What is the appropriate diagnostic work‑up for a suspected insulinoma, including biochemical confirmation, imaging localization, and genetic testing?

Diagnosis of Insulinoma

The diagnosis of insulinoma requires a supervised 48-hour fast (not 72 hours) with biochemical confirmation showing glucose <40-45 mg/dL, insulin >3 mcIU/mL, C-peptide ≥0.6 ng/mL, and proinsulin ≥5 pmol/L, followed by endoscopic ultrasound for tumor localization. 1

Clinical Presentation

Patients with insulinoma present with Whipple's triad, which must include all three components: 2, 3

• Neuroglycopenic symptoms (confusion, lethargy, seizures, or loss of consciousness)
• Documented low plasma glucose (<50 mg/dL) measured at the time of symptoms
• Prompt relief of symptoms when glucose is raised to normal

Common pitfall: Symptoms often occur during fasting states, particularly in the morning, and patients may report weight gain from frequent eating to prevent hypoglycemia. 1 Presentations can be atypical, with some patients experiencing seizures or even motor vehicle accidents due to hypoglycemic episodes. 4, 5

Biochemical Confirmation: The 48-Hour Fast

The supervised 48-hour fast has replaced the outdated 72-hour fast as the diagnostic standard. 1, 6

Fast Protocol and Diagnostic Criteria

When glucose falls below 55 mg/dL during the supervised fast, measure the following simultaneously: 1

• Insulin level >3 mcIU/mL (inappropriately elevated for the glucose level)
• C-peptide ≥0.6 ng/mL (confirms endogenous insulin production)
• Proinsulin ≥5 pmol/L (even mild elevations indicate aberrant insulin secretion)
• Beta-hydroxybutyrate suppression (insulin suppresses ketone production)

Diagnostic Performance

The 48-hour fast achieves a diagnostic sensitivity of 94.5% for insulinoma: 6

• 42.5% of patients reach diagnostic criteria by 12 hours
• 66.9% by 24 hours
• 94.5% by 48 hours

Critical diagnostic point: Proinsulin is elevated at the beginning of the fast in 90% of insulinoma patients, and an elevated fasting proinsulin-to-insulin ratio strongly suggests an islet-cell tumor. 1, 6

Excluding Factitious Hypoglycemia

C-peptide measurement is essential to differentiate true insulinoma from surreptitious insulin administration: 1

• C-peptide ≥0.6 ng/mL indicates endogenous insulin secretion (insulinoma)
• C-peptide <0.6 ng/mL indicates exogenous insulin use (factitious hypoglycemia)

When hypoglycemia occurs without accompanying elevations in insulin, C-peptide, and proinsulin, insulinoma is unlikely and alternative etiologies should be pursued. 1

Tumor Localization: Imaging Algorithm

Step 1: Initial Cross-Sectional Imaging

Begin with dual-phase multidetector CT or MRI to assess for metastatic disease and initial tumor localization: 1

• CT sensitivity: 57-94% for pancreatic neuroendocrine tumors
• MRI sensitivity: 74-94% (comparable alternative)

These studies are essential for surgical planning but may miss small lesions. 1

Step 2: Endoscopic Ultrasound (EUS)

EUS should be performed in all cases, regardless of CT/MRI findings, as it is the preferred initial localization method: 1

• Sensitivity: 82-93% for detecting pancreatic neuroendocrine tumors
• Dual purpose: tumor localization AND tissue sampling via fine needle aspiration
• Particularly valuable for detecting small tumors and multiple lesions in MEN1 syndrome

EUS is superior to cross-sectional imaging for small insulinomas and should not be skipped even if CT/MRI is positive. 1

Step 3: Advanced Functional Imaging (When Conventional Imaging Fails)

68Ga-DOTATOC/DOTATATE PET/CT demonstrates the highest sensitivity (87-96%) and should be considered when conventional imaging is negative: 1

Critical pitfall to avoid: Do NOT rely on somatostatin receptor scintigraphy (SSRS) for insulinoma detection—its sensitivity is only 50-60% for insulinomas (compared to 75% for other pancreatic NETs). SSRS should only be used if octreotide or lanreotide is being considered for metastatic disease treatment. 1

Step 4: Selective Arterial Calcium Stimulation (For Occult Cases)

Reserve selective arterial calcium stimulation with hepatic venous sampling (Imamura-Doppman procedure) for truly occult cases where all non-invasive studies are negative: 1

• Success rate: up to 90% for localizing occult insulinomas
• Regionalizes the tumor to specific pancreatic arterial territories
• Must be interpreted in combination with other imaging modalities

Step 5: Intraoperative Ultrasound (Mandatory)

Intraoperative ultrasound (IOUS) is mandatory at the time of surgery regardless of preoperative imaging results: 1

• Sensitivity: 92-97% for identifying small lesions
• Enhances detection beyond all preoperative imaging modalities
• Particularly valuable for pancreatic head lesions

Genetic Testing Considerations

Screen for Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome, as 5-10% of insulinomas are associated with MEN1: 2

• Consider genetic testing in patients with:
  • Multiple pancreatic neuroendocrine tumors on imaging
  • Family history of endocrine tumors
  • Young age at presentation
  • Personal history of hyperparathyroidism or pituitary adenomas

Laboratory Pitfalls to Avoid

Do NOT measure chromogranin A in patients on proton pump inhibitors (PPIs)—these medications cause spuriously elevated levels. Patients must be off PPIs for at least 1 week before testing. 1

Prognosis Context

Understanding prognosis helps frame the urgency of diagnosis: 2

• Indolent (non-metastatic) insulinomas: 5-year survival 94-100%
• Aggressive (metastatic) insulinomas: 5-year survival 24-67%
• Surgical cure rate for localized disease: 90%

This excellent prognosis with surgical resection underscores the importance of accurate diagnosis and localization. 1