Hypoglycaemia

Overview

Hypoglycaemia is a plasma glucose concentration low enough to cause autonomic or neuroglycopenic symptoms. Severe or prolonged hypoglycaemia can cause seizures, permanent neurological injury, cardiac arrhythmia, coma and death.

In people with diabetes, a blood glucose level below 4.0 mmol/L should be treated promptly, even if symptoms are absent.¹

In adults without diabetes, investigate a hypoglycaemic disorder when Whipple’s triad is documented:

1. Symptoms or signs consistent with hypoglycaemia
2. A low laboratory-measured plasma glucose concentration
3. Resolution of symptoms after the plasma glucose concentration is corrected.²

Symptoms are divided into:

• Autonomic or neurogenic: tremor, sweating, palpitations, anxiety, hunger and perioral tingling
• Neuroglycopenic: behavioural change, confusion, visual disturbance, weakness, dysarthria, seizure, focal neurological deficit and coma.²

Triage & Approach

Step 1: Immediate Assessment and Stabilisation

• Apply an ABCDE approach.
• Check bedside BGL immediately in any patient with altered consciousness, seizure, behavioural change, diaphoresis, weakness or an unexplained neurological presentation.
• Assess airway protection and ability to swallow.
• Obtain vital signs, cardiac monitoring and intravenous access.
• Treat immediately if the patient is unconscious, seizing, unable to swallow or clinically unstable.
• Recheck BGL approximately 10–15 minutes after treatment and continue monitoring for recurrence.

Step 2: Determine Whether Diabetes Treatment Is Involved

Ask about:

• Insulin type, dose and timing
• Sulfonylureas, particularly long-acting preparations
• Recent dose changes or medication errors
• Missed or delayed meals
• Vomiting or reduced carbohydrate intake
• Unplanned or prolonged exercise
• Alcohol consumption
• Renal or hepatic impairment
• Recent weight loss
• Pregnancy
• Continuous glucose monitor or insulin-pump data

Hypoglycaemia in a person taking insulin or an insulin secretagogue is usually medication-related until proven otherwise. However, infection, organ failure, adrenal insufficiency and other acute illnesses may lower the glucose threshold.

Step 3: If Diabetes Medication Is Not the Obvious Cause

Look for:

• Critical illness or sepsis
• Liver, renal or cardiac failure
• Malnutrition, starvation or prolonged fasting
• Alcohol-related hypoglycaemia
• Adrenal insufficiency or hypopituitarism
• Insulinoma or another cause of endogenous hyperinsulinism
• Non-islet-cell tumour
• Accidental, surreptitious or malicious exposure to insulin or a sulfonylurea
• Post-bariatric or other postprandial hypoglycaemia

Confirm Whipple’s triad before beginning an extensive investigation in an otherwise well adult without diabetes.²

Step 4: Classify the Pattern

• Fasting hypoglycaemia: medication, alcohol, critical illness, hormone deficiency, insulinoma, organ failure or metabolic disease
• Postprandial hypoglycaemia: post-bariatric hypoglycaemia, endogenous hyperinsulinism or a functional postprandial syndrome
• Ketotic hypoglycaemia: prolonged fasting, reduced intake, illness, cortisol or growth hormone deficiency and some metabolic disorders
• Hypoketotic hypoglycaemia: hyperinsulinism or impaired fatty-acid oxidation

Differential Diagnosis

Medication and Toxin-Related

• Exogenous insulin: Most common in insulin-treated diabetes. During hypoglycaemia, insulin is inappropriately detectable or elevated, with suppressed C-peptide and proinsulin.
• Sulfonylurea or meglitinide: Endogenous insulin and C-peptide are both elevated. Confirm using a plasma sulfonylurea/meglitinide screen. Long-acting agents may cause recurrent or prolonged hypoglycaemia.
• Alcohol: Inhibits hepatic gluconeogenesis, particularly after fasting or poor nutritional intake. May coexist with liver disease, hypothermia or trauma.
• Other medications: Consider quinine, pentamidine and medication interactions, particularly in patients with renal or hepatic impairment.

