January 17, 2007


Synonyms and related keywords: insulinoma, hyperinsulinism, endogenous hyperinsulinism, islet cell adenoma, pancreatic islet cell, neuroendocrine tumor, hypoglycemia, B-cell tumor of the pancreas, adenoma of the islets of Langerhans


Background: In 1927, Wilder established the association between hyperinsulinism and a functional islet cell tumor. In 1929, Graham achieved the first surgical cure of an islet cell adenoma. Insulinomas can be difficult to diagnose. It was not uncommon for patients to have been misdiagnosed with psychiatric illnesses or seizure disorders before insulinoma was recognized.

In a large single-center series of 125 patients with neuroendocrine tumors, insulinomas constituted the majority of cases (55%), followed by gastrinomas (36%), VIPomas (vasoactive intestinal polypeptide tumor) (5%), and glucagonomas (3%).

Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism.

Pathophysiology: An insulinoma is a neuroendocrine tumor deriving mainly from pancreatic islet cells that produce excessive amounts of insulin. About 90% of insulinomas are benign. In healthy individuals, insulin and C-peptide are secreted in equimolar quantities because they derive from the same inactive precursor, proinsulin. Normally, less than 20% of proinsulin is released directly into the circulation.

Some insulinomas secrete additional hormones, such as gastrin, 5-hydroxyindolic acid, adrenocorticotropic hormone (ACTH), glucagon, human chorionic gonadotropin, and somatostatin. The tumor may secrete insulin in short bursts, causing wide fluctuations in blood levels.

Approximately 10% of insulinomas are malignant (metastases are present), and 10% are multiple, particularly in patients with multiple endocrine neoplasia type 1 (MEN 1). Of patients with multiple insulinomas, 50% have MEN 1. Insulinomas are associated with MEN 1 in 5% of patients. On the other hand, 21% of patients with MEN 1 develop insulinomas.



Sex: The male-to-female ratio is 2:3.




Physical: Insulinomas are characterized clinically by the Whipple triad (which occurred in 75% of 67 insulinoma patients as reported recently).

Causes: The genetic changes in neuroendocrine tumors are under investigation.


Other Problems to be Considered:

Factitious hypoglycemia can occur in patients who have psychiatric disturbances or a need for attention and access to insulin or sulfonylurea drugs (eg, medical staff). The triad of hypoglycemia, high immunoreactive insulin levels, and suppressed plasma C-peptide immunoreactivity is pathognomonic of exogenous origin. Insulin-induced hypoglycemia can be detected by a ratio of insulin to C-peptide that is greater than 1.0.

Hypoglycemia can occur after inadvertent ingestion of sulfonylurea due to patient or pharmacist error.

Autoimmune hypoglycemia is a rare disorder caused by the interaction of endogenous antibodies with insulin or the insulin receptor. The condition is more common in Japan than in the United States or Europe. The syndrome may produce severe neuroglycopenic symptoms, making immunosuppressive therapy occasionally necessary.

Nesidioblastosis is defined as hyperplasia of the islet cells causing hyperinsulinemic hypoglycemia. It is a predominantly neonatal disorder, although cases in adults have been reported recently.

Noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS) is a condition in which pancreatic islet hyperplasia is present. This is manifested with postprandial neuroglycopenia, a negative normal fasting test, negative pancreatic imaging results, and positive intra-arterial calcium stimulation of serum insulin.

Familial persistent hyperinsulinemia is manifested with inappropriately high insulin secretions seen in families with mutations in the glucokinase enzymes, glutamate dehydrogenase and short-chain3-hydroxyacyl1-CoA dehydrogenase.

Other causes for hypoglycemia include liver disease, endocrine deficiencies, extrapancreatic insulin-producing tumors (an insulin-secreting small-cell carcinoma of the cervix recently has been described), and pentamidine-induced hypoglycemia.


Lab Studies:

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Other Tests:

Histologic Findings: Insulinomas are solitary tumors in 90% of patients. In MEN 1 syndrome, multiple microinsulinomas and macroinsulinomas are found, although hypoglycemia may be caused by a single tumor. The tumors are distributed evenly throughout the pancreas. Tumor size does not relate to the severity of clinical symptoms. Ectopic insulinomas may be found in the ligament of Treitz.

