View source for Medicine:Hypoglycemia

{{Short description|Health condition}}
{{Infobox medical condition (new)
| name          = Hypoglycemia
| synonyms      = Hypoglycaemia, hypoglycæmia, low blood glucose, low blood sugar
| image         = Glucose test.JPG
| caption       = [[Engineering:Glucose meter|Glucose meter]]
| field         = [[Biology:Endocrinology|Endocrinology]]
| complications =
| onset         = Rapid<ref name=NIH2008/>
| duration      =
| causes        = Medications ([[Biology:Insulin|insulin]], glinides and [[Chemistry:Sulfonylurea|sulfonylurea]]s), [[Medicine:Sepsis|sepsis]], [[Medicine:Kidney failure|kidney failure]], certain tumors, liver disease<ref name=NIH2008/><ref name=ReferenceA/>
| risks         =
| diagnosis     = Whipple's triad: Symptoms of hypoglycemia, serum blood glucose level <70 mg/dL (3.9 mmol/L), and resolution of symptoms when blood glucose returns to normal <ref name="Cry2009" />
| differential  =
| prevention    =
| treatment     = Eating foods high in simple sugars, dextrose, [[Medicine:Glucagon (medication)|glucagon]]<ref name=NIH2008/>
| medication    =
| prognosis     =
| frequency     = In type 1 diabetics, mild hypoglycemia occurs twice per week on average, and severe hypoglycemia occurs once per year.<ref name="Jameson_2018">{{Cite book|url=https://www.worldcat.org/oclc/1029074059|title=Harrison's principles of internal medicine|date=2018|vauthors=Jameson JL, Kasper DL, Longo DL, Fauci AS, Hauser SL, Loscalzo J|isbn=978-1-259-64403-0|edition=20th|location=New York|oclc=1029074059|access-date=12 January 2022|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829112440/https://www.worldcat.org/title/harrisons-principles-of-internal-medicine/oclc/1029074059|url-status=live}}</ref>
| deaths        = In type 1 diabetics, 6–10% will die of hypoglycemia.<ref name="Jameson_2018" />
}}
<!-- Definition and symptoms -->
'''Hypoglycemia''', also called '''low blood sugar''', is a fall in blood sugar to levels below normal, typically below 70&nbsp;mg/dL (3.9&nbsp;mmol/L).<ref name=NIH2008/><ref name="Jameson_2018" /> Whipple's triad is used to properly identify hypoglycemic episodes.<ref name="Cry2009" /> It is defined as blood glucose below 70&nbsp;mg/dL (3.9&nbsp;mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal.<ref name="Cry2009">{{cite journal | vauthors = Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ | title = Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 3 | pages = 709–728 | date = March 2009 | pmid = 19088155 | doi = 10.1210/jc.2008-1410 | doi-access = free }}</ref> Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, [[Medicine:Confusion|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">{{Cite web|title=Low Blood Glucose (Hypoglycemia) |author=National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |url=https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/low-blood-glucose-hypoglycemia|access-date=12 January 2022|website=NIDDK.nih.gov|language=en-US|archive-date=28 July 2017|archive-url=https://web.archive.org/web/20170728180001/https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/low-blood-glucose-hypoglycemia|url-status=live}}</ref>

<!-- Cause -->
The most common cause of hypoglycemia is medications used to treat diabetes such as [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Sulfonylurea|sulfonylurea]]s, and [[Chemistry:Biguanide|biguanide]]s.<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name="ReferenceA">{{cite journal | vauthors = Yanai H, Adachi H, Katsuyama H, Moriyama S, Hamasaki H, Sako A | title = Causative anti-diabetic drugs and the underlying clinical factors for hypoglycemia in patients with diabetes | journal = World Journal of Diabetes | volume = 6 | issue = 1 | pages = 30–36 | date = February 2015 | pmid = 25685276 | pmc = 4317315 | doi = 10.4239/wjd.v6.i1.30 | doi-access = free }}</ref> Risk is greater in diabetics who have eaten less than usual, recently exercised, or consumed [[Chemistry:Ethanol|alcohol]].<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009"/> Other causes of hypoglycemia include severe illness, [[Medicine:Sepsis|sepsis]], [[Medicine:Kidney failure|kidney failure]], liver disease, [[Biology:Hormone|hormone]] deficiency, tumors such as [[Medicine:Insulinoma|insulinoma]]s or non-B cell tumors, inborn errors of metabolism, several medications, and alcohol.<ref name=NIH2008/><ref name="Jameson_2018" /><ref name="Cry2009" /> Low blood sugar may occur in otherwise healthy newborns who have not eaten for a few hours.<ref name=":7" />

