Hypoglycaemia and insulinoma

• Hypoglycaemia is a measured low blood glucose together with symptoms that resolve when glucose is corrected: Whipple triad, not a number in isolation.
• In people with diabetes, hypoglycaemia is usually due to insulin or to medicines that stimulate insulin release, and repeated episodes are dangerous enough to change the treatment plan.
• In people without diabetes, hypoglycaemia is more often a fasting problem: insulinoma is the commonest cause of endogenous hyperinsulinaemic hypoglycaemia.
• An insulinoma is usually a small, benign tumour of the pancreatic beta-cells that secretes insulin inappropriately; it is found by documenting inappropriate insulin and C-peptide during a fast, then by sensitive imaging.
• The first treatment is surgical removal, which usually cures it; diazoxide, somatostatin analogues, everolimus and locoregional treatments control hypoglycaemia when surgery is not possible or the tumour has spread.

By the end of this page you should be able to:

1. State Whipple triad and distinguish a true hypoglycaemic illness from mimic syndromes and from laboratory or device error.
2. Name the goals, risk factors and acute treatment of hypoglycaemia in diabetes, and say when to de-intensify hypoglycaemia-causing therapy.
3. List the causes of hypoglycaemia in people without diabetes, grouped by fasted versus fed and by insulin-mediated versus non-insulin-mediated.
4. Explain the pathophysiology of insulinoma and list the insulin, C-peptide and proinsulin thresholds that separate it from factitious or surreptitious hypoglycaemia.
5. Plan a 72-hour fast or shorter fast, and localise a suspected insulinoma with biochemical, imaging and invasive tests.
6. Choose surgical, medical and locoregional treatment for insulinoma and its metastases, and recognise its link with multiple endocrine neoplasia type 1.

In diabetes care, the American Diabetes Association (ADA) 2026 Standards of Care classify glucose below 3.9 mmol/L (70 mg/dL) as level 1 hypoglycaemia, below 3.0 mmol/L (54 mg/dL) as level 2, and any severe event requiring another person's help for recovery as level 3, irrespective of the glucose value.^[1] These levels are consensus working definitions used to count events and guide targets; symptoms still define the illness.

Insulinoma sits inside the family of pancreatic neuroendocrine neoplasms: the same small epithelial tumours can secrete glucagon, vasoactive intestinal peptide, somatostatin, adrenocorticotropic hormone or other hormones, or secrete nothing at all. The functioning tumours are distinguished by the clinical syndrome their hormone creates, not by histology alone.

Hypoglycaemia in diabetes is common, feared and limiting: it is the principal barrier to achieving lower glucose targets in people treated with insulin or insulin secretagogues.^[1] By contrast, hypoglycaemia in people who do not have diabetes is uncommon. In a six-year Finnish study this accounted for only about 1.1% of hypoglycaemia-related emergency medical service encounters.^[2]

Insulinomas are rare: about 3 to 4 cases per million people per year.^[3] A separate cohort gives an estimate of roughly 1 in 250,000 people, which is equivalent to 4 per million.^[4] About 90% are sporadic and only about 5 to 10% are malignant.^[3] The peak ages reported in series are in the mid-forties to fifties.^[3][4] Insulinomas are slightly more common in women.^[4] Multiple tumours suggest multiple endocrine neoplasia type 1 (MEN1): roughly 4 to 8% of insulinomas occur in this context.^[2]

Non-islet cell tumour hypoglycaemia - hypoglycaemia caused by tumours outside the pancreas - has an estimated incidence of about 1 per million and is about four times rarer than insulinoma.^[2]

In diabetes, hypoglycaemia is iatrogenic: it arises when glucose-lowering action exceeds glucose supply, because of excess insulin or secretagogue dose, missed or delayed meals, exercise, alcohol or reduced counterregulation.

