Insulinoma is a pancreatic insulin-secreting tumor that leads to inappropriately elevated plasma insulin or proinsulin levels with suppression of hepatic glucose output and subsequent hypoglycemia, especially during periods of fasting.

Symptoms typically occur in the morning before breakfast (i.e., fasting hypoglycemia as opposed to reactive hypoglycemia, which is not commonly associated with insulinoma).

• Insulinomas are almost always solitary. Malignant insulinomas account for 5% of the total; they tend to be larger (6 cm). Metastases are usually to the liver (47%), regional lymph nodes (30%), or both.
• Insulinomas are evenly distributed in the head, body, and tail of the pancreas; ectopic insulinomas are rare (1% to 3%). Tumor size: 5% are ≤0.5 cm, 34% are 0.5 to 1 cm, 53% are 1 to 5 cm, and 8% are >5 cm.
• Histologic classification includes insulinoma in 86% of patients, adenomatosis in 5% to 15%, nesidioblastosis in 4%, and hyperplasia in 1%. Adenomatosis consists of multiple macroadenomas or microadenomas and occurs especially in patients with MEN-1. Nesidioblastosis is also a diffuse lesion in which islet cells form as buds on ductular structures.

Hyperinsulinism:

• Insulinoma
• Nonpancreatic tumors
• Severe congestive heart failure
• Severe renal insufficiency in non-insulin-dependent diabetes

Hepatic enzyme deficiencies or decreased hepatic glucose output (primarily in infants and children):

• Glycogen storage diseases
• Endocrine hypofunction
• Hypopituitarism
• Addison disease
• Liver failure
• Alcohol abuse
• Malnutrition

Exogenous agents:

• Sulfonylureas, biguanides
• Insulin
• Other drugs (aspirin, pentamidine)

Functional fasting hypoglycemia:

• Autoantibodies to insulin receptor or insulin

• An overnight fasting blood sugar level combined with a simultaneous plasma insulin, proinsulin, and/or C peptide level will establish the existence of fasting organic hypoglycemia in 60% of patients. Table E1 describes biochemical patterns in patients with various causes of hyperinsulinemic hypoglycemia.
• If single overnight fasting glucose and insulin levels are nondiagnostic, a 72-h fast is usually done with blood glucose and insulin levels determined at 2- to 4-h intervals. A total of 75% of patients with insulinoma develop symptoms and a blood sugar level of <40 mg/dl by 24 h, 92% to 98% develop these by 48 h, and virtually all patients develop them by 72 h. The test is considered positive for insulinoma if the plasma insulin/glucose ratio is more than 0.3. If at any point the patient becomes symptomatic, plasma insulin and glucose values should be obtained and IV glucose should be administered.
• The Endocrine Society guidelines for diagnosis of hypoglycemic disorders is based on glucose level <55 mg/dl (<3.1 mmol/L), elevated C-peptide level ≥0.61 ng/ml (≥0.2 nmol/L). Elevated insulin level ≥18 pmol/L, proinsulin level >5 pmol/L, and suppressed β-hydroxy-butyric acid level.
• An “amended” insulin-glucose ratio that accounts for the normal variation in insulin secretion according to prevailing glycemia has been shown to improve diagnostic accuracy of insulinomas. The “amended” insulin-glucose ratio is derived from the simple insulin-glucose ratio by subtracting 30 mg/dl (1.7 mmol/L) from the measured glucose concentrations.

• Abdominal CT scan (Fig. E1) or MRI detects half to two thirds of insulinomas (abdominal ultrasound is not effective); should be done only after laboratory tests for insulinoma have confirmed the diagnosis
• Intraoperative ultrasound
• Arteriography (Fig. E2)
• Octreotide scan (see Fig. E1)

• Enucleation of single insulinoma
• Partial pancreatectomy for multiple adenomas

• Carbohydrate administration
• Diazoxide directly inhibits insulin release and has an extrapancreatic, hyperglycemic effect that enhances glycogenolysis
• Lanreotide and octreotide (somatostatin analogues)
• Streptozotocin

To an endocrinologist and then to an endocrine surgeon

Hypoglycemia (Related Key Topic)