<!-- Prevention, treatment, and society-->
Hypoglycemia is treated by eating a sugary food or drink, for example glucose tablets or gel, apple juice, soft drink, or lollies.<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009"/> The person must be [[Philosophy:Consciousness|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&nbsp;mg/dL (3.9&nbsp;mmol/L).<ref name="Jameson_2018" /><ref name="Cry2009" /> If a person is not able to take food by mouth, [[Medicine:Glucagon (medication)|glucagon]] by injection or insufflation may help.<ref name=NIH2008/><ref name="Jameson_2018" /><ref>{{cite web |title=FDA approves first treatment for severe hypoglycemia that can be administered without an injection |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-severe-hypoglycemia-can-be-administered-without-injection |website=FDA |access-date=11 November 2019 |language=en |date=11 September 2019 |archive-date=17 May 2020 |archive-url=https://web.archive.org/web/20200517061659/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-severe-hypoglycemia-can-be-administered-without-injection |url-status=live }}</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 [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Sulfonylurea|sulfonylurea]]s, and [[Chemistry:Biguanide|biguanide]]s 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 ==
Blood sugar levels naturally fluctuate throughout the day, however ''hypoglycemia'', also called ''low blood sugar'' or ''low blood glucose,'' is when blood sugar levels drop below 70&nbsp;mg/dL (3.9&nbsp;mmol/L).<ref name="Jameson_2018" /><ref name=":2" />

Blood sugar levels are generally maintained between 70 and 110&nbsp;mg/dL (3.9–6.1&nbsp;mmol/L).<ref name="Jameson_2018" /><ref name="Cry2009" /> Although 70&nbsp;mg/dL (3.9&nbsp;mmol/L) is the lower limit of normal glucose, symptoms of hypoglycemia usually do not occur until 55&nbsp;mg/dL (3.0&nbsp;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&nbsp;mg/dL is also not specific enough 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:

# The signs and symptoms of hypoglycemia are present (see section below on ''Signs and Symptoms'')<ref name="Cry2009" />
# A low blood glucose measurement is present, typically less than 70&nbsp;mg/dL (3.9&nbsp;mmol/L)<ref name="Cry2009" />
# 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">{{cite journal | vauthors = Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Rozance PJ, Simmons RA, Sperling MA, Weinstein DA, White NH, Wolfsdorf JI | display-authors = 6 | title = Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children | language = English | journal = The Journal of Pediatrics | volume = 167 | issue = 2 | pages = 238–245 | date = August 2015 | pmid = 25957977 | doi = 10.1016/j.jpeds.2015.03.057 | s2cid = 10681217 | doi-access = free }}</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 [[Biology:Glucagon|glucagon]] and [[Biology:Adrenaline|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&nbsp;mg/dL (3.0–3.6&nbsp;mmol/L).<ref name=":7"/> This is contrasted by the value in adults, children, and older infants, which is approximately 80–85&nbsp;mg/dL (4.4–4.7&nbsp;mmol/L).<ref name=":7"/>

In children who are aged greater than 48 hours, serum glucose on average ranges from 70 to 100&nbsp;mg/dL (3.9–5.5&nbsp;mmol/L), similar to adults.<ref name=":7" /> Whipple's triad is used to identify hypoglycemia in children who can communicate their symptoms.<ref name=":7"/>

== Differential diagnosis ==
Other conditions that may present at the same time as hypoglycemia include the following:
* Alcohol or [[Medicine:Substance intoxication|drug intoxication]]<ref name="Cry2009" /><ref name=":3">{{Cite web|vauthors=Vella A|title=Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes|url=https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-clinical-manifestations-diagnosis-and-causes|url-status=live|access-date=14 January 2022|website=www.uptodate.com|archive-date=26 January 2022|archive-url=https://web.archive.org/web/20220126212612/https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-clinical-manifestations-diagnosis-and-causes?sectionName=DIFFERENTIAL+DIAGNOSIS&search=hypoglycemia+differential&topicRef=1798&anchor=H18546202&source=see_link#H18546202}}</ref>
* [[Medicine:Arrhythmia|Cardiac arrhythmia]]<ref name="Cry2009" /><ref name=":3"/>
* [[Medicine:Valvular heart disease|Valvular heart disease]]<ref name="Cry2009" /><ref name=":3"/>
* Postprandial syndrome<ref name=":3"/>
* [[Medicine:Hyperthyroidism|Hyperthyroidism]]<ref name=":3"/>
* [[Medicine:Pheochromocytoma|Pheochromocytoma]]<ref name=":3"/>
* Post-gastric bypass hypoglycemia<ref name="Cry2009" /><ref name=":3"/>
* [[Medicine:Generalized anxiety disorder|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 name=":3"/>

