Aetiology
Most episodes of diabetic hypoglycaemia are caused by issues to do with self-management of blood glucose, such as altered eating patterns, taking more insulin than usual, or engaging in more activity than usual.[32][33][34]
Causes related to altered eating patterns include missed or delayed meals, eating less carbohydrates than usual, food insecurity, changing the timing of the biggest meal of the day (e.g., from evening to mid-day), reduced appetite, and lack of access to snacks between meals or before bed.[3][14]
Behavioural and psychosocial reasons (e.g., poor adherence, family dysfunction, personality disorder) may lead to the person taking more insulin than usual.[35][36]
Exercise can cause hypoglycaemia during, immediately after, or with prolonged delay (up to 24 hours) following exercise.[3][37][38]
Hypoglycaemia can occur due to insulin prescription or administration errors (e.g., too much insulin used for correction of hyperglycaemia, or wrong type or dose of insulin given).[14][39][40][41] Examples in hospital include:[14]
Giving 'stat' (immediate) or 'PRN' (when required) rapid/short-acting insulin inappropriately (e.g., repeated doses of rapid-acting insulin given without leaving enough time between doses to allow for onset of action and duration of effect)
Taking an incorrect drug history and failing to correctly reconcile this on admission to hospital
Misreading poorly written prescriptions and giving an incorrect dose of insulin (e.g., if 'U' is written to indicate units, 4U may be interpreted as 40 units)
Confusing the insulin concentration with the dose
Changing the insulin injection site
Mixing intermediate-acting or mixed insulins inadequately
Not monitoring the patient's blood glucose adequately while they are receiving an intravenous insulin infusion.
If the patient is unwell, hypoglycaemia may occur due to:[14]
Acute discontinuation of long-term corticosteroid therapy
Vomiting/reduced appetite
Mobilisation after illness
Recovery from acute illness.
Drinking alcohol can cause hypoglycaemia during and after consumption, particularly if the patient has not eaten recently.[3][37]
Always consider other, non-diabetic causes of hypoglycaemia. In practice, particularly suspect a non-diabetic cause of hypoglycaemia if the episodes of hypoglycaemia:
Cannot be related to timing of insulin injections, increased activity, or reduced carbohydrate intake
Persist despite changes of insulin doses
Are associated with ketonuria or ketonaemia
Are associated with risk factors for non-diabetic causes of hypoglycaemia.
Other causes of non-diabetic hypoglycaemia include:
Non-diabetic drugs
Liver or renal failure
Sepsis
Adrenal, thyroid, or pituitary dysfunction[17]
Malnutrition.
For more information, see Differentials.
See also Non-diabetic hypoglycaemia.
Pathophysiology
In a person with diabetes, the normal counter-regulatory hormone response to a fall in blood glucose is impaired. In a person without diabetes, an initial fall in blood glucose inhibits insulin secretion from the pancreatic beta cells due to a paracrine response within the islets.[10][43] If the blood glucose continues to fall, glucose counter-regulatory responses are activated.[10][43] These consist of the secretion of glucagon from pancreatic beta cells, and activation of the sympathoadrenal nervous system with associated release of epinephrine (adrenaline).[7][10][43] Glucagon acts on the liver by stimulating the release of glucose through glycogenolysis.[10] Activation of the sympathoadrenal nervous system stimulates the liver to increase hepatic glucose production by glycogenolysis and gluconeogenesis, causes reduced glucose uptake in peripheral tissues, and results in the symptoms of hypoglycaemia (e.g., anxiety, tremor, palpitations).[7][43]
However, in a person with diabetes, particularly increasing duration of diabetes, the release of glucagon in response to hypoglycaemia becomes impaired, causing less glucose to be generated in the liver, which increases the person's susceptibility to hypoglycaemia.[7][10][43]
If a person with diabetes has recurrent episodes of hypoglycaemia, activation of the sympathoadrenal nervous system can become impaired.[10][43] This mechanism is very sensitive to recurrent episodes of hypoglycaemia, which can reset the threshold for epinephrine (adrenaline) release to a lower blood glucose level than normal.[7][10] Alteration of this mechanism means that the normal autonomic warning symptoms of hypoglycaemia occur at increasingly lower blood glucose levels, which increases the risk of severe hypoglycaemia.[7][10][33] This is known as impaired awareness of hypoglycaemia.[7][10] There is also an associated maladaptive response in the brain to recurrent episodes of hypoglycaemia, which is characterised by increased activity of the transmembrane protein glucose transporter 1 (GLUT1) (which aims to preserve brain function) and alteration of glucose sensing in the ventromedial hypothalamus (VMH), mediated by elevated levels of gamma-aminobutyric acid (GABA).[7][43]
If the person is taking insulin for their diabetes, this may cause hypoglycaemia even if they have intact glucose counter-regulatory responses.[43] This is because exogenous insulin is not subject to normal physiological feedback regulation.[43]
Exercise can cause hypoglycaemia because it increases non-insulin-dependent glucose uptake into muscle by the translocation of the glucose transporter type 4 (GLUT4) proteins to the cell surface.[37][44] Therefore, glucose uptake into muscle during exercise increases even when insulin levels are low.[37][44] The translocation activity of the GLUT4 proteins also remains high during recovery after exercise.[37] In a person with type 1 diabetes, the pancreas does not regulate insulin levels in response to exercise and there may be impaired glucose counter-regulatory responses.[37] As a result, hypoglycaemia can occur during or after exercise.[37]
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