No histological criteria are available to distinguish benign from malignant insulinomas. Malignant tumors are usually larger (average size 6.2 cm), and a third of them have metastasized to the liver. Insulinoma tumor cells contain less insulin and secretory granules than normal B cells but higher levels of proinsulin. Atypical granules, or even agranular cells, are frequent. The clinical response to diazoxide and somatostatin correlates with the frequency and type of granules.


Medical Care: Medical therapy is indicated in patients with malignant insulinomas and in those who will not or cannot undergo surgery. These measures are designed to prevent hypoglycemia and, in patients with malignant tumors, to reduce the tumor burden.

Surgical Care: Because insulinoma resection achieves cure in 90% of patients, it is currently the therapy of choice.

Consultations: Consult with the anesthetist to plan for precise preoperative and intraoperative blood glucose monitoring.


Activity: Exercise may aggravate hypoglycemia in patients with insulinoma.


Diazoxide is the drug of choice because it inhibits insulin release from the tumor. Adverse effects must be treated with hydrochlorothiazide. In patients not responsive to or intolerant of diazoxide (10%), somatostatin may be indicated to prevent hypoglycemia.

Drug Category: Hyperglycemic agents -- Inhibit insulin release from the tumor.
Drug Name
Diazoxide (Proglycem, Hyperstat) -- Produces an increase in blood glucose within 1 h by inhibition of insulin release from the insulinoma.
Adult Dose3-8 mg/kg/d PO divided q8h
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity; functional hypoglycemia
InteractionsMay displace other substances (coumarin, bilirubin) because it highly binds to proteins; diphenylhydantoin may lose control on seizures
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsInitiate only under close clinical supervision; prolonged treatment requires regular monitoring of the urine for sugar and ketones; monitor blood sugar levels for dose adjustments
The plasma half-life is prolonged in impaired renal function; the antihypertensive effect of other drugs may be enhanced; dose reduction of coumarin or its derivatives may be necessary
Drug Category: Diuretics -- Used to counteract edema and hyperkalemia secondary to diazoxide and to potentiate its hyperglycemic effect.
Drug Name
Hydrochlorothiazide (Microzide, HydroDIURIL, Esidrix) -- Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.
Adult Dose25-50 mg/d PO
Pediatric Dose1 mg/lb/d PO divided bid
ContraindicationsDocumented hypersensitivity; anuria
InteractionsPotentiation of orthostatic hypotension may occur with alcohol, barbiturates, or narcotics; dosage adjustments of the antidiabetic drug may be required; other antihypertensive drugs may cause additive effect or potentiation; discontinue thiazides before testing parathyroid function
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsClosely observe all patients for fluid or electrolyte imbalance; hypokalemia and hypomagnesemia may develop; thiazides may decrease urinary calcium excretion
Drug Category: Somatostatin analogs -- May control symptoms by suppressing secretion of gastroenteropancreatic peptides including insulin. High-dose treatment also may lead to additional antiproliferative effects. However, long-term application of somatostatin may down-regulate receptor expression levels, resulting in decreased efficiency despite increasing doses. Both short- and long-acting depot preparations are available.
Drug Name
Octreotide acetate (Sandostatin) -- Acts similarly to the natural hormone somatostatin and can suppress secretion of gastroenteropancreatic peptides including insulin.
Adult Dose200-300 mcg/d IV/SC divided bid/qid (range 150-750 mcg) during initial 2 wk; adjust dose to individual; LAR long-acting preparation can be used once/mo
Pediatric DoseNot established; 3-40 mcg/kg/d IV/SC has been used
ContraindicationsDocumented hypersensitivity
InteractionsImbalances in fluid and electrolytes or glycemic states may occur, requiring adjustment of doses; has been associated with alterations in nutrient absorption; consider its effect on any orally administered drug
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsDose adjustments may be required to control symptoms; cholelithiasis may develop; may alter insulin requirements in diabetes mellitus; absorption of dietary fats may be altered
In severe renal failure, the half-life may be increased


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