==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 [[Medicine:Neuroglycopenia|neuroglycopenic]] symptoms.<ref name="Jameson_2018" /> The second category of symptoms is caused by the body's reaction to low glucose in the brain, called [[Biology:Adrenergic|adrenergic]] symptoms.<ref name="Jameson_2018" />
{| class="wikitable"
!Neuroglycopenic symptoms
!Adrenergic symptoms
|-
|
* [[Medicine:Headache|Headache]]
* Blurred vision
* Tiredness (also called ''[[Medicine:Fatigue|fatigue]]'')
* Unusual behavior
* [[Medicine:Confusion|Confusion]]
* Lightheadedness
* Difficulty speaking or slurred speech
* [[Medicine:Seizure|Seizure]]s
* [[Medicine:Unconsciousness|Loss of consciousness]] (sometimes called ''passing out'')
* Death, if severe hypoglycemia
|
* [[Medicine:Tachycardia|Fast heart rate]]
* Pounding heartbeat (also called ''[[Medicine:Palpitations|palpitations]]'')
* [[Medicine:Perspiration|Sweating]]
* Clamminess
* Tremors
* Nervousness (also called ''[[Medicine:Anxiety|anxiety]]'')
* Hunger
* Irritability (also called being ''hangry'')
* Nausea
* [[Unsolved:Paresthesia|Pins and needles sensation]]
* Pale skin color
|-
| colspan="2" |References:<ref name="NIH2008" /><ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":2" /><ref name="Young_2016">{{Cite book|vauthors=Young VB|url=https://www.worldcat.org/oclc/909025539|title=Blueprints medicine|date=2016|others=William A. Kormos, Davoren A. Chick|isbn=978-1-4698-6415-0|edition=6th|location=Philadelphia|oclc=909025539|access-date=12 January 2022|archive-date=26 January 2022|archive-url=https://web.archive.org/web/20220126212651/https://www.worldcat.org/title/blueprints-medicine/oclc/909025539|url-status=live}}</ref><ref>{{Cite web |title=Hangry is officially a word in the Oxford English Dictionary |url=https://abcnews.go.com/GMA/Food/hangry-officially-word-oxford-english-dictionary/story?id=52869807 |access-date=2024-01-06 |website=ABC News |language=en}}</ref><ref>{{Cite news |date=2018-07-09 |title=If you've ever been hangry, this is what your body may be telling you |url=https://www.washingtonpost.com/national/health-science/if-youve-ever-been-hangry-this-is-what-your-body-may-be-telling-you/2018/07/06/913a474e-73d2-11e8-805c-4b67019fcfe4_story.html |access-date=2024-01-06 |newspaper=Washington Post |language=en-US |issn=0190-8286}}</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" />

==Pathophysiology==
[[Chemistry:Glucose|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 [[Biology:Insulin|insulin]] production and release, adjust glucose production by the [[Biology:Liver|liver]], and adjust glucose use by the body.<ref name="Jameson_2018" /><ref name=":10" /> The body naturally produces the hormone [[Biology:Insulin|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" /> [[Biology:Glucagon|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 [[Biology:Insulin|insulin]] release by the pancreas.<ref name="Jameson_2018" /><ref name=":10" /> This drop in insulin allows the [[Biology:Liver|liver]] to increase [[Biology:Glycogenolysis|glycogenolysis]].<ref name="Jameson_2018" /><ref name=":10" /> [[Biology:Glycogenolysis|Glycogenolysis]] is the process of [[Biology:Glycogen|glycogen]] breakdown that results in the production of glucose.<ref name="Jameson_2018" /><ref name=":10" /> [[Biology:Glycogen|Glycogen]] can be thought of as the inactive, storage form of glucose.<ref name="Jameson_2018" /> Decreased insulin also allows for increased [[Biology:Gluconeogenesis|gluconeogenesis]] in the [[Biology:Liver|liver]] and kidneys.<ref name="Jameson_2018" /><ref name=":10" /> [[Biology:Gluconeogenesis|Gluconeogenesis]] is the process of glucose production from non-[[Chemistry:Carbohydrate|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 [[Biology:Glucagon|glucagon]], a [[Biology:Hormone|hormone]] that increases glucose production by the liver and kidneys, and increases muscle and fat breakdown to supply [[Biology:Gluconeogenesis|gluconeogenesis]].<ref name="Jameson_2018" /><ref>{{cite book | vauthors = Rix I, Nexøe-Larsen C, Bergmann NC, Lund A, Knop FK | chapter = Glucagon Physiology |date=2000 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK279127/| title = Endotext| pmid = 25905350 | veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, etal |archive-date=15 January 2021|archive-url=https://web.archive.org/web/20210115103349/https://www.ncbi.nlm.nih.gov/books/NBK279127/|url-status=live}}</ref> If increased glucagon does not raise blood sugar levels to normal, the adrenal glands release [[Biology:Adrenaline|epinephrine]].<ref name="Jameson_2018" /><ref name=":10" /> [[Biology:Adrenaline|Epinephrine]] works to also increase [[Biology:Gluconeogenesis|gluconeogenesis]] and [[Biology:Glycogenolysis|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, [[Chemistry:Cortisol|cortisol]] and [[Biology:Growth hormone|growth hormone]] are released to continue [[Biology:Gluconeogenesis|gluconeogenesis]] and [[Biology:Glycogenolysis|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" />

