Hypoglycemia

Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L).<ref name="NIH2008" /><ref name="Jameson_2018" /> Whipple's triad is used to properly identify hypoglycemic episodes.<ref name="Cry2009">Template:Cite journal</ref> It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal.<ref name="NIH2008" /> Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /> Symptoms typically come on quickly.<ref name="NIH2008">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Symptoms can remain even soon after raised blood level.

The most common cause of hypoglycemia is medications used to treat diabetes such as insulin, sulfonylureas, and biguanides.<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name="ReferenceA">Template:Cite journal</ref> Risk is greater in diabetics who have eaten less than usual, recently exercised, or consumed alcohol.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /> Other causes of hypoglycemia include severe illness, sepsis, kidney failure, liver disease, hormone deficiency, tumors such as insulinomas or non-B cell tumors, inborn errors of metabolism, and several medications.<ref name=NIH2008/><ref name="Cry2009" /><ref name="Jameson_2018" /> Low blood sugar may occur in otherwise healthy newborns who have not eaten for a few hours.<ref name=":7" />

Hypoglycemia is treated by eating a sugary food or drink, for example glucose tablets or gel, apple juice, soft drink, or lollipops.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /> The person must be conscious and able to swallow.<ref name="NIH2008" /><ref name="Jameson_2018" /> The goal is to consume 10–20 grams of a carbohydrate to raise blood glucose levels to a minimum of 70 mg/dL (3.9 mmol/L).<ref name="Jameson_2018" /><ref name="Cry2009" /> If a person is not able to take food by mouth, glucagon by injection or insufflation may help.<ref name=NIH2008/><ref name="Jameson_2018" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The treatment of hypoglycemia unrelated to diabetes includes treating the underlying problem.<ref name="Jameson_2018" /><ref name="Cry2009" />

Among people with diabetes, prevention starts with learning the signs and symptoms of hypoglycemia.<ref name="Jameson_2018" /><ref name="Cry2009" /> Diabetes medications, like insulin, sulfonylureas, and biguanides can also be adjusted or stopped to prevent hypoglycemia.<ref name="Jameson_2018" /><ref name="Cry2009" /> Frequent and routine blood glucose testing is recommended.<ref name="NIH2008" /><ref name="Jameson_2018" /> Some may find continuous glucose monitors with insulin pumps to be helpful in the management of diabetes and prevention of hypoglycemia.<ref name="Jameson_2018" />

Definition

Hypoglycemia, also called low blood sugar or low blood glucose, is a blood-sugar level below 70 mg/dL (3.9 mmol/L).<ref name="Jameson_2018" /><ref name=":2" />

Blood-sugar levels naturally fluctuate throughout the day, the body normally maintaining levels between 70 and 110 mg/dL (3.9–6.1 mmol/L).<ref name="Jameson_2018" /><ref name="Cry2009" /> Although 70 mg/dL (3.9 mmol/L) is the lower limit of normal glucose, symptoms of hypoglycemia usually do not occur until blood sugar has fallen to 55 mg/dL (3.0 mmol/L) or lower.<ref name="Jameson_2018" /><ref name="Cry2009" /> The blood-glucose level at which symptoms of hypoglycemia develop in someone with several prior episodes of hypoglycemia may be even lower.<ref name="Cry2009" />

Whipple's triad

The symptoms of low blood sugar alone are not specific enough to characterize a hypoglycemic episode.<ref name="Cry2009" /> A single blood sugar reading below 70 mg/dL is also not specific enough to characterize a hypoglycemic episode.<ref name="Cry2009" /> Whipple's triad is a set of three conditions that need to be met to accurately characterize a hypoglycemic episode.<ref name="Cry2009" />

The three conditions are the following:

1. The signs and symptoms of hypoglycemia are present (see section below on Signs and Symptoms)<ref name="Cry2009" /><ref>Template:Citation</ref>
2. A low blood glucose measurement is present, typically less than 70 mg/dL (3.9 mmol/L)<ref name="Cry2009" />
3. The signs and symptoms of hypoglycemia resolve after blood glucose levels have returned to normal<ref name="Cry2009" />

Age

The biggest difference in blood glucose levels between the adult and pediatric population occurs in newborns during the first 48 hours of life.<ref name=":7">Template:Cite journal</ref> After the first 48 hours of life, the Pediatric Endocrine Society cites that there is little difference in blood glucose level and the use of glucose between adults and children.<ref name=":7" /> During the 48-hour neonatal period, the neonate adjusts glucagon and epinephrine levels following birth, which may cause temporary hypoglycemia.<ref name=":7" /> As a result, there has been difficulty in developing guidelines on interpretation and treatment of low blood glucose in neonates aged less than 48 hours.<ref name=":7" /> Following a data review, the Pediatric Endocrine Society concluded that neonates aged less than 48 hours begin to respond to hypoglycemia at serum glucose levels of 55–65 mg/dL (3.0–3.6 mmol/L).<ref name=":7" /> This is contrasted by the value in adults, children, and older infants, which is approximately 80–85 mg/dL (4.4–4.7 mmol/L).<ref name=":7" />

