Last Literature Review: August 2017 Last Update:

Medical Experts


Insulinomas are the most common functional pancreatic neuroendocrine tumors (PNETs). They result from the growth of islet cells that produce excess insulin. Insulinomas may be associated with multiple endocrine neoplasia type 1 (MEN1) or Wermer syndrome. Only 10% of insulinomas are malignant (National Cancer Institute [NCI], 2018).


Indications for Testing

  • Pancreatic tumor
  • Blood glucose ≤40 mg/dL without other etiology
  • Hypoglycemia symptoms without other etiology
    • Confusion/altered consciousness
    • Sweating/diaphoresis
    • Headache
    • Visual disturbance

Criteria for Diagnosis

  • Diagnosis criteria include (North American Neuroendocrine Tumor Society [NANETS], 2010):
    • Blood glucose ≤40 mg/dL
    • Insulin ≥3 µIU/mL
    • C-peptide levels ≥200 pmol/L
    • High proinsulin concentration
    • Beta-hydroxybutyrate levels ≤2.7 mmol/L
    • Absence of sulfonylurea in plasma and urine

Laboratory Testing

  • 72-hour observed fast is the gold standard for diagnosis; measure the following:
    • Insulin
    • Glucose
    • Proinsulin
    • C-peptide
    • Beta-hydroxybutyrate
  • Low C-peptide in combination with high insulin: suggestive of surreptitious insulin administration
  • Serum/urine sulfonylurea: rule out surreptitious drug-induced hypoglycemia


  • Useful immunohistochemistry stains may include synaptophysin and neuron-specific enolase (polyclonal)

Imaging Studies

  • Multiphasic computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasound (EUS) generally can detect most tumors (NCI, 2018)
  • Venous drainage catheter localization and calcium stimulation with transhepatic venous sampling are technically challenging and typically not used except in unusual circumstances (NCI, 2018)

Differential Diagnosis

  • Hypoglycemia
    • Diabetes mellitus
    • Persistent hyperinsulinemia of infancy (nesidioblastosis of the pancreas)
    • Noninsulinoma pancreatogenous hypoglycemia syndrome
    • Sulfonylurea-induced hypoglycemia
    • Factitious use of sulfonylurea or insulin
    • Insulin autoimmune hypoglycemia
    • Other causes (eg, sepsis)
  • Pancreatic mass
    • Other pancreatic neuroendocrine tumor
    • Pancreatic adenocarcinoma



  • Incidence: 1-32/million (European Neuroendocrine Tumor Society [ENETS] consensus, 2016)
  • Age
    • Median onset: 40s-50s
    • Rare in adolescents
  • Sex: M<F (minimal)

Risk Factors

Genetic: a small percentage are malignant, and these tend to be associated with familial disease (MEN1)


  • Generally sporadic
    • Majority are benign
    • >99% located in the pancreas
  • Islet cells (type beta [β]) can develop into hyperplasia, macroadenomas, microadenomas, or malignant adenocarcinomas (almost always pancreatic in location)
    • If multiple tumors are present, suspect MEN1
    • Only 5-8% of insulinomas are associated with MEN1 (NCI, 2018)
  • Symptoms are caused by excess secretion of insulin
    • Insulin is synthesized as preproinsulin and released as proinsulin
    • With proinsulin release, equal amounts of C-peptide are also released
  • Catecholamine excess is common

Clinical Presentation

  • Whipple triad
    • Neurologic signs/symptoms of hypoglycemia (neuroglycopenia): confusion, headache, sweating, tremor, visual disturbances
    • Blood glucose ≤40 mg/dL
    • Symptom resolution after glucose ingestion (within 5-10 minutes)
  • Other manifestations if a syndromic tumor is present (MEN1): pituitary, pancreatic, and parathyroid tumors

ARUP Laboratory Tests