Insulinomas are such rare tumors that even most specialists treat only a handful of these patients over their entire careers. Moreover, even most major referral centers treat only three or four cases per year. Nevertheless, the widely disparate clinical presentations as well as the complexity of diagnosis, localization, and treatment of these tumors continue to allure and sometimes perplex the team of physicians who care for these patients.

Resection of an insulinoma was first attempted by William J. Mayo in 1926.1 Unfortunately, the patient, a surgeon, was found to have an unresectable metastatic insulinoma and died 1 month later. Two years later, Roscoe Graham of Toronto performed the first successful curative enucleation of a benign insulinoma.2 In 1935, Frantz and Whipple characterized the classic symptoms of endogenous hyperinsulinemia, which subsequently became known as a “Whipple’s triad.”3 This triad of hypoglycemia (plasma glucose <50 mg/dL), symptoms of hypoglycemia, and symptom resolution after glucose administration still serves as the fundamental basis for diagnosis.

Islet cells were first identified by a medical student, Paul Langerhans, in 1869.4 Islets contain several different subtypes of secretory cells with different hormone production profiles. Insulin, which is secreted by the β cell, was discovered by Banting and Best in 1922, winning them a Nobel Prize.5 Insulin is manufactured by the β cell as proinsulin, an inactive peptide made up of two subunits and a linking peptide (C peptide). Before secretion, proinsulin is cleaved into its active form, also releasing C peptide (an inactive, rapidly degraded peptide) in equimolar amounts.6 C peptide is more rapidly degraded in the blood than insulin, with a half-life of about 4 to 6 minutes compared with a half-life of about 11 to 14 minutes for insulin.7 Knowledge of this biochemistry is critical in evaluating patients with suspected hyperinsulinemia because the concomitant measurement of insulin and C-peptide levels may help distinguish between endogenous hyperinsulinemia and exogenous insulin administration (e.g., malingering). Manufactured insulin compounds do not contain C peptide. Hyperinsulinemia with low or undetectable C-peptide levels indicates an exogenous source of insulin.

Insulinoma is an islet cell neoplasm characterized by the excessive unregulated secretion of insulin, which results in the clinical symptoms of hypoglycemia. The incidence is estimated at four per 1 million person-years.8Table 17-1 presents the major reported series of surgically treated insulinomas. The mean age of presentation is typically in the fourth or fifth decade of life, with a slight predominance in women. Approximately 3% to 7% of tumors are associated with type 1 multiple endocrine neoplasia syndrome (MEN1).9–16

Sporadic insulinomas are almost always benign and single. Islet cell neoplasms in patients with MEN1 are almost universally multiple and scattered throughout the pancreas. The prognosis for patients with malignant insulinoma is better than for patients with exocrine pancreatic cancer, but most patients with liver metastases still have a relatively poor median survival of only 2 years.8,17

The only documented risk factor for insulinoma is MEN1 syndrome. This syndrome results from a mutation in the menin gene on the long arm of chromosome 11, which predisposes patients to neuroendocrine tumors.18 Neuroendocrine tumors of the pancreas and duodenum are the second most common manifestation of MEN1, affecting more than 50% of patients, and are the most common cause of death.19 These tumors include insulinomas, gastrinomas, and other rare hormone-secreting tumors (glucagonomas, vasoactive intestinal peptide [VIP]-omas, carcinoid tumors) but predominantly are nonfunctional islet cell tumors (pancreatic polypeptide [PP]-omas, producing only pancreatic polypeptide, or nonsecreting tumors). Hyperparathyroidism and pituitary adenomas are also encountered in MEN1 patients, with hyperparathyroidism affecting 88% to 97% of patients.19 Treatment of MEN1 patients must take into consideration the multicentric nature of the disease as well as the predilection for other tumors, especially hormonally active duodenal carcinoid tumors. These patients should have close lifelong surveillance.

The diagnosis of insulinoma is often delayed because of the vague and sometimes bizarre nature of the symptoms. The key to the diagnosis is clinical suspicion and the presence of neuroglycopenic symptoms. Mild hypoglycemia stimulates both autonomic and adrenergic responses, resulting in symptoms of sweating, tachycardia, tremor, anxiety, palpitations, and weakness. This may progress as hypoglycemia worsens to neurologic dysfunction; the neurologic symptoms of hypoglycemia are the key to suspecting the diagnosis. The neurologic effects of hypoglycemia (<50 mg/dL) ranges from mild (e.g., confusion or forgetfulness, blurred vision) to severe (e.g., loss of consciousness, seizures). Rarely, focal neurologic deficits are seen and are confused with transient ischemic attacks.8 Symptoms are typically encountered after fasting or exercise, are stereotypic for a given patient, and are often described as “spells.” Family and friends typically confirm episodes of unusual behavior or disorientation. Confirmation of hypoglycemia while symptoms are present is critical to establishing the diagnosis. Many patients gain weight before diagnosis because of increased oral intake at the onset of hypoglycemic “spells” in an effort to prevent or abort their hypoglycemic symptoms.

In taking a patient’s history, the social history (e.g., health care professional, close contact with diabetic family members) can be important because access to injectable insulin may raise the suspicion of surreptitious insulin self-administration. Timing of symptoms is also important because whereas those occurring early in the morning (e.g., from fasting overnight) and after exercise are suggestive of insulinoma, postprandial symptoms suggest non-insulinoma, pancreatogenous hyperinsulinemia syndrome (NIPHS; discussed later).

Currently, four concomitant criteria must be met for the diagnosis of insulinoma:

1. 
   

   Plasma glucose <45 to 50 mg/dL

   
   
2. 
   

   Elevated insulin level (>6 μU/mL by IRMA or >3 μU/mL by ICMA)

   
   
3. 
   

   C-peptide levels ≥200 pmol/L

   
   
4. 
   

   Negative screening test results for sulfonylureas

A supervised fast (classically described but now rarely extending to 72 hours) is performed. This may be initiated and often completed in the outpatient setting if the patient begins the fast the evening before evaluation (with the start time dependent on the usual time to onset of symptoms and scheduled clinic appointment time). An intravenous (IV) line is started at the time of the patient’s arrival at the hospital, and initial glucose levels are drawn and repeated periodically by reflectance meter until symptom onset. Biochemical tests that need to be obtained at the time the patient experiences symptoms (with concomitant reflectance meter glucose levels <50 mg/mL) include serum levels of glucose, insulin, β-hydroxybutyrate, and C peptide. Glucagon (1 mg IV) is then administered, and glucose is monitored every 10 minutes for an additional 30 minutes to allow for measurement of insulin surrogates (discussed later). Low (or undetectable) C-peptide levels in the setting of hyperinsulinemic hypoglycemia suggests administration of exogenous insulin (and suppression of endogenous insulin or C-peptide production). Insulin:glucose ratios are not routinely helpful because fewer than 50% of patients with insulinomas have ratios of 0.30 or below. More important are the absolute levels of glucose and insulin because any measurable insulin in the setting of severe hypoglycemia (<45 to 50 mg/dL) is abnormal.