Medication causes:

• Insulin, from exogenous injection. Risk is highest with intensive insulin regimens (multiple daily injections, pump, automated insulin delivery) and falls away through basal insulin alone to sulfonylureas and meglitinides alone.^[1]
• Sulfonylureas and meglitinides, which close the ATP-sensitive potassium channel on the beta-cell and drive insulin release. They can produce prolonged and recurrent hypoglycaemia.
• Combination of insulin with a sulfonylurea further increases risk.^[1]

Risk factors sorted by the ADA 2026 Standards of Care into major and other markers include intensive or basal insulin therapy, recent level 2 or 3 hypoglycaemia, impaired hypoglycaemia awareness, kidney failure, cognitive impairment or dementia, and cardiovascular, chronic kidney and neurological disease.^[1] Age 75 years and older carries the highest hypoglycaemia risk in type 2 diabetes, while younger people with type 1 diabetes are also at very high risk.^[1] Social risk factors - low income, food or housing insecurity, fasting for religious or cultural reasons, underinsurance and low health literacy - belong in the same assessment.^[1]

Causes split into two useful groups: insulin-mediated (excess insulin action) and non-insulin-mediated (impaired glucose production or excess use without insulin drive). They also split by timing: fasting versus postprandial.^[2]

Non-insulin-mediated (the plasma insulin is appropriately low)

• Critical illness: sepsis, hepatic or renal failure, heart failure.^[2]
• Malnutrition and starvation: glycogen depletion after 24 to 48 hours of fasting, with impaired gluconeogenesis.^[2]
• Alcohol: ethanol metabolism shifts the redox state and inhibits gluconeogenesis; clinically significant usually with malnutrition or liver disease.^[2]
• Adrenal or growth hormone deficiency.^[2]
• Glycogen storage diseases.^[2]
• Non-islet cell tumour hypoglycaemia from IGF-II secreting solid tumours.^[2]
• Medications given to people without diabetes (alcohol, beta-blockers, antibiotics such as sulfamethoxazole/trimethoprim, chloroquine, quinine, pentamidine, and others).^[2]
• Unripe ackee fruit.^[2]

Insulin-mediated

• Insulinoma.^[2]
• Non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS, sometimes called adult nesidioblastosis, often after bariatric surgery).^[2][3]
• Post-bariatric hypoglycaemia.^[2]
• Insulin autoimmune syndrome (Hirata disease).^[2]
• Factitious or surreptitious insulin or insulin-secretagogue use (especially in people with access to these drugs).^[2]
• Drugs that stimulate insulin release (sulfonylureas, meglitinides) given to a person without diabetes.^[2]

Timing matters clinically. Insulinoma usually produces fasting hypoglycaemia. Post-bariatric hypoglycaemia and insulin autoimmune syndrome are usually postprandial. However, the split is not perfect: up to one fifth of insulinomas also cause postprandial symptoms, and insulin autoimmune syndrome can produce fasting hypoglycaemia.^[2][3]

Glucose homeostasis is a feed-forward, not a feedback, process: falling glucose triggers a hierarchical response. As glucose falls below about 3.9 mmol/L (70 mg/dL), glucagon and adrenergic discharge produce the warning symptoms of sweating, tremor, palpitation and anxiety.^[1] Below about 3.0 mmol/L (54 mg/dL), neuroglycopenic symptoms set in - slowed thinking, confusion, behavioural change, focal weakness, seizure - because the brain has no meaningful glucose reserve and depends on continuous supply.^[1] Consciousness fails when the glucose is very low.