In children who are aged greater than 48 hours, serum glucose on average ranges from 70 to 100 mg/dL (3.9–5.5 mmol/L), similar to adults.<ref name=":7" /> Elderly patients and patients who take diabetes pills such as sulfonylureas are more likely to suffer from a severe hypoglycemic episode.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Whipple's triad is used to identify hypoglycemia in children who can communicate their symptoms.<ref name=":7" />

Signs and symptoms

Hypoglycemic symptoms are divided into two main categories.<ref name="Jameson_2018" /> The first category is symptoms caused by low glucose in the brain, called neuroglycopenic symptoms.<ref name="Jameson_2018" /> The second category of symptoms is caused by the body's reaction to low glucose in the blood, called adrenergic symptoms.<ref name="Jameson_2018" />

Neuroglycopenic symptoms	Adrenergic symptoms
Headache Blurred vision Tiredness (also called fatigue) Unusual behavior Confusion Lightheadedness Difficulty speaking or slurred speech Seizures Loss of consciousness (sometimes called passing out) Death, if severe hypoglycemia	Fast heart rate Pounding heartbeat (also called palpitations) Sweating Clamminess Tremors Nervousness (also called anxiety) Hunger Irritability Nausea Pins and needles sensation Pale skin color
References:<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":2" /><ref name="Young_2016">Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation		CitationClass=web }}</ref><ref>Template:Cite news</ref>

Everyone experiences different symptoms of hypoglycemia, so someone with hypoglycemia may not have all of the symptoms listed above.<ref name="Jameson_2018" /><ref name=":2" /><ref name="Young_2016" /> Symptoms also tend to have quick onset.<ref name=":2" /> It is important to quickly obtain a blood glucose measurement in someone presenting with symptoms of hypoglycemia to properly identify the hypoglycemic episode.<ref name=":2" /><ref name="Cry2009" />

Causes

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}Hypoglycemia is most common in those with diabetes treated by insulin, glinides, and sulfonylureas.<ref name="Jameson_2018" /><ref name="Cry2009" /> Hypoglycemia is rare in those without diabetes, because there are many regulatory mechanisms in place to appropriately balance glucose, insulin, and glucagon.<ref name="Jameson_2018" /><ref name="Cry2009" />

Diabetics

Medications

The most common cause of hypoglycemia in diabetics is medications used to treat diabetes such as insulin, sulfonylureas, and biguanides.<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name="ReferenceA" /> This is often due to excessive doses or poorly timed doses.<ref name="Jameson_2018" /> Sometimes diabetics may take insulin in anticipation of a meal or snack; then forgetting or missing eating that meal or snack can lead to hypoglycemia.<ref name="Jameson_2018" /> This is due to increased insulin without the presence of glucose from the planned meal.<ref name="Jameson_2018" />

Hypoglycemic unawareness

Recurrent episodes of hypoglycemia can lead to hypoglycemic unawareness, or the decreased ability to recognize hypoglycemia.<ref name=":18">Template:Cite journal</ref><ref name=":19">Template:Cite journal</ref><ref name=":20">Template:Cite journal</ref> As diabetics experience more episodes of hypoglycemia, the blood glucose level which triggers symptoms of hypoglycemia decreases.<ref name=":18" /><ref name=":19" /><ref name=":20" /> In other words, people without hypoglycemic unawareness experience symptoms of hypoglycemia at a blood glucose of about 55 mg/dL (3.0 mmol/L).<ref name="Jameson_2018" /><ref name="Cry2009" /> Those with hypoglycemic unawareness experience the symptoms of hypoglycemia at far lower levels of blood glucose.<ref name=":18" /><ref name=":19" /><ref name=":20" /> This is dangerous for a number of reasons.<ref name=":18" /><ref name=":19" /><ref name=":20" /> The hypoglycemic person not only gains awareness of hypoglycemia at very low blood glucose levels, but they also require high levels of carbohydrates or glucagon to recover their blood glucose to normal levels.<ref name=":18" /><ref name=":19" /><ref name=":20" /> These individuals are also at far greater risk of severe hypoglycemia.<ref name=":18" /><ref name=":19" /><ref name=":20" />

While the exact cause of hypoglycemic unawareness is still under research, it is thought that these individuals progressively begin to develop fewer adrenergic-type symptoms, resulting in the loss of neuroglycopenic-type symptoms.<ref name=":19" /><ref name=":20" /> Neuroglycopenic symptoms are caused by low glucose in the brain, and can result in tiredness, confusion, difficulty with speech, seizures, and loss of consciousness.<ref name="Jameson_2018" /> Adrenergic symptoms are caused by the body's reaction to low glucose in the brain, and can result in fast heart rate, sweating, nervousness, and hunger.<ref name="Jameson_2018" /> See section above on Signs and Symptoms for further explanation of neuroglycopenic symptoms and adrenergic symptoms.

