An insulinoma is a type of functional neuroendocrine tumor that manifests with hypoglycemia due to autologous secretion of insulin. It more commonly presents as a solitary benign tumor but can sometimes be associated with MEN type 1 (MEN1). Patients present with fasting hypoglycemia, which may manifest as episodes of diaphoresis, palpitations, tremor, and confusion. Insulinoma is usually diagnosed with high insulin, C peptide, and proinsulin levels despite the patient’s hypoglycemia. Localization of the insulinoma is done with imaging. Surgical removal of the insulinoma is the treatment of choice, but medical therapy may be utilized to prevent hypoglycemia in those who cannot undergo surgery.

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Definition and Epidemiology


Insulinomas are pancreatic neuroendocrine tumors that are derived from beta cells and secrete insulin.


  • Incidence: approximately 1–4 cases per million people per year
  • No sex or ethnic predisposition
  • All age groups
  • In 5%–10% of cases, insulinomas are malignant.
  • 6% of cases associated with MEN type 1 (MEN1) syndrome (associated with parathyroid, pituitary, and pancreatic tumors)

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Normal insulin physiology


  • Proinsulin:
    • Stored in secretory granules
    • Composed of three peptide chains: A, B, and C
    • Cleaved in the Golgi apparatus → insulin and C peptide
  • Insulin: 
    • Consists of 2 chains connected by 2 disulfide linkages: A and B chains
    • Released from pancreatic beta cells


  • Stimulated by:
    • Meal constituents:
      • Glucose
      • Amino acids
      • Free fatty acids
    • Enteric hormones:
      • Glucagon-like peptide 1 (GLP-1)
      • Gastric inhibitory polypeptide (GIP, also known as glucose-dependent insulinotropic polypeptide)
      • Cholecystokinin
    • Neural agonists:
      • Beta-adrenergic receptor stimulation via norepinephrine
      • Acetylcholine 
      • Vasoactive intestinal polypeptide (VIP)
  • Inhibited by:
    • Alpha-adrenergic receptor stimulation via norepinephrine
    • Somatostatin 


  1. Glucose enters beta cells.
  2. ATP production from glucose metabolism
  3. Closure of ATP-sensitive K-channels
  4. Beta cell depolarization
  5. Calcium (Ca) influx due to voltage-gated Ca-channel opening 
  6. Insulin and C-peptide exocytosis


  • ↑ Glucose uptake in skeletal muscle and adipose tissue via glucose transporter type 4 (GLUT4, an insulin-dependent transporter)
  • ↑ Glycogen synthesis
  • ↑ Protein synthesis and ↓ proteolysis
  • ↑ Triglyceride synthesis and ↓ lipolysis
  • ↓ Gluconeogenesis and glycogenolysis 
  • ↓ Glucagon release
The conversion of proinsulin to insulin

The conversion of proinsulin to insulin:
The A and B chains remain connected by disulfide bridges, while the C peptide is cleaved.

Image by Lecturio.

Pathophysiology of insulinomas

  • Insulinomas are functional neuroendocrine tumors derived from pancreatic islet cells.
  • Results in autonomously secreted insulin even when plasma glucose concentration is low
  • Failure to suppress insulin plus inhibited glucose synthesis → hypoglycemia
  • A catecholamine response occurs → symptoms
  • ↓ Cerebral glucose → neuroglycopenic symptoms

Clinical Presentation

Patients generally present with fasting hypoglycemia, which may manifest in episodes of sympathetic stimulation and/or central nervous system disturbances.

  • Symptoms of sympathetic activation:
    • Tremor
    • Pallor
    • Anxiety
    • Diaphoresis
    • Palpitations
  • Neuroglycopenic symptoms:
    • Confusion
    • Blurred vision
    • Ataxia
    • Seizures
    • Coma


Whipple triad

A collection of criteria that signal that a patient’s symptoms are a result of hypoglycemia, which will be present in patients with an insulinoma:

  • ↓ Serum glucose
  • Symptoms of hypoglycemia
  • Resolution of symptoms after glucose administration

Laboratory evaluation

The following laboratory values can assist in the diagnosis. These may be performed during a 48- or 72-hour fasting evaluation:

  • ↓ Serum glucose level
  • Inappropriately ↑ serum insulin
  • ↑ C-peptide
  • ↑ Proinsulin
  • Negative test for sulfonylureas

MEN1 genetic testing may be performed for: 

