Hypoglycemia

Hypoglycemia is a blood glucose concentration low enough to cause symptoms — conventionally below 3.9 mmol/L (70 mg/dL), with neuroglycopenic features typically appearing below 2.8 mmol/L (50 mg/dL). The brain is the reason it matters: it cannot synthesize or store glucose in useful quantity and depends on a continuous supply, so a falling glucose becomes a neurological emergency well before it becomes anything else.

The body defends against this in a well-defined sequence. Insulin secretion falls first, at around 4.4 mmol/L. Glucagon and adrenaline are released at around 3.8 mmol/L, driving glycogenolysis and gluconeogenesis. Cortisol and growth hormone follow. Symptoms appear at around 3.0 mmol/L, and cognitive impairment below about 2.8.

By far the commonest cause is the treatment of diabetes — insulin, sulfonylureas and glinides. Contributing factors are a missed or delayed meal, a dose that does not match intake, unaccustomed exercise, alcohol, and deteriorating renal function reducing drug clearance.

In people without diabetes it is uncommon and always warrants explanation:

• Alcohol, which inhibits gluconeogenesis — typically after a binge with little food, and a frequent cause in the emergency department
• Reactive (postprandial) hypoglycemia — an exaggerated insulin response two to five hours after a high-carbohydrate meal
• Post-bariatric surgery hypoglycemia, from accelerated gastric emptying and an exaggerated incretin response
• Insulinoma — a rare insulin-secreting pancreatic tumour, causing fasting hypoglycemia
• Adrenal insufficiency, hypopituitarism and severe hypothyroidism, through loss of counter-regulatory hormones
• Advanced liver or renal failure, sepsis, and starvation
• Drugs — quinine, pentamidine, high-dose salicylates, beta-blockers (which also mask warning symptoms)
• Factitious hypoglycemia from surreptitious insulin or sulfonylurea use

In hypoglycemia unawareness, repeated episodes blunt the counter-regulatory and symptomatic response, so warning symptoms are progressively lost and the first sign becomes confusion or collapse. It is a major hazard in long-standing type 1 diabetes and is partly reversible by scrupulously avoiding lows for several weeks.

Symptoms fall into two groups that appear in order, and the distinction is clinically useful.

Autonomic symptoms come first and are the warning: sweating, trembling, palpitations, anxiety, hunger, tingling around the mouth, and pallor. They are driven by adrenaline, not by the low glucose itself — which is why beta-blockers mask them.

Neuroglycopenic symptoms follow as the brain runs short: difficulty concentrating, confusion, slurred speech, incoordination, behaviour change, blurred vision, drowsiness, and in severe cases seizures and loss of consciousness. Behaviour change can closely resemble intoxication and is frequently misread as such.

Nocturnal hypoglycemia presents differently — night sweats, vivid dreams or nightmares, morning headache and unrefreshing sleep — and is easily missed.

In a person treated for diabetes, hypoglycemia is diagnosed by capillary glucose and treated immediately; investigation is directed at why it happened, not whether it did.

In a person without diabetes, the standard is Whipple’s triad, and all three parts are required: symptoms consistent with hypoglycemia, a low plasma glucose measured at the time of those symptoms, and relief of symptoms when glucose is restored. Symptoms alone, or a low reading from a home meter without symptoms, do not establish the diagnosis — and this is the single commonest source of overdiagnosis.

Where the triad is met, the critical step is to draw samples during an episode, before treating: plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and a sulfonylurea screen. The pattern separates the causes — high insulin with high C-peptide indicates endogenous secretion (insulinoma or sulfonylurea, distinguished by the drug screen), while high insulin with suppressed C-peptide indicates exogenous insulin. A supervised 72-hour fast is used where spontaneous episodes cannot be captured. Cortisol and a short Synacthen test exclude adrenal insufficiency.

A low reading on a continuous glucose monitor or home meter, without corresponding symptoms, is common and usually reflects measurement limitation rather than disease.

Recurrent hypoglycemia is closely tied to diabetes management and is the principal limiting factor in tight glycemic control. It is associated with falls and fracture in older people, with cardiac arrhythmia, and with an increased risk of dementia after severe episodes. Fear of hypoglycemia is itself a significant problem, driving deliberate under-treatment and persistently high glucose. Chronic kidney disease, liver disease and adrenal insufficiency all raise the risk and should be sought where episodes are recurrent or unexplained.