Diagnostic Approach for Insulinoma
The diagnosis of insulinoma requires a supervised 48-72 hour fast with biochemical confirmation showing insulin ≥3 mcIU/mL (typically >6 mcIU/mL), C-peptide ≥0.6 ng/mL, and proinsulin ≥5 pmol/L when blood glucose falls below 55 mg/dL, followed by imaging with multiphasic CT/MRI and endoscopic ultrasound for tumor localization. 1, 2
Clinical Presentation
Look specifically for:
- Neuroglycopenic symptoms including confusion, lethargy, seizures, numbness, and prolonged episodes of altered mental status 1, 2
- Fasting symptoms, particularly occurring in the morning 2
- Weight gain from frequent eating to prevent hypoglycemic episodes 2
Biochemical Diagnosis
Supervised Fast Test (First-Line)
Perform a 48-72 hour supervised inpatient fast as the primary diagnostic test 1, 2. The 48-hour duration is now considered sufficient based on modern assays, as 94.5% of insulinomas are diagnosed by 48 hours 3. The traditional 72-hour protocol remains acceptable but may be unnecessarily prolonged 1, 3.
Diagnostic criteria at termination of fast (when glucose <55 mg/dL): 1, 2
- Insulin >3 mcIU/mL (usually >6 mcIU/mL)
- C-peptide ≥0.6 ng/mL
- Proinsulin ≥5 pmol/L
Key point: Elevated C-peptide distinguishes endogenous hyperinsulinemia (insulinoma) from exogenous insulin administration 2. Proinsulin is elevated at the beginning of the fast in 90% of insulinoma patients 3.
Alternative Outpatient Testing
While the supervised fast remains the gold standard, recent research suggests that insulin and C-peptide ratios during a 2-hour oral glucose tolerance test may serve as an alternative screening tool for outpatients 4, 5. A logistic regression model using the 2-hour/0-hour insulin ratio and 1-hour/0-hour C-peptide ratio achieved 86.5% sensitivity and 95.2% specificity 4. However, this approach is not yet incorporated into major guidelines and should be considered investigational 1, 2.
Tumor Localization
First-Line Imaging
Order multiphasic CT or MRI to rule out metastatic disease and attempt initial localization 1, 2. Insulinomas appear hypervascular in the arterial phase on CT (sensitivity 57-94%) 6. On MRI, they typically appear hypointense on T1 and isointense to slightly hyperintense on T2 sequences (sensitivity 74-94%) 6.
Proceed to endoscopic ultrasound (EUS) as the preferred localization method, with approximately 82-93% sensitivity for detecting small pancreatic tumors 2, 6. EUS also allows tissue sampling and helps determine the surgical approach 6.
Second-Line Localization
For persistent negative or equivocal imaging, consider selective arterial calcium stimulation with hepatic venous sampling (Imamura-Doppman procedure), which achieves up to 90% success in localizing occult insulinomas 1, 2, 6. Most experts recommend this test only for persistent or recurrent insulinoma cases 1.
Avoid routine somatostatin scintigraphy for insulinoma localization, as insulinomas are less consistently octreotide-avid than other pancreatic neuroendocrine tumors, with only 50-60% sensitivity 1, 6. Consider 68Ga-DOTATOC PET only for difficult cases, as it has higher sensitivity (87-96%) than conventional scintigraphy 6.
Intraoperative Localization
Plan for intraoperative ultrasound during surgery regardless of preoperative localization success, as the combination of surgical palpation and intraoperative ultrasound identifies tumors in 98-100% of cases 6, 7.
Common Pitfalls
- Never use somatostatin analogues (octreotide/lanreotide) for symptom control in insulinoma patients with negative somatostatin scintigraphy, as they suppress counterregulatory hormones (growth hormone, glucagon, catecholamines) and can precipitously worsen hypoglycemia with fatal complications 1, 2
- Proton pump inhibitors cause spuriously elevated chromogranin A levels, which can complicate diagnosis 2
- Do not terminate the fast prematurely—seven patients in one series fasted beyond 48 hours despite subtle neuroglycopenic symptoms because diagnostic criteria were not yet met 3
Preoperative Stabilization
Before surgical resection, stabilize glucose levels with: 1, 2
- Dietary management (frequent small meals)
- Diazoxide as first-line medical therapy
- Everolimus as an alternative option