In diabetes, long-standing disease blunts the glucagon response and repeated hypoglycaemia blunts the adrenergic response, producing impaired hypoglycaemia awareness: the patient can be severely hypoglycaemic with no warning. This is the most dangerous part of the condition and the reason to screen for awareness yearly.^[1]

Insulinoma in detail. The tumour is composed of beta-cells that lack the normal glucose-stimulated regulation of insulin secretion. Insulin is therefore secreted in a glucose-independent manner. Constant insulin drive suppresses hepatic glycogenolysis (breakdown of liver glycogen to free glucose), suppresses gluconeogenesis and promotes peripheral uptake. Plasma glucose falls, pancreatic glucagon and hepatic output cannot compensate, and counterregulation is overwhelmed. Insulin is also anabolic: it inhibits lipolysis, so insulinoma patients often gain weight rather than lose it.^{[2][4] [3]}

Whereas insulinoma cells secrete insulin, normal beta-cells are switched off by hypoglycaemia: endogenous insulin should be undetectable below 3.0 mmol/L (54 mg/dL).^[1] Therefore an insulin level that is inappropriately present, together with C-peptide and proinsulin, pins the diagnosis to endogenous hyperinsulinaemia rather than factitious insulin (which suppresses C-peptide) or a non-insulin-mediated cause (which suppresses insulin, C-peptide and proinsulin together).^[2][4]

Most insulinomas are small, solitary and well-differentiated. The tumour looks like normal islet tissue but is arranged in nests, cords or trabeculae; insulin staining is positive and the proliferation index is usually low. Malignancy is defined by metastasis, not by morphology. Inherited insulinomas in MEN1 are often multifocal and smaller. Molecular studies point to activating mutations in the YY1 transcription factor and activation of the mammalian target of rapamycin (mTOR) pathway in at least some tumours, both of which support beta-cell proliferation and insulin secretion.^[2]

The same symptom may be described by a patient in ordinary language. separating symptom type from its mechanism helps the history:

Neurogenic (autonomic) symptoms - sweating, tremor, palpitations, anxiety, hunger, paraesthesiae - are the early warning signs driven by catecholamines and usually coincide with glucose below about 3.9 mmol/L (70 mg/dL).

Neuroglycopenic symptoms - confusion, behavioural change, slurred speech, focal weakness or visual disturbance, seizure, coma - appear when the brain is deprived of fuel, usually below 3.0 mmol/L (54 mg/dL).

Night symptoms occur in insulinoma because the overnight fast is the longest fast; patients describe morning sweats, vivid dreams, nightmares or waking confused. Hypoglycaemic driving incidents or falls are red flags for any chronic hypoglycaemic disorder.

Insulinoma-specific points^[3]

• Symptoms occur with fasting, often after missed meals or exertion, and frequently at night.
• The median delay from first symptoms to diagnosis is often 2 to 5 years, because the symptoms are non-specific and patients learn to carry snacks.^[3]
• Weight gain is common: about half of patients gain weight, driven by insulin's anabolic actions.^[3]
• In chronic hypoglycaemia, adrenergic symptoms may be blunted or absent, so neuroglycopenic symptoms dominate.
• With MEN1, there may be a personal or family history of parathyroid, pituitary or other pancreatic disease.

Examination often shows little. Look for features of MEN1 (lipomas, angiofibromas), of an underlying malignancy in non-islet cell tumour hypoglycaemia, and of adrenal failure: pigmentation, hypotension, salt craving. Between episodes, a person with insulinoma can look entirely well, which is itself part of the diagnostic difficulty.

Two questions arise: what else causes the same symptom complex, and, in a well-looking person with fasting hypoglycaemia, what mimics insulinoma. The table groups the common differentials by mechanism.

First confirm Whipple triad using a laboratory or professional plasma glucose, not a home device alone, because home glucometers become less accurate as glucose falls.^[2] Portable continuous glucose monitors are helpful for detecting patterns but can show falsely low interstitial readings from compression or skin problems.^[2] Plasma should be drawn at the time of symptoms, before treatment, for glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate and, in suspected sulfonylurea use, a drug screen.^[4]

The level at which counterregulatory symptoms usually begin - around 3.9 mmol/L (70 mg/dL) - is the same level the ADA uses as the level 1 threshold for counting hypoglycaemic events.^[1]

