Insulinoma

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Insulinoma
Pancreatic insulinoma (2).JPG
Pathology of pancreatic endocrine tumour (insulinoma).
Specialty Oncology

An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional pancreatic neuroendocrine tumour (PNET) group ("functional" because it increases production of insulin). [1] In the Medical Subject Headings classification, insulinoma is the only subtype of "islet cell adenoma". [2]

Contents

Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels, the point at which further secretion of insulin is stopped. In contrast, the secretion of insulin by insulinomas is rather independent of blood glucose; these tumours continue to secrete insulin, causing blood glucose levels to fall further below normal. [3]

As a result, patients present symptoms of low blood glucose (hypoglycemia), 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 localizing the tumour with medical imaging or angiography. The definitive treatment is surgery. [3]

Signs and symptoms

Patients with insulinomas usually develop neuroglycopenic symptoms. These include recurrent headache, lethargy, diplopia, and blurred vision, particularly with exercise or fasting. Severe hypoglycemia may result in seizures, coma, and permanent neurological damage. Symptoms resulting from the catecholaminergic response to hypoglycemia (i.e. tremulousness, palpitations, tachycardia, sweating, hunger, anxiety, nausea) are not as common. Sudden weight gain is sometimes seen.[ citation needed ]

Diagnosis

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: [4] [5]

  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

These blood tests are needed to diagnose insulinoma: [6]

If available, a proinsulin 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.[ citation needed ]

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, 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 then stopped at that point, and the hypoglycemia is treated with intravenous dextrose or carbohydrate-containing food or drink.[ citation needed ]

Diagnostic imaging

The insulinoma might be localized by noninvasive means, using ultrasound, CT scan, or MRI techniques. An indium-111 pentetreotide scan is more sensitive than ultrasound, CT, or MRI for detection of somatostatin receptor positive tumours, but not a good diagnostic tool for insulinomas. An endoscopic ultrasound has a sensitivity of 40-93% (depending on the location of the tumour) for detecting insulinomas. [7]

Sometimes, angiography with percutaneous transhepatic pancreatic vein catheterization to sample the blood for insulin levels is required. Calcium 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 intraoperative ultrasound can sometimes localize the tumour, which helps guide the surgeon in the operation and has a higher sensitivity than noninvasive imaging tests.[ citation needed ]

Treatment

Gross appearance of insulinoma showing the typical red-brown appearance of tumour Insulinoma.jpg
Gross appearance of insulinoma showing the typical red-brown appearance of tumour

The definitive management is the surgical removal of the insulinoma. This may involve removing part of the pancreas, as well (Whipple procedure and distal pancreatectomy). Medications such as diazoxide and 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 used in islet cell carcinomas which produce excessive insulin. Combination chemotherapy is used, either doxorubicin and streptozotocin, or fluorouracil and streptozocin in patients where doxorubicin is contraindicated. In metastasizing tumours with intrahepatic growth, hepatic arterial occlusion or embolization can be used.[ citation needed ]

Prognosis

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 2% of patients develop diabetes mellitus after their surgery.[ citation needed ]

Incidence

Insulinomas are rare neuroendocrine tumours with an incidence estimated at one to four new cases per million persons per year. Insulinoma is one of the most common types of tumours arising from the islets of Langerhans 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) and are more likely to be multiple and malignant. Most insulinomas are small, less than 2 cm.[ citation needed ]

History

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 nondiabetics. A pioneering description of hyperinsulinism as a cause of hypoglycemia was published by Seale Harris in 1924. The first report of a surgical cure of hypoglycemia by removing an islet cell tumour was in 1929.[ citation needed ]

An insulinoma removed from a woman in Munich provided insulin mRNA that was used in the first human gene cloning experiment. In 1979, Axel Ulrich cloned this gene into E. coli. Most therapeutic insulin used today derives from this woman's tumour. [8]

Additional images

See also

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Health condition

Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

<span class="mw-page-title-main">Pancreas</span> Organ of the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e., it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins and fats in food entering the duodenum from the stomach.

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells), are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels.Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Blood sugar level</span> Concentration of glucose present in the blood (Glycaemia)

The blood sugar level, blood sugar concentration, blood glucose level, or glycemia, is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis.

<span class="mw-page-title-main">C-peptide</span> Chemical compound

The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum levels can be used to distinguish between different conditions with similar clinical features.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

<span class="mw-page-title-main">Hyperinsulinism</span> Medical condition

Hyperinsulinism refers to an above normal level of insulin in the blood of a person or animal. Normal insulin secretion and blood levels are closely related to the level of glucose in the blood, so that a given level of insulin can be normal for one blood glucose level but low or high for another. Hyperinsulinism can be associated with several types of medical problems, which can be roughly divided into two broad and largely non-overlapping categories: those tending toward reduced sensitivity to insulin and high blood glucose levels (hyperglycemia), and those tending toward excessive insulin secretion and low glucose levels (hypoglycemia).

