DIABETES (/MEDICINE/DIABETES/NOTES)

Hypoglycaemia
NOTES

Overview

Hypoglycaemia refers to an abnormally low plasma glucose concentration with or

without symptoms.

Hypoglycaemia is very common among patients with diabetes mellitus, usually secondary to
insulin or certain hypoglycaemic agents (e.g. suphonylureas). Hypoglycaemia may also occur in
patients without diabetes mellitus. In this situation, hypoglycaemia is uncommon and may occur
due to a range of abnormalities, some very rare.

Hypoglycaemia is generally defined as an abnormally low blood glucose concentration (< 4.0
mmol/L).

Normal fasting range: 4.0-5.4 mmol/L

Normal post-prandial range: 4.0-7.8 mmol/L (up to two hours after eating)

Clinically significant hypoglycaemia is generally defined as < 3.0 mmol/L. At this level,
hypoglycaemia can be associated with serious immediate and long-term consequences. A blood
glucose concentration < 3.0 mmol/L rarely occurs in the absence of diabetes mellitus.

Key terms
Severe hypoglycaemia: a hypoglycaemic event whereby the affected patient requires
assistance to restore blood glucose concentration.
Asymptomatic hypoglycaemia: blood glucose concentration < 4.0 mmol/L without
accompanying symptoms.
 Symptomatic hypoglycaemia: blood glucose concentration < 4.0 mmol/L with accompanying
symptoms (i.e. meets Whipple’s triad - see below).
Pseudohypoglycaemia: symptoms of hypoglycaemia but blood glucose concentration ≥ 4.0
mmol/L. Usually due to long-standing poor glycemic control with symptoms when blood
glucose concentration falls into physiological range.

Whipple’s triad

A formal diagnosis of hypoglycaemia should be based on Whipple’s triad.

In clinical practice, there may be a discrepancy between plasma glucose concentration and
symptoms. A confident diagnosis of hypoglycaemia is therefore made on the basis of symptoms
correlating with the episode of hypoglycaemia.

1. Low blood glucose concentration

2. Symptoms of hypoglycaemia
3. Reversal of symptoms when blood glucose concentration is restored to normal

In patients with diabetes mellitus, they may have reduced hypoglycaemic awareness due to a
reduced neurogenic symptom response. Therefore, Whipple’s triad is more clinically relevant to
further investigate patients without diabetes mellitus.

Physiology

Activation of counter-regulatory mechanisms are vital to prevent or rapidly correct low

plasma glucose concentration.

During a fasting state, when blood glucose concentrations fall, there is activation of four main
counterregulatory mechanisms:

Decrease in insulin secretion

Increase in glucagon secretion: increases hepatic glucose production through glycogenolysis
and gluconeogenesis. Threshold for glucagon secretion is 3.6-3.9 mmol/L. If there are poor
hepatic stores of glycogen or hepatic impairment, this response is ineffective.
Increases in adrenaline secretion: increases hepatic glucose production similar to glucagon.
Inhibits insulin secretion. Inhibits glucose utilisation of peripheral tissues. Threshold for
 adrenaline secretion is 3.6-3.9 mmol/L. Similar to glucagon, an adequate response requires
hepatic glycogen stores and normal functioning.
Secretion of cortisol and growth hormone: released if hypoglycaemia ongoing for hours.
Decreases peripheral tissue utilisation of glucose and increase hepatic glucose production.

The fall in insulin secretion and increase in glucagon secretion are the main counter-regulatory
mechanisms. Alongside these biochemical responses, hypoglycaemia (usually at levels <3.1
mmol/L) stimulates autonomic symptoms (e.g. anxiety, hunger), which triggers the ingestion of
food to restore plasma glucose concentration.

Aetiology

Hypoglycaemia most commonly occurs in association with treatment for diabetes

mellitus.

Diabetes mellitus
Hypoglycaemia may occur in type 1, or less commonly, type 2 diabetes mellitus. This may be due
to medication changes, concurrent illness, dietary or activity changes.

Patients with type 1 diabetes mellitus (T1DM) report an average of three episodes of severe
hypoglycaemia per year. Hypoglycaemia in T1DM is commonly due to incorrect dosage of insulin
and can occur during the day or night.