The Endocrine Society criteria, cited in the fasting-test literature,^[4] regard a plasma glucose below 3.1 mmol/L (55 mg/dL) together with insulin 3 mIU/L (18 pmol/L) or higher, C-peptide 0.6 ng/mL (0.2 nmol/L) or higher, and proinsulin 5 pmol/L or higher as evidence of endogenous insulin-mediated hypoglycaemia. In insulinoma series using a 72-hour fast the stopping threshold is a plasma glucose of 2.5 mmol/L (45 mg/dL), with insulin above 3 mIU/L, C-peptide above 200 pmol/L (0.6 ng/mL), proinsulin above 5 pmol/L and suppressed beta-hydroxybutyrate.^[3]

If the patient is well and presenting values are borderline, a supervised fast is the next step. The insulin and C-peptide drawn during this fast are interpreted against the contemporary glucose, never in isolation.

A 72-hour fast, done as an inpatient, is the reference standard and has sensitivity approaching 100%.^[4] The patient's last meal contains complex carbohydrate; glucose is monitored and venous samples are drawn at 0, 6-hourly and more frequently as glucose falls. The fast ends when Whipple triad is documented, when plasma glucose reaches 2.5 mmol/L (45 mg/dL), or at 72 hours. One milligram of glucagon is given intravenously at the end, with glucose measured at 10, 20 and 30 minutes, to demonstrate preserved glycogen stores and endogenous insulin action.^[4]

Timing is helpful for planning a ward admission:

• 42.5% of patients are positive within 12 hours.^[3][4]
• 67% are positive within 24 hours.^[3][4]
• 93 to 95% are positive within 48 hours.^[3][4]
• A delayed minority are positive only after 48 hours; hence the full 72 hours remains the diagnostic reference.^[3][4]

A shorter outpatient fast may be adequate as first-line screening when a 72-hour bed is not available: one retrospective series found diagnostic values in 91.7% of insulinoma patients within 24 hours of an overnight fast followed by daytime monitoring.^[4] Whichever protocol is used, blood should already be drawn at baseline after the overnight fast, because insulinoma patients are often hypoglycaemic at presentation.

Insulinomas are small: about 30% are below 1 cm, many are around 2 to 5 mm, and some are multifocal, especially in MEN1.^[2][3] Sensitivities vary, so combining modalities is standard practice.

• Multiphasic contrast-enhanced computed tomography (arterial phase): 83 to 88% sensitivity in recent reviews; insulinomas appear as small, round, avidly enhancing lesions and rarely obstruct the pancreatic duct.^[3]
• Magnetic resonance imaging: sensitivity around 54% and specificity around 65%; useful but inferior to CT for small lesions.^[3]
• Endoscopic ultrasound: sensitivity around 81 to 87% and specificity around 90 to 98%; detects lesions as small as 2 to 5 mm and shows their distance from the pancreatic duct before enucleation.^[2][3]
• Combined computed tomography and endoscopic ultrasound: a reported sensitivity of 100%.^[3]
• 68Ga-exendin-4 (GLP-1 receptor) PET-CT: pooled sensitivity around 94 to 98% and specificity around 83% for insulinomas, outperforming somatostatin-receptor SPECT/CT (which has lower sensitivity, around 58%, because insulinomas often express little SSTR2).^{[3] [2]}
• Arterial calcium stimulation with hepatic venous sampling: the gold standard invasive test for occult tumours, with sensitivity around 93% and specificity around 86%. Calcium injected into the gastroduodenal, splenic and superior mesenteric arteries triggers insulin release only from insulinoma cells; a twofold or greater rise in hepatic venous insulin at 30 or 60 seconds localises the source.^[3]

The diagnostic criteria of insulinoma are clinical plus biochemical, then anatomical.

