This diagnosis relates to an insulin secreting tumour of the pancreas. This section also covers the investigation of spontaneous hypoglycaemia of any cause.

Baseline investigations - all patients

Full blood count

This is a useful indicator of general health and underlying malignancy.

Urea and electrolytes

Hypokalaemic acidosis may occur with severe diarrhoea, and hyponatraemia may occur with salt and water depletion.

Liver function test

This is a useful screen for malignant diseases.

Bone profile

Hypercalcaemia indicates possible MEN1 in a patient with insulinoma, although it may complicate any malignancy, or be secondary to many medications and supplements.

Fasting glucose and HbA1c

HbA1c is typically low in a patient with insulinoma and elevated in a patient with early glucose intolerance and reactive hypoglycaemia.

If the patient has already had a fasting glucose measured this is very helpful and can be highly suggestive of insulinoma.

However, if the symptoms are highly suggestive of insulinoma, the patient should be instructed to eat as necessary and only fast under supervised conditions LINK.

Thyroid stimulating hormone, free thyroxine

Thyrotoxicosis should be excluded before further investigation in a patient presenting with anxiety.

9am cortisol

Addison's disease or glucocorticoid deficiency of any cause should also be considered in patients presenting with unexplained collapses or documented hypoglycaemia. Where levels are not clearly normal, synacthen or insulin stress testing may be required.

Glucose, insulin, c peptide, proinsulin and beta hydroxybutyrate during spontaneous hypoglycaemia

Patients with suggestive symptoms in whom an episode of hypoglycaemia has not already been captured, should always be admitted for a prolonged supervised fast.

Hypoglycaemic symptoms at any time, should prompt immediate near patient testing of blood glucose. Levels below 2.6mmol/l have previously been required to confirm hypoglycaemia, and should be confirmed in the laboratory and simultaneous blood sampled for insulin, C peptide, proinsulin and beta-hydroxybutyrate analysis. However, most recent guidelines suggest that plasma glucose concentrations below 3.0mmol/l should also prompt evaluation.

Insulin levels above 18pmol/l (3.0micounit/ml), c peptide above 0.6ng/ml (0.2nmol/l), and proinsulin above 5.0pmol/l confirm endogenous hyperinsulinism in the presence of hypoglycaemia.

Further investigations - selected cases only

Supervised fast

Unless an episode of spontaneous hypoglycaemia has been documented, and all appropriate blood tests taken at that time, a formal 72 hour supervised fast is required.

The fast should be terminated after 72 hours, or earlier if the patient develops symptoms or signs of hypoglycaemia, the plasma glucose has been confirmed as below 2.6mmol/l, and simultaneous blood has been sampled for insulin, C peptide, proinsulin and beta hydroxybutyrate analysis according to most recent guidelines.  At the end of the fast, blood should also be sampled for beta hydroxybutyrate and urine for sulphonylureas. A progressive rise in beta hydroxybutyrate signals a negative fast.  Glucagon is then administered and the glucose response determined. Lack of response indicates that hypoglycaemia if present is non insulin and non IGFII mediated. 

Insulin levels above 18pmol/l (3.0micounit/ml), c peptide above 0.6ng/ml (0.2nmol/l), and proinsulin above 5.0pmol/l confirm endogenous hyperinsulinism in the presence of hypoglycaemia.

Insulin antibodies

Recent guidelines suggest that all patients with documented hypoglycaemia should have insulin antibodies measured. Imaging and localisation studies are only necessary in those with documented hyperinsulinism, negative screens for hypoglycaemic agents, and negative insulin antibodies.

Prolonged oral glucose tolerance test

Where symptoms appear to occur after eating, a prolonged glucose tolerance test may be useful, although ideally, the patient should identify and eat a mixed meal containing those elements that most often precipitate symptoms.

Reactive hypoglycaemia does not rule out an insulinoma, and so a prolonged fast should still be arranged whenever significant hypoglycaemia has been documented.

Urine screen for sulphonylureas

Patients with documented hypoglycaemia should have urine analysed for the presence of sulphonylureas in case of factitious hypoglycaemia.

Parathyroid hormone, Vitamin D

If calcium is elevated, PTH must be tested to confirm hyperparathyroidism. Vitamin D is also useful to aid interpretation of PTH levels.

Fasting gut hormones

Gut hormones should be documented in patients with MEN1 to detect other neuroendocrine tumours, but only when it is safe for the patient to fast. This might be during hospital admission, with a dextrose infusion, post operatively, or after treatment has been instituted.

Proton pump inhibitors need to be stopped for at least two weeks, and H2 (histamine 2 receptor) antagonists stopped for at least three days prior to testing serum gut levels in the screening of pancreatic disease.

Baseline pituitary function: prolactin, growth hormone, insulin like growth factor I, luteinising hormone, follicle stimulating hormone, estrodiol/testosterone

If insulinoma is confirmed, or if calcium is elevated, full pituitary function should be assessed at baseline as well as cortisol and TSH as above.

Prolactin is the most useful blood test to screen for pituitary pathology, as prolactinomas are the most frequent pituitary tumour encountered in MEN1, and elevated prolactin also occurs with non functioning tumours due to loss of dopaminergic inhibition.

Insulin like growth factor II

IGF II secreting tumours are rare, but should be considered in patients with obvious signs of malignancy, and where insulin levels are undetectable during hypoglycaemia.

Chest radiograph

This should be performed at baseline as a screen for malignant disease, for thymic or bronchial lesions, as part of the cardiovascular assessment, and prior to considering surgery.


ECG should be performed in all patients at baseline to document and confirm any arrhythmias or other changes.

Pancreatic and abdominal ultrasound

Insulinomas tend to be small, 0.5 to 5cm, and may occur anywhere throughout the pancreas and so may not be visualised on trans abdominal ultrasound. However, it is a cheap and easy test to perform which may locate the tumour immediately.

Endoscopic ultrasound scan

Endoscopic ultrasound is useful to help define anatomy and identify small pancreatic lesions.

CT pancreas

Abdominal CT or MRI scanning should be performed in all cases at biochemical diagnosis of insulinoma.

Selective venous sampling of the pancreas

Selective venous sampling, together with calcium infusion to stimulate peptide secretion, may be performed to aid precise localisation and to define anatomy prior to pancreatic surgery. 

This is essential where a single clear lesion has not been identified on CT or ultra sound scanning.

Octreotide uptake scan

This may be performed to aid localisation of neuro-endocrine tumours, as well as to visualise metastatic disease, though this is rarely necessary with isolated insulinomas.

Metaiodo-benzylguianidine scan

This may be performed to aid localisation and to visualise metastatic disease if necessary.

Consider referral to clinical geneticist for counselling, DNA testing and family screening

If the diagnosis of MEN1 is clinically likely, for example in a patient with insulinoma and hyperparathyroidism, discuss genetic testing.

2x24hr urinary 5-hydroxyindole-acetic acid

5HIAA is a metabolite of serotonin produced by carcinoid tumours and should be assessed if carcinoid syndrome is suspected.

2x24hr urinary metanephrines

Although phaeochromocytoma is not usually associated with insulinomas or MEN1, symptoms may be difficult to distinguish if not clearly related to fasting. Urinary metanephrines are the first line screen for phaeochromocytoma.

Synacthen test

A formal synacthen test should be performed if Addison’s disease is suspected, unless random or waking cortisol is above 590nmol/l which excludes this diagnosis.