In terms of epidemiology, hypoglycemic unawareness occurs in 20–40% of type 1 diabetics.<ref name=":18" /><ref name=":20" /><ref>Template:Cite journal</ref>

Other causes

Other causes of hypoglycemia in diabetics include the following:

• Fasting, whether it be a planned fast or overnight fast, as there is a long period of time without glucose intake<ref name="NIH2008" /><ref name="Jameson_2018" />
• Exercising more than usual as it leads to more use of glucose, especially by the muscles<ref name="NIH2008" /><ref name="Jameson_2018" />
• Drinking alcohol, especially when combined with diabetic medications, as alcohol inhibits glucose production<ref name="NIH2008" /><ref name="Jameson_2018" />
• Kidney disease, as insulin cannot be cleared out of circulation well<ref name="Jameson_2018" />

Non-diabetics

Serious illness

Serious illness may result in low blood sugar.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":10">Template:Cite book</ref> Severe disease of many organ systems can cause hypoglycemia as a secondary problem.<ref name="Jameson_2018" /><ref name="Cry2009" /> Hypoglycemia is especially common in those in the intensive care unit or those in whom food and drink is withheld as a part of their treatment plan.<ref name="Jameson_2018" /><ref name=":10" />

Sepsis, a common cause of hypoglycemia in serious illness, can lead to hypoglycemia through many ways.<ref name="Jameson_2018" /><ref name=":10" /> In a state of sepsis, the body uses large amounts of glucose for energy.<ref name="Jameson_2018" /><ref name=":10" /> Glucose use is further increased by cytokine production.<ref name="Jameson_2018" /> Cytokines are a protein produced by the body in a state of stress, particularly when fighting an infection.<ref name="Jameson_2018" /> Cytokines may inhibit glucose production, further decreasing the body's energy stores.<ref name="Jameson_2018" /> Finally, the liver and kidneys are sites of glucose production, and in a state of sepsis those organs may not receive enough oxygen, leading to decreased glucose production due to organ damage.<ref name="Jameson_2018" />

Other causes of serious illness that may cause hypoglycemia include liver failure and kidney failure.<ref name="Jameson_2018" /><ref name=":10" /> The liver is the main site of glucose production in the body, and any liver failure or damage will lead to decreased glucose production.<ref name="Jameson_2018" /><ref name=":10" /> While the kidneys are also sites of glucose production, their failure of glucose production is not significant enough to cause hypoglycemia.<ref name="Jameson_2018" /> Instead, the kidneys are responsible for removing insulin from the body, and when this function is impaired in kidney failure, the insulin stays in circulation longer, leading to hypoglycemia.<ref name="Jameson_2018" />

Drugs

A number of medications have been identified which may cause hypoglycemia, through a variety of ways.<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":8">Template:Cite journal</ref> Moderate quality evidence implicates the non-steroidal anti-inflammatory drug indomethacin and the anti-malarial quinine.<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":8" /> Low quality evidence implicates lithium, used for bipolar disorder.<ref name="Cry2009" /><ref name=":8" /> Finally, very low quality evidence implicates a number of hypertension medications including angiotensin converting enzyme inhibitors (also called ACE-inhibitors), angiotensin receptor blockers (also called ARBs), and β-adrenergic blockers (also called beta blockers).<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":8" /> Other medications with very low quality evidence include the antibiotics levofloxacin and trimethoprim-sulfamethoxazole, progesterone blocker mifepristone, anti-arrhythmic disopyramide, anti-coagulant heparin, and chemotherapeutic mercaptopurine.<ref name="Cry2009" /><ref name=":8" />

If a person without diabetes accidentally takes medications that are traditionally used to treat diabetes, this may also cause hypoglycemia.<ref name="Jameson_2018" /><ref name="Cry2009" /> These medications include insulin, glinides, and sulfonylureas.<ref name="Jameson_2018" /><ref name="Cry2009" /> This may occur through medical errors in a healthcare setting or through pharmacy errors, also called iatrogenic hypoglycemia.<ref name="Jameson_2018" />

Surreptitious insulin use

When individuals take insulin without needing it, to purposefully induce hypoglycemia, this is referred to as surreptitious insulin use or factitious hypoglycemia.<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":9">Template:Cite book</ref> Some people may use insulin to induce weight loss, whereas for others this may be due to malingering or factitious disorder, which is a psychiatric disorder.<ref name=":9" /> Inappropriate usage of insulin is most common in people who have had exposure to diabetes management, such as healthcare workers, people who have relatives with diabetes, or people with diabetes themselves.<ref name="Jameson_2018" /><ref name=":9" /> The classic way to identify surreptitious insulin use is through blood work revealing high insulin levels with low C-peptide and proinsulin.<ref name="Jameson_2018" /><ref name=":9" />