==Causes==
{{main|List of causes of hypoglycemia}}Hypoglycemia is most common in those with diabetes treated by [[Chemistry:Insulin (medication)|insulin]], glinides, and [[Chemistry:Sulfonylurea|sulfonylurea]]s.<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 [[Chemistry:Glucose|glucose]], [[Chemistry:Insulin (medication)|insulin]], and [[Biology:Glucagon|glucagon]].<ref name="Jameson_2018" /><ref name="Cry2009" /> Please refer to ''Pathophysiology'' section (above) for more information on [[Chemistry:Glucose|glucose]], [[Chemistry:Insulin (medication)|insulin]], and [[Biology:Glucagon|glucagon]].

=== Diabetics ===

==== Medications ====
The most common cause of hypoglycemia in diabetics is medications used to treat diabetes such as [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Sulfonylurea|sulfonylurea]]s, and [[Chemistry:Biguanide|biguanide]]s.<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">{{cite journal | vauthors = Johnson-Rabbett B, Seaquist ER | title = Hypoglycemia in diabetes: The dark side of diabetes treatment. A patient-centered review | journal = Journal of Diabetes | volume = 11 | issue = 9 | pages = 711–718 | date = September 2019 | pmid = 30983138 | doi = 10.1111/1753-0407.12933 | s2cid = 115202581 }}</ref><ref name=":19">{{cite journal | vauthors = Ibrahim M, Baker J, Cahn A, Eckel RH, El Sayed NA, Fischl AH, Gaede P, Leslie RD, Pieralice S, Tuccinardi D, Pozzilli P, Richelsen B, Roitman E, Standl E, Toledano Y, Tuomilehto J, Weber SL, Umpierrez GE | display-authors = 6 | title = Hypoglycaemia and its management in primary care setting | journal = Diabetes/Metabolism Research and Reviews | volume = 36 | issue = 8 | pages = e3332 | date = November 2020 | pmid = 32343474 | doi = 10.1002/dmrr.3332 | s2cid = 216594548 | url = https://findresearcher.sdu.dk/ws/files/170369949/dmrr.3332.pdf }}</ref><ref name=":20">{{cite journal | vauthors = Martín-Timón I, Del Cañizo-Gómez FJ | title = Mechanisms of hypoglycemia unawareness and implications in diabetic patients | journal = World Journal of Diabetes | volume = 6 | issue = 7 | pages = 912–926 | date = July 2015 | pmid = 26185599 | pmc = 4499525 | doi = 10.4239/wjd.v6.i7.912 | doi-access = free }}</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&nbsp;mg/dL (3.0&nbsp;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>{{cite journal | vauthors = Lucidi P, Porcellati F, Bolli GB, Fanelli CG | title = Prevention and Management of Severe Hypoglycemia and Hypoglycemia Unawareness: Incorporating Sensor Technology | journal = Current Diabetes Reports | volume = 18 | issue = 10 | pages = 83 | date = August 2018 | pmid = 30121746 | doi = 10.1007/s11892-018-1065-6 | s2cid = 52039366 }}</ref>

==== Other causes ====
Other causes of hypoglycemia in diabetics include the following:
* Fasting, whether it be a planned [[Philosophy:Fasting|fast]] or overnight [[Philosophy:Fasting|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" />
* [[Medicine:Kidney disease|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">{{cite book|vauthors=Mathew P, Thoppil D|chapter=Hypoglycemia|date=2022|chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK534841/|title=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=30521262|access-date=24 January 2022|archive-date=30 August 2021|archive-url=https://web.archive.org/web/20210830033137/https://www.ncbi.nlm.nih.gov/books/NBK534841/|url-status=live}}</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 [[Medicine:Intensive care unit|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" />

