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  • Hypoglycemic symptoms—often neuroglycopenic (confusion, blurred vision, anxiety, convulsions).

  • Immediate recovery upon administration of glucose.

  • Blood glucose 40–50 mg/dL (2.2–2.8 mmol/L) with a serum insulin level of ≥ 6 microunits/mL.


Fasting hypoglycemia in an otherwise healthy, well-nourished adult is rare and is most commonly due to an adenoma of the islets of Langerhans. Ninety percent of such tumors are single and benign, but multiple adenomas can occur as well as malignant tumors with functional metastases. Adenomas may be familial, and multiple adenomas have been found in conjunction with tumors of the parathyroids and pituitary (MEN type 1 [MEN 1]). About 30% of sporadic insulinoma tumors have a somatic mutation in the YY1 gene (T372R) that encodes the transcriptional repressor YY1. Over 99% of insulinomas are located within the pancreas and less than 1% in ectopic pancreatic tissue.


A. Symptoms and Signs

The most important prerequisite to diagnosing an insulinoma is simply to consider it, particularly in relatively healthy-appearing persons who have fasting hypoglycemia associated with some degree of CNS dysfunction such as confusion or abnormal behavior. A delay in diagnosis can result in unnecessary treatment for epilepsy or psychiatric disorders and may cause irreversible brain damage. In long-standing cases, obesity can result as a consequence of overeating to relieve symptoms.

The so-called Whipple triad is characteristic of hypoglycemia regardless of the cause. It consists of (1) a history of hypoglycemic symptoms, (2) an associated low plasma glucose level (40–50 mg/dL), and (3) relief of symptoms upon ingesting fast-acting carbohydrates in approximately 15 minutes. The hypoglycemic symptoms in insulinoma often develop in the early morning or after missing a meal. Occasionally, they occur after exercise.

Patients typically complain of neuroglycopenic symptoms such as blurred vision or diplopia, headache, feelings of detachment, slurred speech, and weakness. Personality and mental changes vary from anxiety to psychotic behavior, and neurologic deterioration can result in convulsions or coma. Hypoglycemic unawareness is very common and adrenergic symptoms of palpitations and sweating may be blunted. With the ready availability of home blood glucose–monitoring systems, patients sometimes present with documented fingerstick blood glucose levels in the 40s and 50s at time of symptoms. Access to sulfonylureas or insulin should be explored—does a family member have diabetes, or does the patient or family member work in the medical field? Medication-dispensing errors should be excluded—has the patient’s prescription medication changed in shape or color? Patients with insulinoma or factitious hypoglycemia usually have a normal physical examination.

B. Laboratory Findings

B cell adenomas do not reduce secretion of insulin in the presence of hypoglycemia, and the critical diagnostic test is to demonstrate inappropriately elevated serum insulin, proinsulin, and C-peptide levels, at a time when plasma glucose level is below ...

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