Alcohol misuse

The production of glucose is blocked by alcohol.<ref name="Jameson_2018" /> In those who misuse alcohol, hypoglycemia may be brought on by a several-day alcohol binge associated with little to no food intake.<ref name="NIH2008" /><ref name="Jameson_2018" /> The cause of hypoglycemia is multifactorial, where glycogen becomes depleted in a state of starvation.<ref name="Jameson_2018" /> Glycogen stores are then unable to be repleted due to the lack of food intake, all compounded the inhibition of glucose production by alcohol.<ref name="Jameson_2018" />

Hormone deficiency

Children with primary adrenal failure, also called Addison's disease, may experience hypoglycemia after long periods of fasting.<ref name="Jameson_2018" /> Addison's disease is associated with chronically low levels of the stress hormone cortisol, which leads to decreased glucose production.<ref name="Jameson_2018" />

Hypopituitarism, leading to decreased growth hormone, is another cause of hypoglycemia in children, particularly with long periods of fasting or increased exercise.<ref name="Jameson_2018" />

Inborn errors of metabolism

Briefly, inborn errors of metabolism are a group of rare genetic disorders that are associated with the improper breakdown or storage of proteins, carbohydrates, or fatty acids.<ref name=":11">Template:Cite book</ref> Inborn errors of metabolism may cause infant hypoglycemia, and much less commonly adult hypoglycemia.<ref name=":11" />

Disorders that are related to the breakdown of glycogen, called glycogen storage diseases, may cause hypoglycemia.<ref name="Jameson_2018" /><ref name=":11" /> Normally, breakdown of glycogen leads to increased glucose levels, particularly in a fasting state.<ref name="Jameson_2018" /> In glycogen storage diseases, however, glycogen cannot be properly broken down, leading to inappropriately decreased glucose levels in a fasting state, and thus hypoglycemia.<ref name="Jameson_2018" /> The glycogen storage diseases associated with hypoglycemia include type 0, type I, type III, and type IV, as well as Fanconi syndrome.<ref name="Jameson_2018" />

Some organic and amino acid acidemias, especially those involving the oxidation of fatty acids, can lead to the symptom of intermittent hypoglycemia,<ref name=":14">Template:Cite journal</ref><ref>Template:Cite journal</ref> as for example in combined malonic and methylmalonic aciduria (CMAMMA),<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> propionic acidemia<ref name=":15">Template:Citation</ref><ref name=":14" /> or isolated methylmalonic acidemia.<ref name=":15" /><ref name=":14" />

Insulinomas

A primary B-cell tumor, such as an insulinoma, is associated with hypoglycemia.<ref name="Jameson_2018" /> This is a tumor located in the pancreas.<ref name="Jameson_2018" /> An insulinoma produces insulin, which in turn decreases glucose levels, causing hypoglycemia.<ref name="Jameson_2018" /> Normal regulatory mechanisms are not in place, which prevent insulin levels from falling during states of low blood glucose.<ref name="Jameson_2018" /> During an episode of hypoglycemia, plasma insulin, C-peptide, and proinsulin will be inappropriately high.<ref name="Jameson_2018" />

Non-B cell tumors

Hypoglycemia may occur in people with non-B cell tumors such as hepatomas, adrenocorticoid carcinomas,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and carcinoid tumors.<ref name="Jameson_2018" /> These tumors lead to a state of increased insulin, specifically increased insulin-like growth factor II, which decreases glucose levels.<ref name="Jameson_2018" />

Post-gastric bypass postprandial hypoglycemia

The Roux-en-Y gastric bypass, is a weight-loss surgery performed on the stomach, and has been associated with hypoglycemia, called post-gastric bypass postprandial hypoglycemia.<ref name="Jameson_2018" /> Although the entire mechanism of hypoglycemia following this surgery is not fully understood, it is thought that meals cause very high levels of glucagon-like peptide-1 (also called GLP-1), a hormone that increases insulin, causing glucose levels to drop.<ref name="Jameson_2018" />

Autoimmune hypoglycemia

Antibodies can be formed against insulin, leading to autoimmune hypoglycemia.<ref name="Jameson_2018" /><ref name=":12">Template:Cite journal</ref> Antibodies are immune cells produced by the body, that normally attack bacteria and viruses, but sometimes can attack normal human cells, leading to an autoimmune disorder.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In autoimmune hypoglycemia, there are two possible mechanisms.<ref name="Jameson_2018" /><ref name=":12" /> In one instance, antibodies bind to insulin following its release associated with a meal, resulting in insulin being non-functional.<ref name="Jameson_2018" /><ref name=":12" /> At a later time, the antibodies fall off insulin, causing insulin to be functional again leading late hypoglycemia after a meal, called late postprandial hypoglycemia.<ref name="Jameson_2018" /><ref name=":12" /> Another mechanism causing hypoglycemia is due to antibodies formed against insulin receptors, called insulin receptor antibodies.<ref name="Jameson_2018" /><ref name=":12" /> The antibodies attach to insulin receptors and prevent insulin breakdown, or degradation, leading to inappropriately high insulin levels and low glucose levels.<ref name="Jameson_2018" /><ref name=":12" />