1. Whipple triad - symptoms, a low plasma glucose, and resolution with treatment.^[2][3] (see above)
2. Endogenous insulin-mediated hypoglycaemia - plasma glucose below 3.1 mmol/L (55 mg/dL) together with insulin 3 mIU/L (18 pmol/L) or higher, C-peptide 0.6 ng/mL (0.2 nmol/L) or higher and proinsulin 5 pmol/L or higher.^[4] During a 72-hour fast the stopping glucose is 2.5 mmol/L (45 mg/dL).^[3]
3. Localisation - a pancreatic neuroendocrine tumour visualised on imaging, plus exclusion of mimics.

For people with diabetes, ADA 2026 defines hypoglycaemia by the level and by severity (Table 6.4 of that guideline): level 1 glucose 3.9 to 3.0 mmol/L (70 to 54 mg/dL), level 2 glucose below 3.0 mmol/L (54 mg/dL) with neuroglycopenic risk, level 3 a severe event needing another person's help irrespective of the glucose.^[1] These levels are used to audit control quality: time below range below 4% for most adults and below 1% for level 2 events.^[1]

For a conscious person whose glucose is below 3.9 mmol/L (70 mg/dL), give a fast-acting source of glucose. The ADA 2026 guidance specifically prefers glucose itself to other carbohydrate, avoids foods or drinks high in fat or protein as initial treatment, and reassesses 15 minutes later, repeating treatment if hypoglycaemia persists.^[1] If the person is unconscious, having a seizure or unable to swallow, give glucagon (the ready-to-use preparations are preferred over products that need reconstitution) or intravenous glucose, and call emergency services.^[1]

For people who drive, work at height or live alone, ensure glucagon is prescribed, its location is known, and household members or caregivers are trained to give it.^[1] Emergency care kits should also carry oral glucose.^[1]

• Review hypoglycaemia at every visit, including symptoms, severity and awareness, and ask about fear of hypoglycaemia.^[1]
• Select glucose-lowering therapy with hypoglycaemia risk in mind. De-intensify or switch hypoglycaemia-causing drugs (insulin, sulfonylureas, meglitinides) in people at high risk or who have had a level 2 or 3 event, within individualised goals.^[1]
• Use continuous glucose monitoring in high-risk individuals; it is recommended.^[1]
• Structured education for hypoglycaemia prevention and treatment should be offered to everyone on insulin or at risk.^[1]
• Individualise glycaemic goals. Less stringent goals (such as HbA1c up to 8%) and higher time-in-range targets are appropriate when hypoglycaemia is a major risk. Severe or recurrent hypoglycaemia is an absolute indication to change the plan rather than chase the number.^[1]

Preoperative care. Avoid prolonged fasting. Frequent small meals rich in complex carbohydrate, and intravenous glucose when needed, control symptoms while the patient awaits surgery.^[3]

Surgery is the only curative treatment and should be performed when the patient's condition allows. Parenchyma-sparing resection with intraoperative ultrasound localisation is the first-line approach, open or laparoscopic: enucleation when the tumour is below 2 cm and 3 mm or more from the main pancreatic duct, otherwise distal pancreatectomy or pancreaticoduodenectomy according to position.^[3] Whipple's pancreaticoduodenectomy is reserved for tumours extending beyond the head of the pancreas or failing enucleation.^[2] Lymphadenectomy is not routinely required because nodal metastasis is uncommon.^[3] In metastatic disease, cytoreductive surgery is considered when 70 to 90% of visible disease can be safely debulked with adequate remaining liver function, to control hypoglycaemia and improve the effect of systemic treatment.^[3]

Medical control of hypoglycaemia when surgery is impossible, not yet available, or unlikely to control metastatic disease:

• Diazoxide, a beta-cell ATP-sensitive potassium channel agonist, at doses of 50 to 600 mg daily, is the first-line drug treatment for advanced insulinoma, with an estimated efficacy of about 50%.^[3] It can cause fluid retention, hirsutism and thrombocytopenia.^[2]
• Somatostatin analogues (octreotide and lanreotide) reduce insulin secretion in 50 to 60% of patients.^[2][3] Because they also suppress glucagon, they can paradoxically worsen hypoglycaemia in tumours with little somatostatin receptor subtype 2: a trial with short-acting octreotide under close glucose monitoring is recommended before switching to a long-acting depot.^[3] Tumour regression has also been reported. Pasireotide, with greater affinity for subtype 5 receptors, has shown promise.^[2]
• Everolimus, an mTOR inhibitor, lowers insulin secretion and has produced clinically useful improvement in metastatic insulinoma.^[2][3]
• Glucocorticoids are rarely used because of metabolic and immunosuppressive adverse effects.^[3]
• Verapamil, beta-blockers and phenytoin have produced inconsistent results.^[3]
• Glucagon reverses acute hypoglycaemia and is useful as rescue treatment.
• Endoscopic ultrasound-guided radiofrequency ablation is an option for insulinomas 2 cm or less in patients who are not fit for surgery, although further evidence is needed before it can be considered a routine alternative.^[2][3]
• Peptide receptor radionuclide therapy with 177-lutetium DOTATATE, sunitinib and other targeted systemic options are used for progressive metastatic disease.^[2]
• Diet and glucose: frequent carbohydrate-rich meals, uncooked corn starch and intravenous glucose are adjuncts and bridge therapy.

Other non-diabetic causes are treated at source: resection or effective treatment of the driving tumour in non-islet cell tumour hypoglycaemia (glucocorticoids often control hypoglycaemia in this setting), lifestyle modification and acarbose for post-bariatric hypoglycaemia, and lifestyle or immunosuppressive therapy for the self-limiting insulin autoimmune syndrome.^[2]

Everyone with insulinoma needs long-term follow-up because recurrence and new primaries, especially in MEN1, can appear years later. Clinical and biochemical surveillance follows local endocrine-oncology practice.

Complications of hypoglycaemia itself:

• Neuroglycopenic injury: seizures, focal deficits, coma and, rarely, death.
• Fractures and vehicle accidents during low glucose.
• Impaired hypoglycaemia awareness after repeated episodes, increasing risk of severe events.
• Fear of hypoglycaemia and reduced quality of life.

Complications of insulinoma:

• Metastasis in about 5 to 10% of cases, mostly to liver and lymph nodes.^[3]
• Persistent, dangerous hypoglycaemia if uncontrolled; severe hypo can occur overnight or during exertion.
• Postoperative complications of pancreatic surgery (pancreatic fistula, delayed gastric emptying) depend on the procedure done.
• MEN1-associated disease: multiple tumours, recurrence and other endocrine neoplasms.

Non-metastatic insulinoma has an excellent prognosis after resection, with reported survival of 94 to 100%. Metastatic insulinoma has substantially worse survival, reported between 24 and 67%, reflecting tumour burden rather than the hypoglycaemia alone.^[2] The insulinoma itself is usually slow-growing and the hypoglycaemia is sometimes controlled for years with diazoxide or somatostatin analogues.

• There is no population screening for insulinoma. The clinical trigger is an adult with Whipple triad not explained by medication or illness.
• In diabetes, prevention rests on the ADA 2026 measures above: drug de-intensification, structured education, awareness screening, continuous glucose monitoring and ready access to glucagon.^[1]
• Consider multiple endocrine neoplasia type 1 in younger patients with multiple, recurrent or extra-pancreatic-appearing insulinomas and offer genetic testing and family screening, because insulinoma is one of the commoner functioning tumours of MEN1.^[2][3] Multiple pancreatic tumours in MEN1 do not all secrete insulin.
• A person with insulinoma who presents after bariatric surgery deserves particular care, because a fasting tumour can co-exist with postprandial post-bariatric hypoglycaemia.

