What is an Insulinoma?

An insulinoma is a rare pancreatic tumor that produces excessive insulin, leading to recurrent episodes of hypoglycemia (low blood sugar). It is the most common functional pancreatic neuroendocrine tumor (NET).

Key Facts:

• Incidence: 1-4 cases per million per year (very rare)
• Location: Pancreas (distributed throughout—head, body, tail)
• Size: Usually small (<2 cm)
• Benign in 90%: Only ~10% are malignant
• Solitary: 90% single tumor; 10% multiple (associated with MEN1 syndrome)
• Peak Age: 40-60 years

Symptoms (Whipple's Triad - Must Have All 3):

1. Symptoms of Hypoglycemia
2. Documented Low Blood Glucose (<55 mg/dL) during symptoms
3. Relief of Symptoms with eating or glucose administration

Hypoglycemia Symptoms:

• Autonomic (from adrenaline response): Sweating, tremor, palpitations, hunger, anxiety
• Neuroglycopenic (low brain glucose): Confusion, dizziness, blurred vision, weakness, headache, slurred speech, altered behavior, seizures, loss of consciousness
• Timing: Fasting hypoglycemia (symptoms after fasting, exercise, overnight, before meals)
• Patients often gain weight (frequent eating to prevent hypoglycemia)

Diagnosis:

1. Supervised 72-Hour Fast (Gold Standard):

• Hospital-based test; patient fasts up to 72 hours (under supervision)
• Measure glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate every 4-6 hours (more frequently if glucose drops)
• Diagnostic Findings:
  • Glucose <55 mg/dL
  • Insulin ≥3 µU/mL (inappropriately high for low glucose)
  • C-peptide ≥0.6 ng/mL (proves endogenous insulin production)
  • Proinsulin ≥5 pmol/L
  • Beta-hydroxybutyrate <2.7 mmol/L (ketones suppressed by insulin)
  • Negative sulfonylurea screen (rules out exogenous insulin secretagogue)
• Most patients with insulinoma develop hypoglycemia within 48 hours

2. Imaging (Localize Tumor):

• Multiphasic CT Pancreas: Insulinomas are hypervascular → "light up" on arterial phase
• MRI Abdomen
• Endoscopic Ultrasound (EUS): Most sensitive for small tumors (<1-2 cm); can also biopsy
• Gallium-68 DOTATATE PET/CT: Functional imaging (somatostatin receptor imaging)
• Selective Arterial Calcium Stimulation Test (ASVS): Invasive; calcium injected into pancreatic arteries → stimulates insulin release → localizes tumor region (used if other imaging negative)

Treatment:

1. Surgery (CURATIVE for Benign Tumors):

• Tumor Enucleation: Remove tumor only (if small, superficial)
• Partial Pancreatectomy: Remove portion of pancreas containing tumor
• Success Rate: >90% cure rate for benign tumors
• Intraoperative Ultrasound: Helps locate small tumors during surgery
• Risks: Pancreatitis, pancreatic fistula, diabetes (if extensive resection)

2. Medical Management (If Surgery Not Possible or Malignant):

• Diazoxide (Proglycem®):
  • Inhibits insulin release from pancreas
  • 50-200 mg orally 2-3x/day
  • Side effects: Fluid retention (use with diuretic), hirsutism, nausea
• Somatostatin Analogs (Octreotide, Lanreotide):
  • Suppress insulin secretion
  • Paradoxically can worsen hypoglycemia in some patients (also suppresses glucagon/growth hormone)
  • More useful for malignant insulinomas
• Everolimus (mTOR Inhibitor): For advanced/metastatic disease
• Chemotherapy: Streptozocin-based regimens for malignant tumors

3. Supportive Care:

• Frequent meals, snacks (every 2-3 hours)
• Complex carbs, protein (avoid simple sugars—can trigger rebound hypoglycemia)
• Continuous overnight feeding (via G-tube) if severe nocturnal hypoglycemia
• Glucagon emergency kit

Malignant Insulinoma (10%):

• Metastases (most commonly to liver, lymph nodes)
• Treatment: Surgery (debulking), somatostatin analogs, everolimus, PRRT (Lu-177 DOTATATE), chemotherapy
• Prognosis: Variable; 5-year survival ~40-60%

Association with MEN1:

• ~10% of insulinomas occur in Multiple Endocrine Neoplasia Type 1 (MEN1)
• MEN1 patients: Multiple tumors, younger age, more likely to be malignant
• Check for MEN1 if: Young patient, multiple pancreatic tumors, family history, other endocrine tumors (parathyroid, pituitary)

Differential Diagnosis of Fasting Hypoglycemia:

• Exogenous Insulin: Factitious hypoglycemia (patient injecting insulin)
• Sulfonylureas: Diabetes medications
• Post-Bariatric Hypoglycemia: After gastric bypass (postprandial, not fasting)
• Non-Islet Cell Tumor Hypoglycemia (NICTH): Large tumors (sarcomas, liver tumors) producing IGF-2
• Critical Illness: Sepsis, liver failure, kidney failure
• Alcohol-Induced Hypoglycemia

Prognosis:

• Benign Insulinoma (90%): Excellent; >90% cured with surgery
• Malignant (10%): Poorer prognosis but slow-growing; many patients live years with treatment