Neonatal hypoglycemia

Low blood sugar may occur in healthy neonates aged less than 48 hours who have not eaten for a few hours.<ref name=":7" /> During the 48-hour neonatal period, the neonate adjusts glucagon and epinephrine levels following birth, which may trigger transient hypoglycemia.<ref name=":7" /> In children who are aged greater than 48 hours, serum glucose on average ranges from 70 to 100 mg/dL (3.9–5.5 mmol/L), similar to adults, with hypoglycemia being far less common.<ref name=":7" />

Pathophysiology

Glucose is the main source of energy for the brain, and a number of mechanisms are in place to prevent hypoglycemia and protect energy supply to the brain.<ref name="Jameson_2018" /><ref name=":10" /> The body can adjust insulin production and release, adjust glucose production by the liver, and adjust glucose use by the body.<ref name="Jameson_2018" /><ref name=":10" /> The body naturally produces the hormone insulin, in an organ called the pancreas.<ref name="Jameson_2018" /> Insulin helps to regulate the amount of glucose in the body, especially after meals.<ref name="Jameson_2018" /> Glucagon is another hormone involved in regulating blood glucose levels, and can be thought of as the opposite of insulin.<ref name="Jameson_2018" /> Glucagon helps to increase blood glucose levels, especially in states of hunger.<ref name="Jameson_2018" />

When blood sugar levels fall to the low-normal range, the first line of defense against hypoglycemia is decreasing insulin release by the pancreas.<ref name="Jameson_2018" /><ref name=":10" /> This drop in insulin allows the liver to increase glycogenolysis.<ref name="Jameson_2018" /><ref name=":10" /> Glycogenolysis is the process of glycogen breakdown that results in the production of glucose.<ref name="Jameson_2018" /><ref name=":10" /> Glycogen can be thought of as the inactive, storage form of glucose.<ref name="Jameson_2018" /> Decreased insulin also allows for increased gluconeogenesis in the liver and kidneys.<ref name="Jameson_2018" /><ref name=":10" /> Gluconeogenesis is the process of glucose production from non-carbohydrate sources, supplied from muscles and fat.<ref name="Jameson_2018" /><ref name=":10" />

Once blood glucose levels fall out of the normal range, additional protective mechanisms work to prevent hypoglycemia.<ref name="Jameson_2018" /><ref name=":10" /> The pancreas is signaled to release glucagon, a hormone that increases glucose production by the liver and kidneys, and increases muscle and fat breakdown to supply gluconeogenesis.<ref name="Jameson_2018" /><ref>Template:Cite book</ref> If increased glucagon does not raise blood sugar levels to normal, the adrenal glands release epinephrine.<ref name="Jameson_2018" /><ref name=":10" /> Epinephrine works to also increase gluconeogenesis and glycogenolysis, while also decreasing the use of glucose by organs, protecting the brain's glucose supply.<ref name="Jameson_2018" /><ref name=":10" />

After hypoglycemia has been prolonged, cortisol and growth hormone are released to continue gluconeogenesis and glycogenolysis, while also preventing the use of glucose by other organs.<ref name="Jameson_2018" /><ref name=":10" /> The effects of cortisol and growth hormone are far less effective than epinephrine.<ref name="Jameson_2018" /><ref name=":10" /> In a state of hypoglycemia, the brain also signals a sense of hunger and drives the person to eat, in an attempt to increase glucose.<ref name="Jameson_2018" /><ref name=":10" />

Diagnosis

The most reliable method of identifying hypoglycemia is through identifying Whipple's triad.<ref name="Jameson_2018" /><ref name="Cry2009" /> The components of Whipple's triad are a blood sugar level below 70 mg/dL (3.9 mmol/L), symptoms related to low blood sugar, and improvement of symptoms when blood sugar is restored to normal.<ref name="Jameson_2018" /><ref name="Cry2009" /> Identifying Whipple's triad in a patient helps to avoid unnecessary diagnostic testing and decreases healthcare costs.<ref name="Cry2009" />

In those with a history of diabetes treated with insulin, glinides, or sulfonylurea, who demonstrate Whipple's triad, it is reasonable to assume the cause of hypoglycemia is due to insulin, glinides, or sulfonylurea use.<ref name="Cry2009" /> In those without a history of diabetes with hypoglycemia, further diagnostic testing is necessary to identify the cause.<ref name="Cry2009" /> Testing, during an episode of hypoglycemia, should include the following:

• Plasma glucose level, not point-of-care measurement<ref name="Jameson_2018" /><ref name="Cry2009" />
• Insulin level<ref name="Jameson_2018" /><ref name="Cry2009" />
• C-peptide level<ref name="Jameson_2018" /><ref name="Cry2009" />
• Proinsulin level<ref name="Jameson_2018" /><ref name="Cry2009" />
• Beta-hydroxybutyrate level<ref name="Jameson_2018" /><ref name="Cry2009" />
• Oral hypoglycemic agent screen<ref name="Cry2009" />
• Response of blood glucose level to glucagon<ref name="Cry2009" />
• Insulin antibodies<ref name="Cry2009" />

If necessary, a diagnostic hypoglycemic episode can be produced in an inpatient or outpatient setting.<ref name="Jameson_2018" /> This is called a diagnostic fast, in which a patient undergoes an observed fast to cause a hypoglycemic episode, allowing for appropriate blood work to be drawn.<ref name="Jameson_2018" /> In some, the hypoglycemic episode may be reproduced simply after a mixed meal, whereas in others a fast may last up to 72 hours.<ref name="Jameson_2018" /><ref name="Cry2009" />

In those with a suspected insulinoma, imaging is the most reliable diagnostic technique, including ultrasound, computed tomography (CT) imaging, and magnetic resonance imaging (MRI).<ref name="Jameson_2018" /><ref name="Cry2009" />

Differential diagnosis

Other conditions that may present at the same time as hypoglycemia include the following:

• Alcohol or drug intoxication<ref name="Cry2009" /><ref name=":3">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Cardiac arrhythmia<ref name="Cry2009" /><ref name=":3" />
• Valvular heart disease<ref name="Cry2009" /><ref name=":3" />
• Postprandial syndrome<ref name=":3" />
• Hyperthyroidism<ref name=":3" />
• Pheochromocytoma<ref name=":3" />
• Post-gastric bypass hypoglycemia<ref name="Cry2009" /><ref name=":3" />
• Generalized anxiety disorder<ref name=":3" />
• Surreptitious insulin use<ref name="Cry2009" /><ref name=":3" />
• Lab or blood draw error (lack of antiglycolytic agent in collection tube or during processing)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref name=":3" />

Treatment

After hypoglycemia in a person is identified, rapid treatment is necessary and can be life-saving.<ref name="NIH2008" /> The main goal of treatment is to raise blood glucose back to normal levels, which is done through various ways of administering glucose, depending on the severity of the hypoglycemia, what is on-hand to treat, and who is administering the treatment.<ref name="NIH2008" /><ref name="Jameson_2018" /> A general rule used by the American Diabetes Association is the "15-15 Rule," which suggests consuming or administering 15 grams of a carbohydrate, followed by a 15-minute wait and re-measurement of blood glucose level to assess if blood glucose has returned to normal levels.<ref name=":2" />

Self-treatment

If an individual recognizes the symptoms of hypoglycemia coming on, blood sugar should promptly be measured, and a sugary food or drink should be consumed.<ref name="NIH2008" /> The person must be conscious and able to swallow.<ref name="NIH2008" /><ref name="Jameson_2018" /> The goal is to consume 10–20 grams of a carbohydrate to raise blood glucose levels to a minimum of 70 mg/dL (3.9 mmol/L).<ref name="Jameson_2018" /><ref name="Cry2009" />

Examples of products to consume are:

• Glucose tabs or gel (refer to instructions on packet)<ref name="NIH2008" /><ref name="Cry2009" />
• Juice containing sugar like apple, grape, or cranberry juice, Template:Cups<ref name="NIH2008" /><ref name="Cry2009" />
• Soda or a soft-drink, Template:Cups (not diet soda)<ref name="Cry2009" />
• Candy<ref name="Cry2009" />
• Table sugar or honey, Template:TbspUS<ref name="NIH2008" />

Improvement in blood sugar levels and symptoms are expected to occur in 15–20 minutes, at which point blood sugar should be measured again.<ref name="Jameson_2018" /><ref name="Cry2009" /> If the repeat blood sugar level is not above 70 mg/dL (3.9 mmol/L), consume another 10–20 grams of a carbohydrate and remeasure blood sugar levels after 15–20 minutes.<ref name="Jameson_2018" /><ref name="Cry2009" /> Repeat until blood glucose levels have returned to normal levels.<ref name="Jameson_2018" /><ref name="Cry2009" /> The greatest improvements in blood glucose will be seen if the carbohydrate is chewed or drunk, and then swallowed.<ref name=":5">Template:Cite journal</ref> This results in the greatest bioavailability of glucose, meaning the greatest amount of glucose enters the body producing the best possible improvements in blood glucose levels.<ref name=":5" /> A 2019 systematic review suggests, based on very limited evidence, that oral administration of glucose leads to a bigger improvement in blood glucose levels when compared to buccal administration.<ref name=":13">Template:Cite journal</ref> This same review reported that, based on limited evidence, no difference was found in plasma glucose when administering combined oral and buccal glucose (via dextrose gel) compared to only oral administration.<ref name=":13" /> The second best way to consume a carbohydrate it to allow it to dissolve under the tongue, also referred to as sublingual administration.<ref name=":5" /> For example, a hard candy can be dissolved under the tongue, however the best improvements in blood glucose will occur if the hard candy is chewed and crushed, then swallowed.<ref name=":5" />