[[Medicine:Sepsis|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 [[Biology:Cytokine|cytokine]] production.<ref name="Jameson_2018" /> [[Biology:Cytokine|Cytokine]]s are a protein produced by the body in a state of stress, particularly when fighting an infection.<ref name="Jameson_2018" /> [[Biology:Cytokine|Cytokine]]s may inhibit glucose production, further decreasing the body's energy stores.<ref name="Jameson_2018" /> Finally, the [[Biology:Liver|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 [[Biology:Liver|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">{{cite journal | vauthors = Murad MH, Coto-Yglesias F, Wang AT, Sheidaee N, Mullan RJ, Elamin MB, Erwin PJ, Montori VM | display-authors = 6 | title = Clinical review: Drug-induced hypoglycemia: a systematic review | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 3 | pages = 741–745 | date = March 2009 | pmid = 19088166 | doi = 10.1210/jc.2008-1416 }}</ref> Moderate quality evidence implicates the [[Chemistry:Nonsteroidal anti-inflammatory drug|non-steroidal anti-inflammatory]] drug [[Chemistry:Indometacin|indomethacin]] and the anti-malarial [[Chemistry:Quinine|quinine]].<ref name="Jameson_2018" /><ref name="Cry2009" /><ref name=":8" /> Low quality evidence implicates [[Chemistry:Lithium (medication)|lithium]], used for [[Medicine:Bipolar disorder|bipolar disorder]].<ref name="Cry2009" /><ref name=":8" /> Finally, very low quality evidence implicates a number of [[Medicine:Hypertension|hypertension]] medications including angiotensin converting enzyme inhibitors (also called ACE-inhibitors), [[Chemistry:Angiotensin II receptor blocker|angiotensin receptor blockers]] (also called ARBs), and [[Chemistry:Beta blocker|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 [[Chemistry:Levofloxacin|levofloxacin]] and trimethoprim-sulfamethoxazole, progesterone blocker [[Biology:Mifepristone|mifepristone]], anti-arrhythmic [[Chemistry:Disopyramide|disopyramide]], anti-coagulant [[Chemistry:Heparin|heparin]], and chemotherapeutic [[Chemistry:Mercaptopurine|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 [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Meglitinide|glinides]], and [[Chemistry:Sulfonylurea|sulfonylurea]]s.<ref name="Jameson_2018" /><ref name="Cry2009" /> This may occur through medical errors in a healthcare setting or through pharmacy errors, also called [[Medicine:Iatrogenesis|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">{{cite book|vauthors=Awad DH, Gokarakonda SB, Ilahi M|chapter=Factitious Hypoglycemia|date=2022|chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK542310/|title=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=31194450|access-date=21 January 2022|archive-date=26 January 2022|archive-url=https://web.archive.org/web/20220126212626/https://www.ncbi.nlm.nih.gov/books/NBK542310/|url-status=live}}</ref> Some people may use insulin to induce weight loss, whereas for others this may be due to [[Medicine:Malingering|malingering]] or [[Medicine:Factitious disorder|factitious disorder]], which is a psychiatric disorder.<ref name=":9" /> Demographics affected by factitious hypoglycemia include women aged 30–40, particularly those with diabetes, relatives with diabetes, healthcare workers, or those with history of a psychiatric disorder.<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 [[Chemistry:C-peptide|C-peptide]] and [[Biology:Proinsulin|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 [[Biology:Glycogen|glycogen]] becomes depleted in a state of [[Medicine:Starvation|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 [[Medicine:Addison's disease|Addison's disease]], may experience hypoglycemia after long periods of [[Philosophy:Fasting|fasting]].<ref name="Jameson_2018" /> [[Medicine:Addison's disease|Addison's disease]] is associated with chronically low levels of the stress hormone [[Chemistry:Cortisol|cortisol]], which leads to decreased glucose production.<ref name="Jameson_2018" />

[[Medicine:Hypopituitarism|Hypopituitarism]], leading to decreased [[Biology:Growth hormone|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, [[Biology:Inborn errors of metabolism|inborn errors of metabolism]] are a group of rare [[Medicine:Genetic disorder|genetic disorder]]s that are associated with the improper breakdown or storage of [[Biology:Protein|protein]]s, [[Chemistry:Carbohydrate|carbohydrate]]s, or [[Chemistry:Fatty acid|fatty acid]]s.<ref name=":11">{{cite book|vauthors=Jeanmonod R, Asuka E, Jeanmonod D|chapter=Inborn Errors Of Metabolism|date=2022|chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK459183/|title=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29083820|access-date=24 January 2022|archive-date=13 October 2021|archive-url=https://web.archive.org/web/20211013135517/https://www.ncbi.nlm.nih.gov/books/NBK459183/|url-status=live}}</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 [[Medicine:Glycogen storage disease|''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 [[Medicine:Glycogen storage disease|glycogen storage disease]]s 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 [[Medicine:Glycogen storage disease type 0|type 0]], [[Medicine:Glycogen storage disease type I|type I]], [[Medicine:Glycogen storage disease type III|type III]], and [[Medicine:Glycogen storage disease type IV|type IV]], as well as [[Medicine:Fanconi syndrome|Fanconi syndrome]].<ref name="Jameson_2018" />

