The portal for rare diseases and orphan drugs

The incidence in the general population is 1/250,000-1,000,000 (but higher in autopsy studies). There is a slight female predominance. It is the most common endogenous cause of hyperinsulinemic hypoglycemia. Malignant insulinoma has an incidence 0.01/100,000 in Europe.

Insulinoma can present at any age but the median age of diagnosis is in the fifth decade of life. It manifests with various autonomic and neuroglycopenic symptoms such as tremor, palpitations, weakness, diaphoresis, hyperphagia, visual disturbances, confusion, behavioral and personality changes, seizures and coma. Symptoms occur more often during times of fasting, exercise or with a delay in meals. 20-40% of patients are overweight. Insulinomas are malignant in only 7-10% of cases and the most common sites of metastasis are the liver and lymph nodes. Extra-pancreatic insulinoma is most commonly found in the duodenal wall but is extremely rare. The tumor can also rarely be non-functioning.

The etiology is unknown in most sporadic cases but somatic YY1 (14q32.2) variants are associated with insulinoma in some cases. Insulinoma originates in the islet beta cells that are equally distributed throughout the pancreas. When functioning, the tumor manifests with hypersecretion of insulin and consequently causes hypoglycemia.

Diagnosis is suspected on the presence of Whipple's triad (hypoglycemia with blood glucose levels of < 50 mg/dL, neuroglycopenic symptoms, and immediate relief of symptoms following the administration of glucose) and confirmed by biological testing, including a 72 hour fasting test (measuring levels of insulin, C-peptide and proinsulin during hypoglycemia). The insulin/C-peptide ratio is > 1.0 in patients with insulinoma. Localization of insulinoma can be achieved by imaging techniques such as transabdominal ultrasound, computed tomography and magnetic resonance imaging, as well as by endoscopic ultrasonography (EUS), angiography, and arterial stimulation venous sampling. Occult insulinoma can be located by dotatate or Glucagon-like peptide-1 analog positron emission tomography.

Malignant insulinomas can be associated with multiple endocrine neoplasia type 1 (MEN1). Other differential diagnoses include other causes of hypoglycemia such as diffuse hepatic disease, Addison disease, and alcoholism, but insulin is not elevated in these conditions. Type B insulin resistance and insulin autoimmune syndrome also need to be considered.

With the exception of insulinoma in MEN1, insulinoma is not hereditary.

Surgical resection is the standard treatment for a benign insulinoma and is often curative. Enucleation, partial or middle pancreatomy, laparoscopic resection and radical resection are all options for benign insulinomas. Octreotide, a somatostatin analogue, can be given pre-operatively as it may be successful in controlling blood glucose levels (not necessary in most cases). Malignant insulinomas require aggressive surgical resection (extended pancreatic and liver resection) along with aggressive secondary treatments (i.e. chemoembolization, radiofrequency ablation). In those with unresectable tumors, octreotide should be administered and glucose monitored regularly, and mammalian target of rapamycin (mTOR) inhibitors are particularly effective in controlling hypoglycemia. Sunitinib malate can be used for malignant insulinomas.

In most cases, insulinomas are benign, and surgical resection is curative. The reported 10-year survival rate of those with a malignant insulinoma, however, is 29%.