Insulinoma

Insulinomas are insulin-secreting pancreatic beta-cell tumors. They are the most common cause of endogenous hyperinsulinism and are benign in 90% of patients. Most insulinomas occur sporadically but they can also occur in patients with multiple endocrine neoplasias (e.g., parathyroid tumors, pituitary adenomas, gastrinomas). Typical clinical features include recurrent attacks of symptomatic hypoglycemia in individuals without diabetes. The diagnosis is established if serum insulin and C-peptide are elevated despite hypoglycemia, either during a spontaneous episode or during a hypoglycemic episode provoked by a 72-hour fasting test. The treatment of choice is surgical enucleation of the insulinoma. In inoperable cases and patients with persistent hypoglycemic attacks, pharmacotherapy (e.g., diazoxide, somatostatin analogues) can be used to decrease insulin secretion.

• Insulinoma: the most common type of pancreatic neuroendocrine tumor (arising from beta cells); causes endogenous hyperinsulinism
• Hyperinsulinism: a condition of elevated blood insulin levels
• Endogenous hyperinsulinism: a condition characterized by inappropriately high serum insulin levels relative to blood sugar levels; manifests as hypoglycemic symptoms

• Sex: ♀ > ♂
• Age range: ∼ 30–60 years
• Incidence: ∼ 4 cases/1,000,000 persons per year ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Insulinomas are neuroendocrine tumors that arise from beta cells of the pancreas. ^[1]
  • < 1% occur at ectopic sites (e.g., spleen).
  • ∼ 90% of insulinomas occur as solitary tumors. ^[1][2]
• Most insulinomas occur sporadically.
• Over 90% of insulinomas are benign. ^[1]
• ∼ 5% of insulinomas are associated with multiple endocrine neoplasia type 1 (MEN 1). ^[3]

References:^[4][5]

• Clinical features of hypoglycemia, e.g., lethargy, syncope, and double vision
  • Hypoglycemic symptoms usually occur several hours after a meal and may be precipitated by exercise and/or alcohol consumption.
  • Neuroglycopenic symptoms may be preceded by symptoms of sympathetic overactivity.
• Relief of symptoms of hypoglycemia after administering glucose (see also Whipple triad)
• Weight gain
• Symptoms characteristic of other endocrine neoplasias may occur (see “Multiple endocrine neoplasias” for more information).

Approach ^[6]

• Consider insulinoma in patients with both:
  • Whipple triad
  • No other known cause of hypoglycemia (e.g., diabetes mellitus, drugs that cause hypoglycemia, critical illness)
• Order laboratory studies to confirm endogenous hyperinsulinism.
• Obtain imaging to confirm insulinoma.
• Evaluate patients with confirmed insulinoma for clinical features of MEN 1 and neurocutaneous syndromes.
• If insulinoma is ruled out or there is clinical suspicion for other causes of endogenous hyperinsulinism, consider additional workup, e.g.:
  • Hepatic vein insulin sampling to evaluate for NIPHS
  • IGF-1/IGF-2 to evaluate for NICTH
  • Endocrine tests for adrenal insufficiency

Laboratory studies ^[6]

Initial studies

• Obtain during a symptomatic episode of hypoglycemia in patients with suspected insulinoma.
• Findings consistent with endogenous hyperinsulinism
  • ↓ Glucose: < 55 mg/dL
  • ↑ Insulin: > 3.0 μU/mL
  • ↑ C-peptide: > 0.6 ng/mL
  • ↑ Proinsulin: > 5.0 pmol/L
  • ↓ β-hydroxybutyrate: < 2.7 mmol/L
  • Negative screening for oral hypoglycemic agents (e.g., negative sulfonylurea levels)
  • Negative insulin antibodies

Factitious hypoglycemia secondary to exogenous insulin use will not raise C-peptide levels, whereas factitious hypoglycemia secondary to the use of insulin secretagogues (e.g., sulfonylureas, meglitinides) can elevate both C-peptide and proinsulin levels.

72-hour fasting test

Obtain in consultation with a specialist, e.g., endocrinology.

• Indication: patients with no spontaneous hypoglycemic episodes during the evaluation to provoke hypoglycemia
• Procedure
  • The patient fasts for 72 hours, only drinking noncaloric beverages, and all nonessential medications are discontinued.
  • Measure insulin, C-peptide, and glucose every 4–6 hours.
  • Once blood glucose < 45 mg/dL or < 55 mg/dL with documented Whipple triad, obtain initial studies for hyperinsulinism. ^[6]
• Supportive findings: findings consistent with endogenous hyperinsulinism, e.g., low glucose and high insulin levels
• Limitations ^[7]
  • Results may be inaccurate if the physiological glucose level is low.
  • Rarely, insulinomas may suppress insulin release in response to hypoglycemia.
  • Insulin levels can be artificially elevated in the presence of circulating anti-insulin antibodies.

Glucagon stimulation test

Glucagon stimulation test may be obtained in conjunction with a fasting test or alone.

• Procedure
  • Inject glucagon.
  • Measure serum glucose and insulin at baseline, and again at 10, 20, and 30 minutes after injection.
• Supportive finding: an increase in serum glucose of ≥ 25 mg/dL within 30 minutes of glucagon injection ^[6]
• Limitations ^[7]
  • Unreliable in patients with malnutrition, hepatic disease, and cirrhosis with portocaval anastomosis
  • Medication interference: diazoxide, hydrochlorothiazide, diphenylhydantoin, sulfonylureas, aminophylline
  • Patients with nonislet cell tumors can have insulinoma-like responses.
  • The glucagon tolerance test can induce nausea, vomiting, and hypoglycemia.
  • In 8% of insulinomas, the expected peak is not observed.

Interpretation of laboratory studies

Imaging studies ^[3][6]

Imaging is usually guided by a specialist (e.g., endocrine surgery).

• Indication: confirmed endogenous hyperinsulinism to localize insulinoma for surgical planning ^[3]
• Modalities
  • Noninvasive, e.g.:
    • Ultrasound, CT, and/or MRI abdomen ^[3]
    • Triphasic CT of the pancreas
    • Somatostatin receptor scintigraphy
  • Invasive, e.g., endoscopic ultrasound (EUS) with or without hepatic vein insulin sampling ^[3]

Insulinomas are commonly < 1.0 cm in diameter and difficult to detect with noninvasive imaging. ^[6]

Provide oral glucose, IV dextrose, or IM glucagon to patients with acute hypoglycemia. See also “Treatment of hypoglycemia.”

Surgical therapy ^[3][9]

• Tumor resection is the first-line treatment for localized insulinoma.
• Options
  • Enucleation of the tumor: preferred
  • Partial pancreatic resection: if the tumor is within 3 mm of the pancreatic duct

Pharmacological treatment ^[6]

• Consider agents that inhibit insulin secretion for:
  • Short-term bridge therapy until tumor resection is feasible
  • Long-term management of inoperable tumors or recurrent symptoms after excision
• Options
  • Diazoxide
  • Somatostatin analogs: e.g., octreotide

Tumor resection has a good prognosis and a low risk of recurrence.