Patients with type 2 diabetes mellitus (T2DM) are much less likely to develop hypoglycaemia.
Classically, patients treated with insulin and sulphonylureas are at increased risk of
hypoglycaemia. Other diabetic medications such as metformin, glucagon-like peptide-1 (GLP-1)
receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter
2 (SGLT2) inhibitors do not usually cause hypoglycaemia.

Absence of diabetes mellitus

There are numerous causes of hypoglycaemia in the absence of diabetes mellitus. There are
different ways of classifying these causes, which include:

Insulin-mediated versus non-insulin mediated

 Fasting versus post-prandial
Clinically unwell versus clinically well.

The differentiation between unwell and well is felt to be the most practically useful and is
discussed below.

Clinically unwell

Medications: for example insulin, hypoglycaemic agents, quinolones, pentamidine, quinine,

beta blockers, angiotensin-converting enzyme inhibitors)
Alcohol: as ethanol inhibits gluconeogenesis but not glycogenolysis, it can take several days of
increased ethanol consumption for hypoglycaemia to develop with exhaustion of glycogen
stores
Critical illness: sepsis, renal impairment, hepatic or cardiac failure
Malnourishment: glycogen store depletion and limited substrates for gluconeogenesis
Hormone deficiency: hypocortisolaemia from adrenal insufficiency
Paraneoplastic syndrome: often from secretion of insulin-like growth factor from non-islet cell
tumours.

Clinically well

Among those who appear well, hypoglycaemia may be secondary to accidental or malicious use of
diabetic medications (e.g. insulin, beta cell secretagogues) or endogenous hyperinsulinaemia. The
use of beta cell secretagogues will lead to endogenous hyperinsulinaemia, so it occurs in both
groups.

Causes of endogenous hyperinsulinaemia:

Beta cell secretagogue ingestion (e.g. ingestion of a medication that stimulates insulin release
from beta cells)
Islet beta-cell tumour (e.g. insulinoma - discussed below)
Functional beta cell disorder (e.g. high insulin secretion not due to an insulinoma)
Insulin autoimmune hypoglycaemia (antibodies develop against insulin or its receptor)

Insulinoma
 An insulinoma refers to a tumour of the beta cells within the islets of Langerhan of the
pancreas.

Insulinomas are most commonly benign tumours that cause an excess secretion of insulin. This
leads to recurrent fasting hypoglycaemia due to an inappropriately high level of insulin for the
blood glucose concentration. Insulinomas may occur de novo, or occur in association with multiple
endocrine neoplasia, an autosomal dominant inherited condition. See our notes on MEN
syndromes (https://app.pulsenotes.com/medicine/endocrinology/notes/men-syndromes).

The diagnosis is usually made through a combination of prolonged fasting over 72 hours, which
shows an inappropriately high level of insulin during an induced or spontaneous episode of
hypoglycaemia, and imaging of the pancreas. The treatment of choice is surgical resection.

Clinical features

Hypoglycaemia is characterised by development of autonomic and neuroglycopaenic

symptoms.

Autonomic features
Onset of symptoms usually occur when blood glucose concentration falls below 3 mmol/L.

Tremor
Palpitations
Anxiety
Sweating
Hunger
Paraesthesia

Neuroglycopaenic features
These are a collection of more severe symptoms that typically develop at a blood glucose
concentration <2.8 mmol/L

Dizziness
 Weakness
Drowsiness
Confusion
Altered mental status
Seizure

NOTE: Patients with diabetes mellitus may lose their hypoglycaemic awareness. This may lead to
reduced symptoms and presentation with severe hypoglycaemia. It can occur in patients with
type 1 diabetes and long-standing type 2 diabetes mellitus. It is usually a combination of defective
glucose counter-regulatory mechanisms and hypoglycaemia awareness. Collectively, this leads to
recurrent hypoglycaemia.

Diagnosis

The diagnosis of hypoglycaemia is based on capillary blood glucose or serum blood

glucose measurements.

