Insulinoma
Summary
Insulinoma is a rare functioning neuroendocrine tumour of the pancreatic beta-cells that secretes insulin autonomously, causing recurrent episodes of hypoglycaemia. It is the most common functioning pancreatic neuroendocrine tumour (PNET). The classic presentation is fasting hypoglycaemia with Whipple's Triad. Diagnosis requires demonstrating inappropriately elevated insulin and C-peptide in the presence of hypoglycaemia (typically via a 72-hour supervised fast). Most insulinomas are small (less than 2cm), solitary, and benign (>90%). Surgical resection (enucleation or partial pancreatectomy) is curative in the vast majority. Insulinomas are associated with MEN1 Syndrome (~5-10%), where they may be multiple. [1,2]
Clinical Pearls
Whipple's Triad: 1) Symptoms of Hypoglycaemia; 2) Documented Low Blood Glucose at time of symptoms; 3) Relief of symptoms with Glucose administration. Essential for diagnosis.
Fasting Hypoglycaemia: Insulinomas classically cause hypoglycaemia during fasting (e.g., overnight, skipping breakfast). This distinguishes them from reactive hypoglycaemia (post-prandial).
High C-Peptide = Endogenous Insulin: If Insulin is high because the patient is injecting insulin (factitious/Munchausen), C-peptide will be LOW. In Insulinoma, both Insulin AND C-peptide are HIGH (endogenous production includes both).
Tiny Tumours: Insulinomas are often less than 2cm and can be very difficult to localise on imaging. Endoscopic Ultrasound (EUS) is often required.
Demographics
- Incidence: ~1-4 per million per year. Rare.
- Age: Can occur at any age; peak 40-60 years.
- Sex: Slightly more common in females.
- Malignancy: less than 10% are malignant (metastases, usually to liver).
Associations
| Condition | Notes |
|---|---|
| MEN1 Syndrome | ~5-10% of insulinomas occur in MEN1 (Multiple Endocrine Neoplasia Type 1). Screen family history. May be multiple insulinomas. |
| Sporadic | ~90% are sporadic, solitary. |
Mechanism of Hypoglycaemia
- Beta-Cell Tumour: Tumour arises from insulin-secreting beta-cells of the Islets of Langerhans.
- Autonomous Insulin Secretion: Insulinoma releases insulin independent of blood glucose levels. Normal negative feedback is lost.
- Hyperinsulinaemia: Sustained or episodic high insulin levels.
- Suppression of Gluconeogenesis: Insulin suppresses hepatic glucose output.
- Increased Glucose Uptake: Insulin drives glucose into muscle and fat.
- Hypoglycaemia: Blood glucose falls, often during fasting when there is no dietary glucose input.
- Symptoms: Brain (Neuroglycopenic: Confusion, Seizures) and Adrenergic (Sweating, Tremor, Palpitations) symptoms manifest.
Why C-Peptide Matters
- Proinsulin is cleaved into Insulin + C-Peptide in equal amounts.
- In Insulinoma: Both Insulin and C-Peptide are HIGH (endogenous).
- In Exogenous Insulin Injection: Insulin is HIGH, C-Peptide is LOW (exogenous insulin has no C-peptide).
- In Sulfonylurea Overdose: Both Insulin and C-Peptide are HIGH (sulfonylureas stimulate endogenous insulin release). Screen for sulfonylurea metabolites.
