An insulinoma is a tumour of the pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

 that is derived from beta cell
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...

s and secretes insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....


Beta cells secrete insulin in response to increases in blood glucose
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...

. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is stopped. In contrast, the secretion of insulin by insulinomas is not properly regulated by glucose and the tumours will continue to secrete insulin causing glucose levels to fall further than normal.

As a result patients present with symptoms of low blood glucose (hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

), which are improved by eating. The diagnosis of an insulinoma is usually made biochemically with low blood glucose, elevated insulin, proinsulin and C-peptide levels and confirmed by localising the tumour with medical imaging
Medical imaging
Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...

 or angiography. The definitive treatment is surgery.


Insulinomas are rare neuroendocrine tumours with an incidence estimated at 1 to 4 new cases per million persons per year. Insulinoma is one of the most common types of tumour arising from the islets of Langerhans
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...

 cells (pancreatic endocrine tumours). Estimates of malignancy (metastases) range from 5% to 30%. Over 99% of insulinomas originate in the pancreas, with rare cases from ectopic pancreatic tissue. About 5% of cases are associated with tumours of the parathyroid glands and the pituitary (Multiple endocrine neoplasia type 1
Multiple endocrine neoplasia type 1
Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...

) and are more likely to be multiple and malignant. Most insulinomas are small, less than 2 cm.

Signs and Symptoms

Patients with insulinomas usually develop neuroglycopenic symptoms. These include recurrent headache, lethargy, diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...

, and blurred vision, particularly with exercise or fasting. Severe hypoglycemia may result in seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s, coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

, and permanent neurological damage. Symptoms resulting from the catecholaminergic response to hypoglycemia (i.e. tremulousness, palpitations, tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

, sweating, hunger, anxiety, nausea) are not as common. Sudden weight gain (the patient can become massively obese) is sometimes seen.


The diagnosis of insulinoma is suspected in a patient with symptomatic fasting hypoglycemia. The conditions of Whipple’s triad need to be met for the diagnosis of "true hypoglycemia" to be made:
  1. symptoms and signs of hypoglycemia,
  2. concomitant plasma glucose level of 45 mg/dL (2.5 mmol/L) or less, and
  3. reversibility of symptoms with administration of glucose.

Blood tests

The following blood tests are needed to diagnose insulinoma:
  • glucose
    Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

  • insulin
    Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

  • C-peptide
    C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...

If available, a proinsulin
Proinsulin is the prohormone precursor to insulin made in the beta cells of the islets of Langerhans, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene.- Synthesis and post-translational modification :...

 level might be useful as well. Other blood tests may help rule out other conditions which can cause hypoglycemia.

Suppression tests

Normally, endogenous insulin production is suppressed in the setting of hypoglycemia. A 72-hour fast, usually supervised in a hospital setting, can be done to see if insulin levels fail to suppress, which is a strong indicator of the presence of an insulin-secreting tumour.
During the test, the patient may have calorie-free and caffeine-free liquids. Capillary blood glucose is measured every 4 hours using a reflectance meter
Glucose meter
A glucose meter is a medical device for determining the approximate concentration of glucose in the blood. It is a key element of home blood glucose monitoring by people with diabetes mellitus or hypoglycemia...

, until values < 60 mg/dL (3.3 mmol/L) are obtained. Then, the frequency of blood glucose measurement is increased to every hour until values are < 49 mg/dL (2.7 mmol/L). At that point, or when the patient has symptoms of hypoglycemia, a blood test is drawn for serum glucose, insulin, proinsulin, and C-peptide levels. The fast is stopped at that point, and the hypoglycemia treated with intravenous dextrose or calorie-containing food or drink.

Diagnostic imaging

The insulinoma might be localized by non-invasive means, using ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...

, CT scan, or by MRI techniques. An Indium-111 pentetreotide scan is more sensitive than ultrasound, CT, or MRI for detection of somatostatin receptor positive tumors.

Sometimes, angiography with percutaneous transhepatic pancreatic vein catheterization to sample the blood for insulin levels is required. Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 can be injected into selected arteries to stimulate insulin release from various parts of the pancreas, which can be measured by sampling blood from their respective veins. The use of calcium stimulation improves the specificity of this test.

During surgery to remove an insulinoma, an intra-operative ultrasound can sometimes localize the tumour, which helps guide the surgeon in the operation and has a higher sensitivity than noninvasive imaging tests.


The definitive management is surgical removal of the insulinoma. This may involve removing part of the pancreas as well (Whipple procedure and distal pancreatectomy).

Medications such as diazoxide
Diazoxide is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions...

 and somatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...

 can be used to block the release of insulin for patients who are not surgical candidates or who otherwise have inoperable tumours.

Streptozotocin is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals...

 is used in islet cell carcinoma
Islet cell carcinoma
Islet cell carcinoma or nesidioblastoma is an uncommon cancer of the endocrine pancreas.It accounts for approximately 1.3% of pancreatic cancer.The term "nesidioblastoma" dates to at least 1938.-Survival:...

s which produce excessive insulin. Combination chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 is used: either doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....

 + streptozotocin, or fluorouracil
Fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites...

 + streptotozocin in patients where doxorubicin is contraindicated.

In metastasizing tumours with intrahepatic growth, hepatic arterial
Hepatic artery
Hepatic artery can refer to:* Common hepatic artery * Hepatic artery proper...

 occlusion or embolization
Embolization is a non-surgical, minimally-invasive procedure performed by an interventional radiologist and interventional neuroradiologists. It involves the selective occlusion of blood vessels by purposely introducing emboli.-Therapeutic applications:...

 can be used.


Most patients with benign insulinomas can be cured with surgery. Persistent or recurrent hypoglycemia after surgery tends to occur in patients with multiple tumours. About two percent of patients develop diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

after their surgery.


Hypoglycemia was first recognized in the 19th century. In the 1920s, after the discovery of insulin and its use in the treatment of diabetics, hyperinsulinism was suspected to be a cause of hypoglycemia in non-diabetics. The first report of a surgical cure of hypoglycemia by removing an islet cell tumour was in 1929.

External links

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