Insulinoma: Causes, Symptoms & Treatment

What is an Insulinoma?

An insulinoma is a rare, usually benign tumor of the pancreas. It arises from the beta cells of the islets of Langerhans, which are normally responsible for producing the hormone insulin. In an insulinoma, insulin production occurs in an uncontrolled manner, independent of the current blood glucose level. This leads to recurrent, sometimes life-threatening episodes of low blood sugar (hypoglycemia). Insulinomas belong to the group of pancreatic neuroendocrine tumors (pNETs). They occur in approximately 1 to 4 people per million per year and are therefore very rare.

Causes and Risk Factors

The exact cause of an insulinoma is unknown in most cases. Approximately 90 percent of insulinomas occur sporadically, without an identifiable genetic basis. In rare cases, insulinomas are associated with genetic syndromes:

• Multiple Endocrine Neoplasia Type 1 (MEN1): An inherited condition in which tumors can develop in multiple endocrine glands.
• Von Hippel-Lindau syndrome and other rare hereditary disorders.

The vast majority of insulinomas (about 90 percent) are benign, while approximately 10 percent are malignant. They are typically very small (under 2 cm) and can be located throughout the pancreas.

Symptoms

Symptoms of an insulinoma result from excessive insulin secretion and the resulting low blood glucose levels. The hallmark diagnostic triad is known as Whipple's triad:

• Symptoms consistent with hypoglycemia, especially during fasting or after physical exertion
• Low blood glucose (< 50 mg/dL) documented during symptomatic episodes
• Relief of symptoms following glucose administration

Symptoms can be divided into two categories:

Neuroglycopenic Symptoms (due to glucose deprivation in the brain)

• Confusion and difficulty concentrating
• Visual disturbances
• Personality changes and unusual behavior
• Seizures
• Loss of consciousness (in severe cases)

Adrenergic Symptoms (due to counter-regulatory hormones)

• Sweating and trembling
• Rapid heartbeat (tachycardia)
• Anxiety and restlessness
• Intense hunger

Because symptoms are often non-specific, it can take several years before the correct diagnosis is made. Many patients are initially treated for epilepsy, psychiatric disorders, or cardiac conditions.

Diagnosis

Diagnosing an insulinoma requires both biochemical testing and imaging studies.

Biochemical Testing

• 72-hour supervised fast: This is the gold standard diagnostic test. The patient fasts under medical supervision for up to 72 hours. Blood glucose, insulin, C-peptide, and proinsulin levels are measured at regular intervals. In insulinoma, insulin levels remain elevated even when blood glucose is low.
• Measurement of insulin, C-peptide, and proinsulin in the blood
• Exclusion of factitious hypoglycemia caused by external insulin administration (via C-peptide and sulfonylurea measurements)

Imaging Studies

• Endoscopic ultrasound (EUS): Ultrasound performed from within the stomach; highly sensitive for localizing small tumors
• Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen
• Somatostatin receptor scintigraphy (SRS) or 68Ga-DOTATATE PET/CT for suspected malignant tumors
• Selective arterial calcium stimulation (SACS): An invasive procedure used for precise localization when other methods are inconclusive

Treatment

The treatment of choice for an insulinoma is surgical removal of the tumor.

Surgical Treatment

• Enucleation: Careful removal of the tumor from the pancreatic tissue, suitable for superficially located benign tumors.
• Pancreatic resection: Partial removal of the pancreas (e.g., distal pancreatectomy or Whipple procedure) for deeply located or malignant tumors.
• Minimally invasive (laparoscopic) approaches are possible for suitable tumors.

The cure rate following complete surgical removal of benign insulinomas is very high, reaching up to 90 percent.

Medical Treatment

If surgery is not possible, or as a temporary measure, the following medications may be used:

• Diazoxide: Inhibits insulin secretion from beta cells and is the most commonly used medication for symptomatic control.
• Somatostatin analogues (e.g., octreotide): Can reduce insulin release.
• Everolimus: An mTOR inhibitor that may be used in malignant, inoperable insulinomas.

Supportive Measures

• Frequent small meals to prevent hypoglycemic episodes
• Emergency glucose administration during acute hypoglycemia

Prognosis

For benign insulinomas, the prognosis after successful surgery is excellent. Recurrence occurs in fewer than 10 percent of cases. For malignant insulinomas, the prognosis is less favorable and depends on the extent of metastasis. Regular follow-up examinations are recommended in both cases.

References

1. Falconi M. et al. - ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology, 2016.
2. Service FJ. - Hypoglycemic disorders. New England Journal of Medicine, 1995; 332(17):1144–1152.
3. Kann PH. et al. - Insulinoma Guidelines. German Society of Endocrinology (DGE), 2021.