Critical Illness and Organ Failure

• Sepsis: Increased glucose consumption, reduced intake and impaired hepatic glucose production. Look for fever or hypothermia, hypotension, altered mental state and elevated lactate.
• Hepatic failure: Impaired glycogenolysis and gluconeogenesis. Associated jaundice, coagulopathy and elevated transaminases.
• Renal failure: Reduced insulin clearance and impaired gluconeogenesis. Insulin or sulfonylurea doses may become excessive as renal function declines.
• Cardiac failure: Severe disease may impair hepatic perfusion and glucose production.
• Malnutrition or starvation: Depleted glycogen stores and limited gluconeogenic substrate. Consider eating disorders, frailty, malignancy and gastrointestinal disease.

Hormonal Deficiency

• Adrenal insufficiency: Hypotension, weight loss, nausea, abdominal pain, hyponatraemia and hyperkalaemia. Primary adrenal insufficiency may cause hyperpigmentation.
• Hypopituitarism: Cortisol and growth hormone deficiency. May coexist with hypothyroidism, amenorrhoea or other pituitary deficits.

Endogenous Hyperinsulinism

• Insulinoma: Recurrent fasting or exercise-related hypoglycaemia. Symptoms may occur in the morning or after missed meals and improve with eating. Demonstrated biochemically before localisation imaging.
• Non-insulinoma pancreatogenous hypoglycaemia: Rare endogenous hyperinsulinaemic disorder. May be predominantly postprandial.
• Insulin autoimmune syndrome: Hypoglycaemia with very high insulin levels and insulin antibodies without exogenous insulin use.

Postprandial Causes

• Post-bariatric hypoglycaemia: Typically occurs 1–3 hours after eating, especially after high-glycaemic-index carbohydrate. Associated with an exaggerated incretin and insulin response.
• Functional postprandial syndrome: Adrenergic symptoms following meals without documented biochemical hypoglycaemia. Does not fulfil Whipple’s triad.

Non-Islet-Cell Tumour Hypoglycaemia

• Usually associated with a large mesenchymal, hepatic or epithelial tumour.
• Often mediated by incompletely processed insulin-like growth factor 2.
• Insulin, C-peptide and ketones are suppressed during hypoglycaemia.

Investigations

Immediate Bedside and Laboratory Tests

• Bedside capillary BGL
• Confirmatory venous plasma glucose when feasible
• Blood gas: glucose, pH, bicarbonate and lactate
• Electrolytes, urea, creatinine and liver function tests
• Full blood count and inflammatory markers if infection is suspected
• Blood ketones, particularly beta-hydroxybutyrate
• ECG and cardiac monitoring in severe or prolonged hypoglycaemia
• Toxicology or medication screen when exposure is possible

Point-of-care glucometers and continuous glucose monitors are less accurate in the hypoglycaemic range. Confirm unexplained low readings using a laboratory or blood-gas glucose measurement, but do not delay emergency treatment.

Critical Sample

In unexplained hypoglycaemia, collect a critical blood and urine sample during the episode and before glucose is given, if this can be done without delaying treatment:

• Laboratory plasma glucose
• Insulin
• C-peptide
• Proinsulin
• Beta-hydroxybutyrate
• Cortisol
• Growth hormone when hypopituitarism is clinically suspected
• Sulfonylurea and meglitinide screen
• Insulin antibodies
• Electrolytes, liver function and lactate
• Free fatty acids

Interpret insulin concentrations relative to the low glucose. During genuine hypoglycaemia, insulin should normally be nearly completely suppressed.