Whipple's triad is a collection of three signs that suggests that a patient's symptoms result from hypoglycaemia that may indicate insulinoma. The essential conditions are symptoms of hypoglycaemia, low blood plasma glucose concentration, and relief of symptoms when plasma glucose concentration is increased. It was first described by the pancreatic surgeon Allen Whipple, who aimed to establish criteria for exploratory pancreatic surgery to look for insulinoma.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Reactive hypoglycemia</span> Medical condition

Reactive hypoglycemia, postprandial hypoglycemia, or sugar crash is a term describing recurrent episodes of symptomatic hypoglycemia occurring within four hours after a high carbohydrate meal in people with and without diabetes. The term is not necessarily a diagnosis since it requires an evaluation to determine the cause of the hypoglycemia.

<span class="mw-page-title-main">Multiple endocrine neoplasia type 1</span> Medical condition

Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. Individuals suffering from this disorder are prone to developing multiple endocrine and nonendocrine tumors. It was first described by Paul Wermer in 1954.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

A VIPoma or vipoma is a rare endocrine tumor that overproduces vasoactive intestinal peptide. The incidence is about 1 per 10,000,000 per year. VIPomas usually originate from the non-β islet cells of the pancreas. They are sometimes associated with multiple endocrine neoplasia type 1. Roughly 50–75% of VIPomas are malignant, but even when they are benign, they are problematic because they tend to cause a specific syndrome: the massive amounts of VIP cause a syndrome of profound and chronic watery diarrhea and resultant dehydration, hypokalemia, achlorhydria, acidosis, flushing and hypotension, hypercalcemia, and hyperglycemia. This syndrome is called Verner–Morrison syndrome (VMS), WDHA syndrome, or pancreatic cholera syndrome (PCS). The eponym reflects the physicians who first described the syndrome.

<span class="mw-page-title-main">Neuroendocrine tumor</span> Medical condition

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

An insulin tolerance test (ITT) is a medical diagnostic procedure during which insulin is injected into a patient's vein, after which blood glucose is measured at regular intervals. This procedure is performed to assess pituitary function, adrenal function, insulin sensitivity, and sometimes for other purposes. An ITT is usually ordered and interpreted by an endocrinologist.

<span class="mw-page-title-main">Pancreatic neuroendocrine tumor</span> Medical condition

Pancreatic neuroendocrine tumours, often referred to as "islet cell tumours", or "pancreatic endocrine tumours" are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas.

In medicine, a nesidioblastoma is an uncommon, insulin-secreting, pancreatic neuroendocrine tumor (PanNET). The term dates to at least 1938. In that report, these lesions were adjudicated as histologically benign adenoma growths, that were associated with severe, long-standing hypoglycemia due to hyperinsulinism. Surgical removal corrected the low glucose problems. There is no rigorous definitional separation from insulinoma, other than the original emphasis that was placed on the observed precise histological recapitulation of normal islet cell structure within the adenomas, which lacked microscopic features of aggressivity.

A metastatic insulinoma is a rare form of a malignant insulinoma involving metastatic growth. An insulinoma is a small tumor localized to the pancreas, originating from islet beta cells, which produce an excess of insulin. The increase in insulin ultimately leads to hypoglycemia. Insulinomas are commonly benign tumors, but can metastasize and become malignant. The metastatic growth can be characterized as a local invasion or distal metastasis. However, insulinomas are often difficult to detect due to their relatively small size, with a diameter oftentimes less than 2 cm. Therefore, clinical appearance and pathology are not sufficient in diagnosing a malignant insulinoma. Malignant insulinomas are not easily treated, as they require various treatments dependent on each person's case.

References

  1. Burns, William R.; Edil, Barish H. (March 2012). "Neuroendocrine Pancreatic Tumors: Guidelines for Management and Update". Current Treatment Options in Oncology. 13 (1): 24–34. doi:10.1007/s11864-011-0172-2. PMID   22198808. S2CID   7329783.
  2. MeSH website, tree at: "Pancreatic Neoplasms [C04.588.322.475]",[ dead link ] accessed 16 October 2014
  3. 1 2 "Insulinomas". The Lecturio Medical Concept Library. Retrieved 27 July 2021.
  4. Melmed, Shlomo (2016). Williams textbook of endocrinology (13 ed.). Elsevier. pp. 1582–1607. ISBN   978-0-323-29738-7.
  5. Martens, Pieter; Tits, Jos (June 2014). "Approach to the patient with spontaneous hypoglycemia". European Journal of Internal Medicine. 25 (5): 415–421. doi:10.1016/j.ejim.2014.02.011. PMID   24641805.
  6. "Insulinomas". The Lecturio Medical Concept Library. Retrieved 22 July 2021.
  7. Sotoudehmanesh, Rasoul; Hedayat, Anooshirvan; Shirazian, Nahid; Shahraeeni, Shadi; Ainechi, Sanaz; Zeinali, Fatemeh; Kolahdoozan, Shadi (17 September 2007). "Endoscopic ultrasonography (EUS) in the localization of insulinoma". Endocrine. 31 (3): 238–241. doi:10.1007/s12020-007-0045-4. PMID   17906369. S2CID   5634475.
  8. "Genentech and Axel Ulrich clone the human insulin gene". Tacomed.com. Archived from the original on 27 September 2017. Retrieved 13 June 2017.

Further reading