below 2.5 mmol/L (45 mg/dL) with concomitant insulin ≥3 mcIU/mL (usually >6 mcIU/mL) and C-peptide ≥0.2 nmol/L 1
• Proinsulin >5 pmol/L with glucose <2.5 mmol/L has 100% sensitivity and specificity for endogenous hyperinsulinism 2
• Critical pitfall: Always test for sulfonylurea in urine to exclude factitious hypoglycemia before diagnosing insulinoma 1, 3

2. Insulin Autoimmune Syndrome (IAS)

• Rare cause of hyperinsulinemia, particularly in non-Asian populations, but must be considered 4
• Presents with excessively high total insulin levels (often >100 μIU/mL) and elevated C-peptide due to anti-insulin antibodies 4
• Distinguishing feature: Free C-peptide levels (measured after polyethylene glycol precipitation) will be normal or low in IAS, whereas total C-peptide is elevated 4
• Anti-insulin antibodies interfere with immunoassays, causing falsely elevated insulin and C-peptide measurements 4
• Diagnostic test: Measure anti-insulin antibodies and free C-peptide levels after polyethylene glycol precipitation 4

3. Early Type 2 Diabetes with Insulin Resistance

• Type 2 diabetes patients have insulin resistance with compensatory hyperinsulinemia and elevated C-peptide 1
• However, this diagnosis is unlikely given the normal HbA1c, as type 2 diabetes requires HbA1c ≥6.5% for diagnosis 1
• These patients typically have obesity and would show hyperglycemia, not the pattern your patient presents 1

4. Nesidioblastosis (Non-Insulinoma Pancreatogenous Hypoglycemia)

• Diffuse β-cell hyperplasia causing inappropriate insulin secretion 1
• Presents similarly to insulinoma with elevated insulin and C-peptide during hypoglycemia 1
• More common in infants but can occur in adults, particularly post-gastric bypass surgery 1
• Diagnosis requires selective arterial calcium stimulation testing and is often made after negative imaging for insulinoma 1

5. Factitious Hypoglycemia (Exogenous Insulin)

• This is excluded by the elevated C-peptide, as exogenous insulin suppresses endogenous C-peptide production to <0.10 nmol/L 3
• Patients with insulin factitial hypoglycemia have high insulin but low C-peptide 3

6. Sulfonylurea/Meglitinide Use

• These medications stimulate endogenous insulin secretion, causing elevated insulin and C-peptide 1
• Always screen urine for sulfonylureas in any patient with hyperinsulinemic hypoglycemia 1, 3
• Patient history should clarify medication access

Recommended Diagnostic Algorithm

Step 1: Confirm endogenous hyperinsulinism

• Perform supervised 72-hour fast with serial glucose, insulin, C-peptide, and proinsulin measurements 1
• Obtain urine sulfonylurea screen 1, 3

Step 2: If fasting test confirms hyperinsulinism

• Measure anti-insulin antibodies to exclude IAS 4
• If antibodies present, measure free C-peptide after polyethylene glycol precipitation 4
• Obtain multiphasic CT or MRI of pancreas to localize tumor 1
• Consider endoscopic ultrasound (EUS), which localizes 82% of pancreatic neuroendocrine tumors 1

Step 3: If imaging is negative

• Consider selective arterial calcium stimulation test (Imamura-Doppman procedure) 1
• Evaluate for nesidioblastosis, particularly if history of gastric surgery 1

Step 4: Preoperative preparation if insulinoma confirmed

• Stabilize glucose with frequent meals and/or diazoxide 1
• Avoid octreotide unless tumor is octreotide-scan positive, as it can paradoxically worsen hypoglycemia in insulinoma 1

Critical Clinical Pearls

• The combination of insulin >6 mcIU/mL, C-peptide >0.2 nmol/L, and glucose <45 mg/dL during supervised fast is pathognomonic for endogenous hyperinsulinism 1, 3
• Normal HbA1c does not exclude insulinoma; it simply indicates that hypoglycemic episodes are not frequent or severe enough to lower the average glucose 1
• 90% of insulinomas are benign and curable with surgical resection 1
• Proinsulin measurement adds diagnostic value, with levels >5 pmol/L during hypoglycemia achieving 100% sensitivity and specificity 2