Key Facts

Hypoglycaemia is the major acute barrier to tight glycaemic control. It can be fatal and causes significant morbidity including falls, fractures, cardiac arrhythmias, and cognitive impairment. Identification and management of hypoglycaemia unawareness is critical in T1DM.

Epidemiology

Most T1DM patients experience ~2 mild hypoglycaemic episodes per week; ~1 severe episode per year. T2DM on insulin: ~0.5-1 severe episodes per year. Severe hypoglycaemia is more common with long duration of diabetes, tight HbA1c targets, and hypoglycaemia unawareness.

Aetiology

Diabetic patients: insulin (too much, wrong timing, wrong type), sulfonylureas, missed/delayed meals, excess exercise, alcohol, renal impairment (reduced insulin clearance), adrenal insufficiency (associated with T1DM). Non-diabetic: insulinoma, post-bariatric surgery (dumping syndrome), adrenal insufficiency (Addison, secondary), alcohol, drugs (quinine, pentamidine, salicylates), critical illness (liver failure, sepsis, renal failure), non-islet cell tumour (IGF-2 secreting).

Pathophysiology

Glucose is the primary fuel for the brain. When glucose falls: counter-regulatory hormones activate (glucagon → hepatic glycogenolysis/gluconeogenesis; adrenaline → glycogenolysis, lipolysis; cortisol, GH). Adrenergic symptoms are the early warning system. With recurrent hypoglycaemia, the counter-regulatory response becomes blunted (hypoglycaemia-associated autonomic failure — HAAF) → loss of warning symptoms (hypoglycaemia unawareness) → increased risk of severe hypoglycaemia.

Adrenergic/Autonomic Symptoms (Glucose ~3.0-3.9 mmol/L)

• Sweating, tremor, palpitations, anxiety, hunger, pallor, nausea

Neuroglycopaenic Symptoms (Glucose <3.0 mmol/L)

• Confusion, difficulty concentrating, behavioural change (aggression, uncooperativeness)
• Visual disturbance, slurred speech
• Incoordination, weakness
• Seizures, coma
• Focal neurological deficit (may mimic stroke)

Severity Classification

• Mild: self-treated; adrenergic symptoms only
• Moderate: self-treated with difficulty; neuroglycopaenic symptoms but conscious
• Severe: requires third-party assistance; may be unconscious or seizing

Red Flags

• Recurrent unexplained hypoglycaemia in non-diabetic → insulinoma, adrenal insufficiency
• Hypoglycaemia unawareness in T1DM → needs CGM, relaxed targets
• Factitious hypoglycaemia: low glucose + high insulin + low C-peptide = exogenous insulin; high insulin + high C-peptide = sulfonylurea/insulinoma

Immediate

• Capillary/venous blood glucose: confirm hypoglycaemia

During Hypoglycaemia (Critical — Before Treatment if Possible)

• Paired samples: blood glucose, insulin, C-peptide, beta-hydroxybutyrate, sulfonylurea screen, proinsulin
• Interpretation: high insulin + high C-peptide = endogenous insulin source (insulinoma, sulfonylurea); high insulin + low C-peptide = exogenous insulin
• Beta-hydroxybutyrate: appropriately elevated in hypoglycaemia with suppressed insulin (normal); suppressed if hyperinsulinaemic hypoglycaemia

If Insulinoma Suspected

• 72-hour supervised fast: gold standard; monitor glucose, insulin, C-peptide; symptomatic hypoglycaemia with inappropriate insulin confirms diagnosis
• CT/MRI pancreas: localise tumour
• Endoscopic ultrasound: most sensitive for small pancreatic lesions

Other

• Short Synacthen test: if adrenal insufficiency suspected
• LFTs, U&Es: hepatic/renal failure
• Cortisol: if adrenal cause suspected

Acute Treatment

Conscious (mild-moderate):

• 15-20g fast-acting glucose: dextrose tablets (3-4 × Dextrosol), 150-200mL juice, 4-5 glucose tablets
• Recheck glucose after 15 minutes; repeat if <4.0 mmol/L
• Follow with long-acting carbohydrate (toast, biscuits, next meal)

Unconscious/Unable to Swallow (severe):

• IM glucagon 1mg (GlucaGen HypoKit): acts within 10-15 minutes; may cause nausea/vomiting; less effective if alcohol-related or glycogen-depleted
• IV glucose 10% 200mL (20g glucose): if IV access available; preferred in hospital
• Avoid IV 50% glucose: causes thrombophlebitis; use 10% or 20% instead
• Recovery position; protect airway

Sulfonylurea-Induced:

• May need prolonged glucose infusion (sulfonylureas have long half-life — gliclazide up to 20h)
• IV 10% glucose infusion; monitor for 24-48 hours
• Consider octreotide 50-100 mcg SC 8-hourly (inhibits insulin secretion)

Prevention

• Diabetes review: adjust insulin/sulfonylurea doses; education on carb counting, sick-day rules
• CGM: for hypoglycaemia unawareness (alarms for low glucose)
• Relaxed HbA1c targets: if recurrent severe hypoglycaemia
• Structured programmes: DAFNE, BGAT (Blood Glucose Awareness Training)

Non-Diabetic Hypoglycaemia

• Insulinoma: surgical excision (curative in >90%); diazoxide 3-8 mg/kg/day if inoperable
• Adrenal insufficiency: hydrocortisone replacement
• Post-bariatric: dietary modification (low GI, small frequent meals); acarbose

Referral Criteria

• Recurrent severe hypoglycaemia in T1DM: specialist diabetes team, pump/CGM assessment
• Non-diabetic hypoglycaemia: endocrinology
• Suspected insulinoma: endocrine surgery

Mild hypoglycaemia: fully reversible with prompt glucose. Severe prolonged hypoglycaemia: can cause permanent brain injury (hippocampal damage — memory impairment) and death. Severe hypoglycaemia is associated with increased cardiovascular mortality (NICE-SUGAR trial). Recurrent hypoglycaemia causes hypoglycaemia unawareness (reversible with strict avoidance for 2-3 weeks). Insulinoma: >90% cure rate with surgical excision.

Causes of Hypoglycaemia in Diabetic vs Non-Diabetic

Biochemical Diagnosis of Hypoglycaemia