Some [[Medicine:Organic acidemia|organic]] and amino acid acidemias, especially those involving the oxidation of fatty acids, can lead to the symptom of intermittent hypoglycemia,<ref name=":14">{{Cite journal |last=Ozand |first=Pinar T. |date=2000 |title=Hypoglycemia in association with various organic and amino acid disorders |url=https://linkinghub.elsevier.com/retrieve/pii/S0146000500800324 |journal=Seminars in Perinatology |language=en |volume=24 |issue=2 |pages=172–193 |doi=10.1053/sp.2000.6367|pmid=10805172 }}</ref> as for example in [[Medicine:Combined malonic and methylmalonic aciduria|combined malonic and methylmalonic aciduria]] (CMAMMA),<ref>{{Cite journal |last1=NIH Intramural Sequencing Center Group |last2=Sloan |first2=Jennifer L |last3=Johnston |first3=Jennifer J |last4=Manoli |first4=Irini |last5=Chandler |first5=Randy J |last6=Krause |first6=Caitlin |last7=Carrillo-Carrasco |first7=Nuria |last8=Chandrasekaran |first8=Suma D |last9=Sysol |first9=Justin R |last10=O'Brien |first10=Kevin |last11=Hauser |first11=Natalie S |last12=Sapp |first12=Julie C |last13=Dorward |first13=Heidi M |last14=Huizing |first14=Marjan |last15=Barshop |first15=Bruce A |date=2011 |title=Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria |journal=Nature Genetics |language=en |volume=43 |issue=9 |pages=883–886 |doi=10.1038/ng.908 |issn=1061-4036 |pmc=3163731 |pmid=21841779}}</ref><ref>{{Cite journal |last1=Wehbe |first1=Zeinab |last2=Behringer |first2=Sidney |last3=Alatibi |first3=Khaled |last4=Watkins |first4=David |last5=Rosenblatt |first5=David |last6=Spiekerkoetter |first6=Ute |last7=Tucci |first7=Sara |date=2019 |title=The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism |url=https://linkinghub.elsevier.com/retrieve/pii/S1388198119301349 |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |language=en |volume=1864 |issue=11 |pages=1629–1643 |doi=10.1016/j.bbalip.2019.07.012|pmid=31376476 |s2cid=199404906 }}</ref><ref>{{Cite journal |last1=Levtova |first1=Alina |last2=Waters |first2=Paula J. |last3=Buhas |first3=Daniela |last4=Lévesque |first4=Sébastien |last5=Auray-Blais |first5=Christiane |last6=Clarke |first6=Joe T.R. |last7=Laframboise |first7=Rachel |last8=Maranda |first8=Bruno |last9=Mitchell |first9=Grant A. |last10=Brunel-Guitton |first10=Catherine |last11=Braverman |first11=Nancy E. |date=2019 |title=Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort |url=https://onlinelibrary.wiley.com/doi/10.1002/jimd.12032 |journal=Journal of Inherited Metabolic Disease |language=en |volume=42 |issue=1 |pages=107–116 |doi=10.1002/jimd.12032 |pmid=30740739 |s2cid=73436689 |issn=0141-8955}}</ref> [[Medicine:Propionic acidemia|propionic acidemia]]<ref name=":15">{{Citation |last1=Ozand |first1=Pinar T. |title=Disorders of Organic Acid and Amino Acid Metabolism |date=2012 |url=http://link.springer.com/10.1007/978-3-642-02202-9_38 |work=Textbook of Clinical Pediatrics |pages=451–514 |editor-last=Elzouki |editor-first=Abdelaziz Y. |access-date= |place=Berlin, Heidelberg |publisher=Springer Berlin Heidelberg |language=en |doi=10.1007/978-3-642-02202-9_38 |isbn=978-3-642-02201-2 |last2=Al-Essa |first2=Mohammed |editor2-last=Harfi |editor2-first=Harb A. |editor3-last=Nazer |editor3-first=Hisham M. |editor4-last=Stapleton |editor4-first=F. Bruder}}</ref><ref name=":14" /> or isolated [[Medicine:Methylmalonic acidemia|methylmalonic acidemia]].<ref name=":15" /><ref name=":14" />

==== Insulinomas ====
A primary B-cell [[Medicine:Neoplasm|tumor]], such as an [[Medicine:Insulinoma|insulinoma]], is associated with hypoglycemia.<ref name="Jameson_2018" /> This is a tumor located in the pancreas.<ref name="Jameson_2018" /> An insulinoma produces [[Biology:Insulin|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 [[Biology:Insulin|insulin]], [[Chemistry:C-peptide|C-peptide]], and [[Biology:Proinsulin|proinsulin]] will be inappropriately high.<ref name="Jameson_2018" />