| Condition | Key Features |
|---|---|
| Insulinoma | Fasting hypoglycaemia. High Insulin, High C-Peptide. Tumour on imaging. |
| Factitious Hypoglycaemia (Exogenous Insulin) | High Insulin, LOW C-Peptide. Healthcare worker? Psychiatric history? Insulin on drug screen. |
| Sulfonylurea Ingestion (Accidental or Factitious) | High Insulin, High C-Peptide. Sulfonylurea detected on urine/blood screen. |
| Reactive (Post-Prandial) Hypoglycaemia | Hypoglycaemia 1-3h after meals. Insulin and C-Peptide not inappropriately elevated during fasting. Post-bariatric surgery can cause this. |
| Adrenal Insufficiency | Low Cortisol. Often morning hypoglycaemia. Other features: Hypotension, Hyponatraemia. |
| Hypopituitarism | Low Cortisol, Low GH. Pituitary pathology history. |
| Non-Islet Cell Tumour Hypoglycaemia (NICTH) | Large mesenchymal tumours (e.g., Solitary Fibrous Tumour) secrete IGF-2. Low Insulin, Low C-Peptide, High IGF-2. |
| Liver Failure | Severe liver disease impairs gluconeogenesis. |
| Alcohol-Induced Hypoglycaemia | Alcohol inhibits gluconeogenesis. History of alcohol binge. |
| Sepsis | Critical illness. |
Symptoms of Hypoglycaemia
Neuroglycopenic (Brain Glucose Deprivation)
Autonomic / Adrenergic (Counter-Regulatory Response)
Timing
Duration Before Diagnosis
Diagnostic Workup
1. 72-Hour Supervised Fast (Gold Standard)
- Protocol: Patient fasts under observation until hypoglycaemia develops or 72 hours is reached.
- At Time of Hypoglycaemia (Glucose less than 2.5 mmol/L / less than 45 mg/dL), draw:
- Plasma Glucose: Confirm low.
- Plasma Insulin: Inappropriately elevated (should be suppressed).
- C-Peptide: Elevated (proves endogenous source).
- Proinsulin: Elevated.
- Beta-Hydroxybutyrate: Low (insulin suppresses ketogenesis; high ketones suggest non-insulin-mediated hypoglycaemia).
- Screen for Sulfonylurea Metabolites: To exclude surreptitious ingestion.
- Diagnostic Criteria for Insulinoma: Hypoglycaemia + Insulin ≥3 μU/mL + C-Peptide ≥0.6 ng/mL + Proinsulin ≥5 pmol/L + Negative Sulfonylurea Screen.
2. Localisation Imaging
| Modality | Notes |
|---|---|
| CT Abdomen (Triple Phase) | First-line. Insulinomas enhance on arterial phase. May miss small tumours. |
| MRI Abdomen | Alternative. High soft tissue contrast. Insulinomas are T2 bright. |
| Endoscopic Ultrasound (EUS) | Most sensitive for small pancreatic tumours. Allows biopsy. |
| 68Ga-DOTATATE PET-CT | Functional imaging for somatostatin receptor positive tumours. Good for metastatic disease. |
| Selective Arterial Calcium Stimulation with Hepatic Venous Sampling | Invasive. Localises region of pancreas secreting insulin. Reserved for occult tumours not found on other imaging. |
Management Algorithm
SUSPECTED INSULINOMA
(Fasting Hypoglycaemia + Whipple's Triad)
↓
72-HOUR SUPERVISED FAST
+ Biochemistry at hypoglycaemia
↓
CONFIRMATORY RESULTS?
(Low Glucose + High Insulin + High C-Peptide +
Suppressed Ketones + Neg Sulfonylurea Screen)
↓
LOCALISATION IMAGING
(CT / MRI / EUS / DOTATATE PET)
↓
TUMOUR LOCALISED?
┌────────────┴────────────┐
YES NO
↓ ↓
SURGICAL RESECTION FURTHER IMAGING
(Curative) (EUS, Calcium Stim Test)
- Enucleation (small)
- Distal Pancreatectomy
- Whipple (rare)
↓
MEN1 SCREENING
(Genetic testing if less than 40yo, bilateral, or FHx)
↓
LONG-TERM FOLLOW-UP
(Annual imaging for recurrence/malignancy)
Medical Management (Pre-Operative or Inoperable)
| Agent | Mechanism |
|---|---|
| Diazoxide | Opens K-ATP channels, inhibits insulin release. First-line medical therapy. Side effects: Oedema, Hirsutism. |
| Somatostatin Analogues (Octreotide) | Inhibits hormone secretion. Variable efficacy in insulinoma (not all express somatostatin receptors). |
| Frequent Small Meals / IV Dextrose | Maintain normoglycaemia. |
| Everolimus | mTOR inhibitor. For metastatic/unresectable disease. |
| Sunitinib | Tyrosine kinase inhibitor. For malignant insulinoma. |
Surgical Management (Curative)
- Enucleation: For small, superficial, solitary tumours away from the pancreatic duct.