In patients with suspected hypoglycaemia, a capillary blood glucose measurement should be

taken. This will confirm a blood glucose concentration < 4.0 mmol/L, which is consistent with
hypoglycaemia.

Further investigations depend on the suspected diagnosis (diabetes mellitus versus no

diabetes mellitus), the likely precipitant (e.g. concurrent illness) and whether it is recurrent. In
patients with diabetes, simple adjustments to insulin or medications may be all that is required.

Investigations

In patients without diabetes mellitus, further investigations may be warranted to

determine the underlying cause.

In patients with hypoglycaemia without diabetes mellitus it is first important to document true
hypoglycaemia based on Whipple’s triad. There is unlikely to be an underlying hypoglycaemic
disorder if the blood glucose concentration is > 2.2 mmol/l.
Many cases of hypoglycaemia may occur transiently in an unwell patient (e.g. sepsis, alcohol
consumption) and investigations should be guided by the suspected diagnosis (e.g. serum
cortisol in adrenal insufficiency). Routine blood tests including full blood count, renal function and
liver function are essential.

Hypoglycaemia work-up
In patients who appear well and have recurrent, significant hypoglycaemia, a series of
investigations can be requested

72 hour fast (see below)

Glucose
Insulin: will be inappropriately high in endogenous hyperinsulinaemia
C-peptide: short polypeptide that forms part of proinsulin. It is cleaved to form insulin.
Inappropriately high in endogenous hyperinsulinaemia.
Pro-insulin: prohormone precursor released by beta cells. Cleaved to form insulin and C-
peptide.
Sulfonylurea screen: used to detect accidental or malicious use of oral hypoglycaemic agents
Beta-hydroxybutyrate (BHOB): a blood ketone. Levels should be low in the context of
hyperinsulinaemia because of the anti-ketone effect of insulin.

72 hour fast
This test aims to provoke normal homeostatic responses to keep blood glucose concentration
from failing. In normal individuals, a 72 hour fast should not lead to hypoglycaemia.

Each centre will have their own set test protocol for a 72 hour fast. This includes when blood tests
should be taken and how to monitor individuals.

The test is stopped if:

Plasma glucose concentration falls ≤2.5 mmol/L

The patient has clinical features of hypoglycaemia
The 72 hours elapses
Plasma glucose concentration falls <3.0 mmol/L with previous documentation of Whipple's
triad
At the end of the test, blood os taken for insulin, C-peptide, proinsulin, Beta-hydroxybutyrate, and
oral hypoglycaemic agents. Glucagon may be given intravenously following venepuncture and the
patient is able to eat. These blood tests are then interpreted to determine the cause. In a
insulinoma, there is an inappropriately elevated level of insulin and C-peptide despite the
presence of hypoglycaemia.

Management

Hypoglycaemia may be mild with minimal symptoms or a medical emergency requiring

urgent treatment.

The management of hypoglycaemia depends on whether the patients is alert or has reduced GCS.

Alert and hypoglycaemia

Give an oral glucose load: for example 120 mls of lucozade, single dose of hypostop or
glucogel orally.
Give a more complex carbohydrate meal: oral glucose load will only last an hour
Monitor capillary blood glucose: usually 1-2 hourly until stable
Consider intravenous dextrose (5-10%): if persistent hypoglycaemia, whilst investigating
suspected cause
Determine underlying cause

Coma and hypoglycaemia

ABCDE assessment: if any concerns, call senior help urgently
Establish intravenous access
Give an intravenous load of glucose: 50 mls 50% dextrose, 100 mls 20% dextrose or 200 mls
10% dextrose (often depends on stock available)
Consider 1 mg glucagon (SC/IM/IV): particularly if difficult to establish access. Remember,
unlikely to be effective if poor glycogen stores (e.g. malnourished, hepatic disease).
Reassess: should see rapid improvement in symptoms (i.e. < 10 minutes) if hypoglycaemia is
the cause of low GCS.
Consider starting intravenous glucose infusion: for example, 1 litre 10% dextrose.
Continue monitoring: usually capillary blood glucose 1-2 hourly until stable
 Determine underlying cause

Last updated: March 2021

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