What does it mean to have hypoglycemia (low blood sugar) with high C-peptide (connecting peptide) levels?

Hypoglycemia with High C-peptide: Diagnostic Significance

The combination of hypoglycemia with elevated C-peptide levels most strongly suggests an insulinoma or other form of endogenous hyperinsulinism, which requires prompt evaluation and treatment to prevent serious morbidity and mortality from recurrent hypoglycemic episodes. 1

Pathophysiological Significance

High C-peptide with low blood sugar indicates inappropriate insulin secretion, with several key implications:

• Endogenous vs. Exogenous Insulin: High C-peptide confirms endogenous insulin production, ruling out factitious hypoglycemia from injected insulin (which would show low C-peptide) 1
• Diagnostic Threshold: A C-peptide level ≥0.30 nmol/L with hypoglycemia <2.3 mmol/L (41 mg/dL) has excellent diagnostic performance (sensitivity 96%, specificity 100%) for endogenous hyperinsulinism 2

Differential Diagnosis

1. Insulinoma (most common cause):

   • Neuroendocrine tumor that autonomously secretes insulin
   • Characterized by persistent, inappropriate insulin secretion despite hypoglycemia
   • 90% are benign and can be cured surgically 1

2. Other causes of endogenous hyperinsulinism:

   • Islet cell hyperplasia
   • Nesidioblastosis
   • Extrapancreatic malignancy 3
   • Autoimmune hypoglycemia (insulin autoimmune syndrome) 4

3. Factitious hypoglycemia:

   • Sulfonylurea ingestion (must be ruled out with drug screening)
   • Unlike insulin injection, sulfonylureas stimulate endogenous insulin and will show elevated C-peptide 5

Diagnostic Approach

1. Confirm the pattern with fasting test:

   • Prolonged fast (up to 72 hours) is the gold standard
   • Document Whipple's triad: hypoglycemia, symptoms, and resolution with glucose administration
   • Measure glucose, insulin, C-peptide, and proinsulin at end of fast 5

2. Key diagnostic criteria:

   • Hypoglycemia (glucose <2.3 mmol/L or 41 mg/dL)
   • C-peptide ≥0.20-0.30 nmol/L during hypoglycemia 5, 2
   • Insulin level ≥3.1 mIU/L (21.5 pmol/L) during hypoglycemia 2
   • Absence of sulfonylureas in plasma 5

3. Imaging studies (once biochemical diagnosis is established):

   • Multiphasic CT/MRI scan to localize tumor
   • Endoscopic ultrasound (EUS) - especially useful for small insulinomas
   • Octreoscan if considering octreotide therapy 1

Management Considerations

1. Immediate management of hypoglycemia:

   • Diazoxide is FDA-approved for management of hypoglycemia due to hyperinsulinism in adults with inoperable islet cell tumors 3
   • Can be used preoperatively as temporary measure and postoperatively if hypoglycemia persists

2. Definitive treatment:

   • Surgical resection is optimal for localized pancreatic neuroendocrine tumors 1
   • For inoperable tumors, medical management with diazoxide and other agents may be necessary 3

Important Caveats

• Rare presentations: Some insulinoma cases may present with low insulin but high C-peptide levels due to rapid insulin degradation or assay interference 6
• Assay interference: Anti-insulin antibodies can interfere with insulin and C-peptide measurements; free C-peptide assay after polyethylene glycol precipitation may be needed 4
• Avoid octreotide without testing: Octreotide should only be administered to patients with confirmed somatostatin receptor-positive tumors, as it can worsen hypoglycemia in receptor-negative cases 1

The finding of hypoglycemia with elevated C-peptide warrants urgent evaluation to identify the underlying cause and implement appropriate treatment to prevent potentially life-threatening hypoglycemic episodes.