- Distal Pancreatectomy: For tumours in the body/tail.
- Pancreaticoduodenectomy (Whipple): Rare. For head tumours not amenable to enucleation.
- Laparoscopic Approach: Often feasible for suitable lesions.
- Intra-Operative Ultrasound: Used to locate small tumours.
- Cure Rate: >95% for benign, localised insulinomas.
Of Hypoglycaemia
- Seizures.
- Coma.
- Brain Damage (Prolonged/recurrent severe hypoglycaemia).
- Accidents/Injury (Confusion while driving, etc.).
- Death.
Of Treatment
- Surgical: Pancreatic fistula, Diabetes Mellitus (if extensive resection), Bleeding.
- Diazoxide: Oedema, Hirsutism, Nausea.
- Benign Insulinoma (>90%): Surgical cure rate approaches 95-100%.
- Malignant Insulinoma (~10%): 5-year survival ~50-60%. May respond to Everolimus, Sunitinib, chemotherapy.
- Recurrence: Rare for solitary sporadic tumours. More common in MEN1 (due to multiple tumours).
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Pancreatic NETs | ENETS (European Neuroendocrine Tumor Society) | 72h fast for diagnosis. EUS for localisation. Surgical resection first-line. |
| MEN1 | Endocrine Society | Screen MEN1 patients for insulinoma. |
Landmark Evidence
- Whipple's Triad: Described by Allen Whipple (1930s). Remains cornerstone of diagnosis.
- Medical Therapy: Studies establishing Diazoxide and Octreotide efficacy for symptomatic control.
What is an Insulinoma?
An insulinoma is a very rare, usually non-cancerous (benign) tumour in your pancreas that produces too much insulin. Insulin is the hormone that lowers your blood sugar. When there's too much insulin, your blood sugar drops too low (hypoglycaemia), which can cause sweating, confusion, and even passing out.
How do we diagnose it?
We will admit you for a supervised fast. We will check your blood sugar and insulin levels regularly. If your blood sugar goes low but your insulin stays high, it confirms the diagnosis. We will then scan your abdomen to find where the tiny tumour is.
How is it treated?
Surgery to remove the tumour is almost always curative. The tumours are usually small and benign. After surgery, you should be cured.
Is it cancer?
In about 90% of cases, no. Most insulinomas are benign. Only about 10% are malignant (cancerous). Even if malignant, there are treatment options.
Primary Sources
- Service FJ, et al. Insulinoma: Clinical and Surgical Management. Endocrinol Metab Clin North Am. 1999;28(4):819-844. PMID: 10609122.
- Jensen RT, et al. ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Functional Pancreatic Neuroendocrine Tumour Syndromes. Neuroendocrinology. 2012;95:98-119.
Common Exam Questions
- Diagnosis: "Recurrent fasting hypoglycaemia. High Insulin, High C-Peptide. Diagnosis?"
- Answer: Insulinoma.
- Differentiation: "How to differentiate from Factitious Hypoglycaemia (exogenous insulin)?"
- Answer: In factitious hypoglycaemia, C-Peptide is LOW. In Insulinoma, C-Peptide is HIGH.
- Investigation: "Best imaging for small pancreatic insulinoma?"
- Answer: Endoscopic Ultrasound (EUS).
- Association: "Which syndrome is associated with multiple insulinomas?"
- Answer: MEN1 (Multiple Endocrine Neoplasia Type 1).
Viva Points
- Whipple's Triad: Be able to recite the three criteria.
- Calcium Stimulation Test: Explain the principle (intra-arterial calcium stimulates insulin release from the perfused region; venous sampling from hepatic veins localises the secreting region).
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.