Interpreting the Critical Sample

• High insulin + low C-peptide: Exogenous insulin administration
• High insulin + high C-peptide + positive sulfonylurea screen: Sulfonylurea or meglitinide exposure
• High insulin + high C-peptide + negative medication screen: Endogenous hyperinsulinism
• Low insulin + elevated ketones: Fasting, malnutrition, alcohol, adrenal insufficiency or another non-insulin-mediated cause
• Low insulin + suppressed ketones: Consider insulin-like growth factor 2-mediated tumour or a fatty-acid oxidation disorder

Plasma glucose below approximately 3.0 mmol/L, insulin at least 18 pmol/L, C-peptide at least 0.2 nmol/L and proinsulin at least 5 pmol/L during symptoms support endogenous hyperinsulinism.²

Provocative Testing

• Supervised fast: Used for suspected fasting hypoglycaemia when a spontaneous episode cannot be captured. It must be conducted under specialist supervision, with critical samples obtained when biochemical hypoglycaemia occurs.
• Mixed-meal test: Used for suspected postprandial hypoglycaemia. An oral glucose tolerance test is not recommended for diagnosing postprandial hypoglycaemia.

Imaging

Only perform pancreatic localisation imaging after biochemical confirmation of endogenous hyperinsulinism:

• Pancreatic protocol CT or MRI
• Endoscopic ultrasound
• Functional imaging or selective arterial calcium stimulation when conventional imaging is non-diagnostic

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Critical Management

Conscious and Able to Swallow

1. Give approximately 15 g of fast-acting carbohydrate, such as glucose tablets or gel containing 15 g carbohydrate, 6–7 regular jellybeans, 150 mL regular soft drink, 125 mL fruit juice, or 3 teaspoons of sugar or honey.
2. Recheck BGL after 15 minutes.
3. If BGL remains below 4.0 mmol/L, repeat the fast-acting carbohydrate.
4. Once BGL is above 4.0 mmol/L and symptoms have resolved, provide a meal or longer-acting carbohydrate if the next meal is not imminent.^1,3

Altered Consciousness, Seizure or Unsafe Swallow

• Call for emergency assistance.
• Place the patient in the lateral position and protect the airway.
• Do not give food, drink or glucose gel orally.
• Administer intravenous glucose according to the local emergency protocol.
• If intravenous access is unavailable, administer glucagon IM or subcutaneously if available.
• Recheck BGL after approximately 10 minutes.
• Repeat treatment or commence a glucose infusion if hypoglycaemia persists.
• Investigate and treat the underlying cause.

Glucagon may be less effective when hepatic glycogen stores are depleted, including prolonged fasting, malnutrition, severe liver disease and alcohol-related hypoglycaemia.

Sulfonylurea-Associated Hypoglycaemia

• Expect recurrent hypoglycaemia after initial glucose correction.
• Admit for prolonged glucose monitoring.
• Use intravenous glucose for immediate correction.
• Discuss octreotide with toxicology or endocrinology to suppress recurrent insulin secretion.
• Do not discharge after a single normal glucose reading.

Prevention of Recurrence

Before discharge or transfer:

• Identify and correct the precipitating factor.
• Review insulin and glucose-lowering medication doses.
• Consider renal function, hepatic function, food intake, exercise and alcohol use.
• Ensure access to fast-acting carbohydrate and glucagon where appropriate.
• Provide education to the patient, family and carers.
• Review hypoglycaemia awareness and driving safety.
• Consider continuous glucose monitoring for people at high risk of recurrent hypoglycaemia.⁴
• Arrange diabetes or endocrinology follow-up where indicated.

References

1. Diabetes Australia. Hypoglycaemia (hypo) and hyperglycaemia [Internet]. Canberra (AU): Diabetes Australia; [cited 2026 Aug 13]. Available from: https://www.diabetesaustralia.com.au/managing-diabetes/hypo-hyperglycaemia/
2. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(3):709-728. doi:10.1210/jc.2008-1410
3. National Diabetes Services Scheme. Low blood glucose levels (hypoglycaemia) [Internet]. Canberra (AU): Diabetes Australia; [cited 2026 Aug 13]. Available from: https://www.ndss.com.au/managing-diabetes/blood-glucose-monitoring/hypoglycaemia/
4. McCall AL, Lieb DC, Gianchandani R, MacMaster HW, Maynard GA, Murad MH, et al. Management of individuals with diabetes at high risk for hypoglycemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2023;108(3):529-562. doi:10.1210/clinem/dgac596