After correcting blood glucose levels, people may consume a full meal within one hour to replenish glycogen stores.<ref name="Cry2009" />

Education

Family, friends, and co-workers of a person with diabetes may provide life-saving treatment in the case of a hypoglycemic episode.<ref name="NIH2008" /> It is important for these people to receive training on how to recognize hypoglycemia, what foods to help the hypoglycemic eat, how to administer injectable or intra-nasal glucagon, and how to use a glucose meter.<ref name="NIH2008" />

File:GlucaGen.jpg

A glucagon kit used to treat severe hypoglycemia

Treatment by family, friends, or co-workers

Family, friends, and co-workers of those with hypoglycemia are often first to identify hypoglycemic episodes, and may offer help.<ref name="Jameson_2018" /> Upon recognizing the signs and symptoms of hypoglycemia in a diabetic, a blood sugar level should first be measured using a glucose meter.<ref name="NIH2008" /> If blood glucose is below 70 mg/dL (3.9 mmol/L), treatment will depend on whether the person is conscious and can swallow safely.<ref name="Jameson_2018" /><ref name="Cry2009" /> If the person is conscious and able to swallow, the family, friend, or co-worker can help the hypoglycemic consume 10–20 grams of a carbohydrate to raise blood glucose levels to a minimum of 70 mg/dL (3.9 mmol/L).<ref name="Cry2009" /> Improvement in blood sugar level and symptoms is expected to occur in 15–20 minutes, at which point blood sugar is measured again.<ref name="Jameson_2018" /><ref name="Cry2009" /> If the repeat blood sugar level is not above 70 mg/dL (3.9 mmol/L), the hypoglycemic should consume another 10–20 grams of a carbohydrate and with remeasurement of blood sugar levels after 15–20 minutes.<ref name="Jameson_2018" /><ref name="Cry2009" /> Repeat until blood glucose levels have returned to normal levels, or call emergency services for further assistance.<ref name="Cry2009" />

If the person is unconscious, a glucagon kit may be used to treat severe hypoglycemia, which delivers glucagon either by injection into a muscle or through nasal inhalation.<ref name="Cry2009" /><ref name="Jameson_2018" /><ref name=":10" /> In the United States, glucacon kits are available by prescription for diabetic patients to carry in case of an episode of severe hypoglycemia.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Emergency services should be called for further assistance.<ref name="Cry2009" />

Treatment by medical professionals

In a healthcare setting, treatment depends on the severity of symptoms and intravenous access.<ref name=":6">Template:Cite journal</ref> If a patient is conscious and able to swallow safely, food or drink may be administered, as well as glucose tabs or gel.<ref name=":6" /> In those with intravenous access, 25 grams of 50% dextrose is commonly administered.<ref name=":6" /> When there is no intravenous access, intramuscular or intra-nasal glucagon may be administered.<ref name=":6" />

Other treatments

While the treatment of hypoglycemia is typically managed with carbohydrate consumption, glucagon injection, or dextrose administration, there are some other treatments available.<ref name="Jameson_2018" /> Medications like diazoxide and octreotide decrease insulin levels, increasing blood glucose levels.<ref name="Jameson_2018" /> Dasiglucagon was approved for medical use in the United States in March 2021, to treat severe hypoglycemia.<ref name="Zegalogue FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Dasiglucagon (brand name Zegalogue) is unique because it is glucagon in a prefilled syringe or auto-injector pen, as opposed to traditional glucagon kits that require mixing powdered glucagon with a liquid.<ref name="Zegalogue FDA label" />

Due to its original formulation containing large amounts of glucose, the soft drink Lucozade was recommended by diabetes charities in the United Kingdom as an immediate treatment for hypoglycemia; however, as the drink was reformulated to replace much of its glucose content with artificial sweeteners, this is no longer recommended.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Prevention