==== Non-B cell tumors ====
Hypoglycemia may occur in people with non-B cell [[Medicine:Neoplasm|tumors]] such as hepatomas, adrenocorticoid carcinomas, and [[Medicine:Carcinoid|carcinoid]] tumors.<ref name="Jameson_2018" /> These tumors lead to a state of increased insulin, specifically increased [[Biology:Insulin-like growth factor 2|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 [[Biology:Glucagon-like peptide-1|glucagon-like peptide-1]] (also called GLP-1), a hormone that increases insulin, causing glucose levels to drop.<ref name="Jameson_2018" />

==== Autoimmune hypoglycemia ====
[[Biology:Antibody|Antibodies]] can be formed against insulin, leading to [[Medicine:Autoimmunity|autoimmune]] hypoglycemia.<ref name="Jameson_2018" /><ref name=":12">{{cite journal | vauthors = Lupsa BC, Chong AY, Cochran EK, Soos MA, Semple RK, Gorden P | title = Autoimmune forms of hypoglycemia | language = en-US | journal = Medicine | volume = 88 | issue = 3 | pages = 141–153 | date = May 2009 | pmid = 19440117 | doi = 10.1097/MD.0b013e3181a5b42e | s2cid = 34429211 | doi-access = free }}</ref> [[Biology:Antibody|Antibodies]] are immune cells produced by the body, that normally attack bacteria and viruses, but sometimes can attack normal human cells, leading to an [[Medicine:Autoimmune disease|autoimmune disorder]].<ref>{{Cite web|title=Antibody|url=https://www.genome.gov/genetics-glossary/Antibody|access-date=24 January 2022|website=Genome.gov|language=en|archive-date=9 October 2020|archive-url=https://web.archive.org/web/20201009141818/https://www.genome.gov/genetics-glossary/Antibody|url-status=live}}</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 [[Biology:Receptor (biochemistry)|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 [[Biology:Glucagon|glucagon]] and [[Biology:Adrenaline|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&nbsp;mg/dL (3.9–5.5&nbsp;mmol/L), similar to adults, with hypoglycemia being far less common.<ref name=":7" />

==Diagnostic approach==
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&nbsp;mg/dL (3.9&nbsp;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 [[Medicine:Medical test|diagnostic testing]] and decreases healthcare costs.<ref name="Cry2009" />

In those with a history of diabetes treated with [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Meglitinide|glinides]], or [[Chemistry:Sulfonylurea|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:
* [[Medicine:Blood sugar level|Plasma glucose]] level, not [[Medicine:Point of care|point-of-care]] measurement<ref name="Jameson_2018" /><ref name="Cry2009" />
* Insulin level<ref name="Jameson_2018" /><ref name="Cry2009" />
* [[Chemistry:C-peptide|C-peptide]] level<ref name="Jameson_2018" /><ref name="Cry2009" />
* [[Biology:Proinsulin|Proinsulin]] level<ref name="Jameson_2018" /><ref name="Cry2009" />
* [[Chemistry:Beta-Hydroxybutyric acid|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 [[Biology:Antibody|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 [[Philosophy:Fasting|fast]], in which a patient undergoes an observed fast to cause a hypoglyemic 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 [[Medicine:Insulinoma|insulinoma]], imaging is the most reliable diagnostic technique, including [[Physics:Ultrasound|ultrasound]], [[CT scan|computed tomography]] imaging (also called CT imaging), and [[Physics:Magnetic resonance imaging|magnetic resonsance imaging]] (also called MRI).<ref name="Jameson_2018" /><ref name="Cry2009" />

==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 [[Chemistry:Carbohydrate|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 [[Philosophy:Consciousness|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&nbsp;mg/dL (3.9&nbsp;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, 4 ounces or 1/2 cup<ref name="NIH2008" /><ref name="Cry2009" /> 
* Soda or a soft-drink, 4 ounces or 1/2 cup (not diet soda)<ref name="Cry2009" />
* Candy<ref name="Cry2009" />
* Table sugar or honey, 1 tablespoon<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&nbsp;mg/dL (3.9&nbsp;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">{{cite journal | vauthors = De Buck E, Borra V, Carlson JN, Zideman DA, Singletary EM, Djärv T | title = First aid glucose administration routes for symptomatic hypoglycaemia | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 4 | pages = CD013283 | date = April 2019 | pmid = 30973639 | pmc = 6459163 | doi = 10.1002/14651858.cd013283.pub2 }}</ref> This results in the greatest ''[[Chemistry:Bioavailability|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 [[Medicine:Oral administration|oral administration]] of glucose leads to a bigger improvement in blood glucose levels when compared to [[Medicine:Buccal administration|buccal administration]].<ref name=":13">{{cite journal | vauthors = De Buck E, Borra V, Carlson JN, Zideman DA, Singletary EM, Djärv T | title = First aid glucose administration routes for symptomatic hypoglycaemia | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 4 | pages = CD013283 | date = April 2019 | pmid = 30973639 | pmc = 6459163 | doi = 10.1002/14651858.CD013283.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }}</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 ''[[Medicine:Sublingual administration|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 [[Biology:Glucagon|glucagon]], and how use a [[Engineering:Glucose meter|glucose meter]].<ref name="NIH2008" />

