Etiology
Most episodes of diabetic hypoglycemia 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 midday), reduced appetite, and lack of access to snacks between meals or before bed.[3][14]
Behavioral 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 hypoglycemia during, immediately after, or with prolonged delay (up to 24 hours) following exercise.[3][37]
Hypoglycemia can occur due to insulin prescription or administration errors (e.g., too much insulin used for correction of hyperglycemia, or wrong type or dose of insulin given).[14][38][39][40] Examples in the 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 the 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, hypoglycemia may occur due to:[14]
Acute discontinuation of long-term corticosteroid therapy
Vomiting/reduced appetite
Mobilization after illness
Recovery from acute illness.
Drinking alcohol can cause hypoglycemia during and after consumption, particularly if the patient has not eaten recently.[3][37]
Always consider other, nondiabetic causes of hypoglycemia. In practice, particularly suspect a nondiabetic cause of hypoglycemia if the episodes of hypoglycemia:
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 ketonemia
Are associated with risk factors for nondiabetic causes of hypoglycemia.
Other causes of nondiabetic hypoglycemia include:
Nondiabetic drugs
Liver or renal failure
Sepsis
Adrenal, thyroid, or pituitary dysfunction[17]
Malnutrition.
For more information, see Differentials.
See also Non-diabetic hypoglycemia.
Pathophysiology
In a person with diabetes, the normal counterregulatory 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][42] If the blood glucose continues to fall, glucose counterregulatory responses are activated.[10][42] These consist of the secretion of glucagon from pancreatic beta cells, and activation of the sympathoadrenal nervous system with associated release of epinephrine.[7][10][42] 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 hypoglycemia (e.g., anxiety, tremor, palpitations).[7][42]
However, in a person with diabetes, particularly increasing duration of diabetes, the release of glucagon in response to hypoglycemia becomes impaired, causing less glucose to be generated in the liver, which increases the person's susceptibility to hypoglycemia.[7][10][42]
If a person with diabetes has recurrent episodes of hypoglycemia, activation of the sympathoadrenal nervous system can become impaired.[10][42] This mechanism is very sensitive to recurrent episodes of hypoglycemia, which can reset the threshold for epinephrine release to a lower blood glucose level than normal.[7][10] Alteration of this mechanism means that the normal autonomic warning symptoms of hypoglycemia occur at increasingly lower blood glucose levels, which increases the risk of severe hypoglycemia.[7][10][33] This is known as impaired awareness of hypoglycemia.[7][10] There is also an associated maladaptive response in the brain to recurrent episodes of hypoglycemia, which is characterized 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][42]
If the person is taking insulin for their diabetes, this may cause hypoglycemia even if they have intact glucose counterregulatory responses.[42] This is because exogenous insulin is not subject to normal physiologic feedback regulation.[42]
Exercise can cause hypoglycemia 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][43] Therefore, glucose uptake into muscle during exercise increases even when insulin levels are low.[37][43] 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 counterregulatory responses.[37] As a result, hypoglycemia can occur during or after exercise.[37]
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