Pregnancy. Evidence for insulinoma in pregnancy is limited to small case series; management should be by a multidisciplinary endocrine, obstetric and surgical team. Hypoglycaemia in pregnant people with diabetes is managed within the diabetes-in-pregnancy framework, with tighter glucose targets and lower thresholds for intervention.

Older adults. Age 75 years and older is a major hypoglycaemia risk factor in type 2 diabetes; glucose goals and medications should be reassessed when hypoglycaemia occurs. In older frail people, hypoglycaemia can present as confusion or falls rather than as warning symptoms. ^[2]

Children. Most hypoglycaemia in infants and children has a different differential (congenital hyperinsulinism, inborn errors of metabolism); insulinoma is rare before adulthood.

• A glucometer and a good history make the diagnosis of hypoglycaemia. Laboratory testing is needed to separate causes, but it does not need to be immediate.
• Whipple triad can be documented in a clinic with a glucometer and a single glucose draw; repeating the fast in hospital with samples for insulin and C-peptide is the standard next step.
• Diazoxide, octreotide and pancreatic surgery may be unavailable; frequent high-complex-carbohydrate meals, uncooked corn starch, glucocorticoid rescue, and remote referral become more important.
• When glucagon is unavailable, intravenous glucose or sugar given by mouth to an awake patient (or intravenous dextrose) is the rescue.
• Send all resected pancreatic tissue for histopathology so the neuroendocrine grade and the MEN1 implications can be assessed.

• Hypoglycaemia is a clinical syndrome - Whipple triad - not a blood glucose number alone, and not all symptoms around mealtimes are hypoglycaemia.
• In diabetes, hypoglycaemia is usually due to insulin or to insulin secretagogues; recurrent or severe episodes mandate treatment de-intensification or a switch to lower-risk therapy.
• The ADA 2026 levels are level 1 below 3.9 mmol/L (70 mg/dL), level 2 below 3.0 mmol/L (54 mg/dL), and level 3 any severe event needing someone else's help.^[1]
• Give consciousness-appropriate glucose, reassess at 15 minutes, and prescribe glucagon for people on insulin or at high risk.^[1]
• Insulinoma is the commonest cause of fasting endogenous hyperinsulinaemia in adults: about 3 to 4 cases per million per year, 90% sporadic, 5 to 10% malignant.^[3]
• Document insulin, C-peptide and proinsulin at a glucose of 3.1 mmol/L (55 mg/dL) or lower and during a fast.^[4]
• 42.5% of patients are positive within 12 hours of a 72-hour fast, 67% within 24 hours and 93 to 95% within 48 hours.^{[3][4] [2]}
• Surgery is curative in most cases; diazoxide (50 to 600 mg daily, about 50% efficacy) and somatostatin analogues (50 to 60% efficacy) control metastatic or inoperable disease.^[3]
• Insulinoma is linked to MEN1 in roughly 4 to 8% of cases: think of it in young or multiple-tumour patients and screen relatives.^[2][3]
• Non-metastatic insulinoma carries 94 to 100% survival; metastatic disease 24 to 67%.^[2]

• Multiple endocrine neoplasia (endocrine) - recurrent or multiple insulinomas often occur as part of multiple endocrine neoplasia type 1.
• Pancreatic neuroendocrine tumours (gastrointestinal) - insulinoma is a functioning pancreatic neuroendocrine tumour; the grading, imaging and surgical principles overlap.
• Type 1 diabetes mellitus and diabetic ketoacidosis (endocrine) - insulin treatment is the commonest cause of drug-induced hypoglycaemia and its emergencies.
• Cushing syndrome and adrenal disorders (endocrine) - cortisol deficiency is an important non-insulin-mediated cause of fasting hypoglycaemia.
• Zollinger-Ellison syndrome and gastrinoma (gastrointestinal/endocrine) - a parallel functioning pancreatic neuroendocrine syndrome, managed with proton-pump inhibitors and similar systemic therapy.