  • Young patients
  • Family or personal history of other endocrinopathies 


The following imaging modalities are useful for localizing the insulinoma and preoperative planning:

  • CT or MRI of the abdomen:
    • Can detect 70%–85% of insulinomas
    • Findings:
      • Small, solid mass
      • Enhances with contrast
  • Nuclear imaging: used if conventional imaging is unremarkable
  • EGD with endoscopic ultrasound of the pancreas:
    • Invasive
    • May be utilized if CT and MRI are negative but a strong suspicion remains
Radiographic and surgical findings insulinoma

Radiographic and surgical findings for an insulinoma:
A: A large insulinoma of the pancreatic tail was detected with combined CT and nuclear medicine imaging.
B: The gross appearance of the insulinoma after it was resected laparoscopically

Image: “Preoperative Glucagon-like peptide-1 receptor imaging reduces surgical trauma and pancreatic tissue loss in insulinoma patients: a report of three cases” by Wenning AS, Kirchner P, Antwi K, Fani M, Wild D, Christ E, Gloor B. License: CC BY 4.0


Surgical resection

Removal of the insulinoma is the treatment of choice and provides a favorable cure rate.

For resectable tumors (depending on tumor location and number): 

  • Carries the most favorable prognosis
  • Enucleation of solitary tumors
  • Partial distal pancreatectomy 
  • Total pancreatectomy
  • Whipple procedure 

For metastatic disease to the liver:

  • Resection
  • Cryotherapy
  • Radiofrequency ablation 
  • Embolization 

Medical therapy

Medications to prevent symptomatic hypoglycemia may be used if the insulinoma is unresectable or the patient is a poor surgical candidate.

  • Diazoxide:
    • Potassium channel activator
    • Inhibits insulin secretion
  • Octreotide: 
    • Somatostatin analog
    • 2nd-line treatment after diazoxide
    • Can inhibit secretion of:
      • Insulin
      • Glucagon
      • Gastrin

Differential Diagnosis

  • Factitious hypoglycemia: may result from exogenous self-administration of insulin. Factitious hypoglycemia is often seen with healthcare workers who present with symptoms of hypoglycemia. Unlike insulinomas, a laboratory evaluation will reveal low C-peptide and proinsulin levels despite high insulin levels. Management includes correcting hypoglycemia and psychiatric therapy.
  • Sulfonylurea toxicity: may occur in patients who are not eating or have renal impairment. Patients will present with hypoglycemia. Unlike with insulinomas, serum sulfonylurea testing will be positive. Management includes withdrawal of the causative agent and treatment for hypoglycemia.
  • Persistent hyperinsulinemic hypoglycemia of infancy (PHHI): most common cause of persistent hypoglycemia in neonates and infants, caused by mutations involving different proteins leading to insulin release dysregulation. A laboratory evaluation will show inappropriately detectable levels of insulin and C-peptide, low beta-hydroxybutyrate and free fatty acids, and a glycemic response to glucagon. Genetic testing is often performed. Management may include diazoxide, octreotide, or surgery.
  • Insulin autoimmune hypoglycemia: occurs in patients who have autoantibodies directed to endogenous insulin or the insulin receptor, which results in hypoglycemia. Detection of antibodies to insulin will provide the diagnosis. This condition is managed with small, frequent meals; steroids; and, in severe cases, plasmapheresis.


  1. Vella, A. (2021). Insulinoma. In Mulder, J.E. (Ed.). UpToDate. Retrieved April 13, 2021, from
  2. Service, FJ, et al. (1991). Functioning insulinoma—Incidence, recurrence, and long-term survival of patients: A 60-year study. Mayo Clinic Proceedings. 66(7), 711–19.
  3. Kavlie, H, White, TT. (1972). Pancreatic islet beta cell tumors and hyperplasia: Experience in 14 Seattle hospitals. Annals of Surgery. 175(3), 326–35.
  4. Lupsa, BC, et al. (2009). Autoimmune forms of hypoglycemia. Medicine. 88(3), 141–53.
  5. Nguyen, M. (2021). Insulinoma. MSD Manual Professional Version. Retrieved April 18, 2021, from
  6. Zhuo, F, and Anastasopoulou, C. (2020). Insulinoma. StatPearls. Retrieved April 18, 2021, from
  7. Ali, ZA. (2020). Insulinoma. In Radhakrishnan, N. (Ed.). Medscape. Retrieved April 18, 2021, from

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