File:Insulin pump with infusion set.jpg

An insulin pump used to deliver appropriate levels of insulin

Diabetics

The prevention of hypoglycemia depends on the cause.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /> In those with diabetes treated by insulin, glinides, or sulfonylurea, the prevention of hypoglycemia has a large focus on patient education and medication adjustments.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /> The foundation of diabetes education is learning how to recognize the signs and symptoms of hypoglycemia, as well as learning how to act quickly to prevent worsening of an episode.<ref name="Cry2009" /> Another cornerstone of prevention is strong self-monitoring of blood glucose, with consistent and frequent measurements.<ref name="Cry2009" /> Research has shown that patients with type 1 diabetes who use continuous glucose monitoring systems with insulin pumps significantly improve blood glucose control.<ref>Template:Cite journal</ref><ref name=":4">Template:Cite journal</ref><ref name=":16">Template:Cite journal</ref> Insulin pumps help to prevent high glucose spikes, and help prevent inappropriate insulin dosing.<ref name=":4" /><ref name=":16" /><ref name=":0">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Continuous glucose monitors can sound alarms when blood glucose is too low or too high, especially helping those with nocturnal hypoglycemia or hypoglycemic unawareness.<ref name=":4" /><ref name=":16" /><ref name=":0" /> In terms of medication adjustments, medication doses and timing can be adjusted to prevent hypoglycemia, or a medication can be stopped altogether.<ref name="Jameson_2018" /><ref name="Cry2009" />

Non-diabetics

In those with hypoglycemia who do not have diabetes, there are a number of preventative measures dependent on the cause.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /> Hypoglycemia caused by hormonal dysfunction like lack of cortisol in Addison's disease or lack of growth hormone in hypopituitarism can be prevented with appropriate hormone replacement.<ref name="Jameson_2018" /><ref name="Cry2009" /> The hypoglycemic episodes associated with non-B cell tumors can be decreased following surgical removal of the tumor, as well as following radiotherapy or chemotherapy to reduce the size of the tumor.<ref name="Jameson_2018" /><ref name="Cry2009" /> In some cases, those with non-B cell tumors may have hormone therapy with growth hormone, glucocorticoid, or octreotide to also lessen hypoglycemic episodes.<ref name="Jameson_2018" /><ref name="Cry2009" /> Post-gastric bypass hypoglycemia can be prevented by eating smaller, more frequent meals, avoiding sugar-filled foods, as well as medical treatment with an alpha-glucosidase inhibitor, diazoxide, or octreotide.<ref name="Jameson_2018" /><ref name="Cry2009" />

Some causes of hypoglycemia require treatment of the underlying cause to best prevent hypoglycemia.<ref name="Cry2009" /> This is the case for insulinomas which often require surgical removal of the tumor for hypoglycemia to remit.<ref name="Cry2009" /> In patients who cannot undergo surgery for removal of the insulinoma, diazoxide or octreotide may be used.<ref name="Cry2009" />

Epidemiology

Hypoglycemia is common in people with type 1 diabetes, and in people with type 2 diabetes taking insulin, glinides, or sulfonylurea.<ref name="NIH2008" /><ref name="Jameson_2018" /> It is estimated that type 1 diabetics experience two mild, symptomatic episodes of hypoglycemia per week.<ref name="Jameson_2018" /> Additionally, people with type 1 diabetes have at least one severe hypoglyemic episode per year, requiring treatment assistance.<ref name="Jameson_2018" /> In terms of mortality, hypoglycemia causes death in 6–10% of type 1 diabetics.<ref name="Jameson_2018" />Template:Verify source

In those with type 2 diabetes, hypoglycemia is less common compared to type 1 diabetics, because medications that treat type 2 diabetes like metformin, glitazones, alpha-glucosidase inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase IV inhibitors, do not cause hypoglycemia.<ref name="NIH2008" /><ref name="Jameson_2018" /> Hypoglycemia is common in type 2 diabetics who take insulin, glinides, or sulfonylurea.<ref name="NIH2008" /><ref name="Jameson_2018" /> Insulin use remains a key risk factor in developing hypoglycemia, regardless of diabetes type.<ref name="NIH2008" /><ref name="Jameson_2018" />

History

Hypoglycemia was first discovered by James Collip when he was working with Frederick Banting on purifying insulin in 1922.<ref name=":1" /> Collip was asked to develop an assay to measure the activity of insulin.<ref name=":1" /> He first injected insulin into a rabbit, and then measured the reduction in blood-glucose levels.<ref name=":1" /> Measuring blood glucose was a time-consuming step.<ref name=":1" /> Collip observed that if he injected rabbits with a too large a dose of insulin, the rabbits began convulsing, went into a coma, and then died.<ref name=":1" /> This observation simplified his assay.<ref name=":1" /> He defined one unit of insulin as the amount necessary to induce this convulsing hypoglycemic reaction in a rabbit.<ref name=":1" /> Collip later found he could save money, and rabbits, by injecting them with glucose once they were convulsing.<ref name=":1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Etymology

The word hypoglycemia is also spelled hypoglycaemia or hypoglycæmia. The term means 'low blood sugar' from Greek ὑπογλυκαιμία, from ὑπο- hypo- 'under' + γλυκύς glykys 'sweet' + αἷμᾰ haima 'blood'.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

External links

• Hypoglycemia at the Mayo Clinic
• American Diabetes Association
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