[[File:GlucaGen.jpg|thumb|A glucagon kit used to treat severe hypoglycemia.|421x421px]]

=== 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 [[Engineering:Glucose meter|glucose meter]].<ref name="NIH2008" /> If blood glucose is below 70&nbsp;mg/dL (3.9&nbsp;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 [[Chemistry:Carbohydrate|carbohydrate]] to raise blood glucose levels to a minimum of 70&nbsp;mg/dL (3.9&nbsp;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&nbsp;mg/dL (3.9&nbsp;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 [[Medicine:Glucagon (medication)|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>{{Cite web|title=Severe Low Blood Sugar (Hypoglycemia) Treatment {{!}} Lilly GLUCAGON|url=https://www.lillyglucagon.com/|access-date=24 January 2022|website=www.lillyglucagon.com|archive-date=24 January 2022|archive-url=https://web.archive.org/web/20220124005627/https://www.lillyglucagon.com/|url-status=live}}</ref><ref>{{Cite web|title=Glucacon Emergency Kit|url=https://glucagonemergencykit.com/|access-date=24 January 2022|website=Glucagon Emergency Kit|language=en-US|archive-date=24 January 2022|archive-url=https://web.archive.org/web/20220124033904/https://glucagonemergencykit.com/|url-status=live}}</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 [[Chemistry:Intravenous therapy|intravenous]] access.<ref name=":6">{{cite journal | vauthors = Pasala S, Dendy JA, Chockalingam V, Meadows RY | title = An inpatient hypoglycemia committee: development, successful implementation, and impact on patient safety | journal = The Ochsner Journal | volume = 13 | issue = 3 | pages = 407–412 | date = 2013 | pmid = 24052773 | pmc = 3776519 }}</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 [[Chemistry:Intravenous therapy|intravenous]] access, 25 grams of 50% dextrose is commonly administered.<ref name=":6" /> When there is no intravenous access, [[Biology:Intramuscular injection|intramuscular]] or [[Medicine:Nasal administration|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 [[Chemistry:Diazoxide|diazoxide]] and [[Chemistry:Octreotide|octreotide]] decrease insulin levels, increasing blood glucose levels.<ref name="Jameson_2018" /> [[Chemistry:Dasiglucagon|Dasiglucagon]] was approved for medical use in the United States in March 2021, to treat severe hypoglycemia.<ref name="Zegalogue FDA label">{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214231s000lbl.pdf|title=HIGHLIGHTS OF PRESCRIBING INFORMATION. These highlights do not include all the information needed to use ZEGALOGUE® safely and effectively. See full prescribing information for ZEGALOGUE. ZEGALOGUE (dasiglucagon) injection, for subcutaneous use.|website=Accessdate.fsa.gov|access-date=10 November 2021|archive-date=15 May 2021|archive-url=https://web.archive.org/web/20210515201935/https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214231s000lbl.pdf|url-status=live}}</ref> [[Chemistry:Dasiglucagon|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" />

The soft drink Lucozade has been used for hypoglycemia in the United Kingdom, but it has recently replaced much of its glucose with artificial sweeteners, which do not treat hypoglycemia.<ref>{{cite web |vauthors=Harrold A |title=Diabetic patients should be warned about changes to Lucozade glucose content |url=https://www.nursinginpractice.com/article/diabetic-patients-should-be-warned-about-changes-lucozade-glucose-content |website=Nursing in Practice |access-date=27 February 2019 |archive-date=28 February 2019 |archive-url=https://web.archive.org/web/20190228070127/https://www.nursinginpractice.com/article/diabetic-patients-should-be-warned-about-changes-lucozade-glucose-content |url-status=dead }}</ref>

==Prevention==
[[File:Insulin pump with infusion set.jpg|thumb|258x258px|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 [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Meglitinide|glinides]], or [[Chemistry:Sulfonylurea|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 [[Medicine:Continuous glucose monitor|continuous glucose monitor]]ing systems with [[Engineering:Insulin pump|insulin pump]]s significantly improve blood glucose control.<ref>{{cite journal | vauthors = Langendam M, Luijf YM, Hooft L, Devries JH, Mudde AH, Scholten RJ | title = Continuous glucose monitoring systems for type 1 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD008101 | date = January 2012 | pmid = 22258980 | pmc = 6486112 | doi = 10.1002/14651858.cd008101.pub2 }}</ref><ref name=":4">{{cite journal | vauthors = Azhar A, Gillani SW, Mohiuddin G, Majeed RA | title = A systematic review on clinical implication of continuous glucose monitoring in diabetes management | journal = Journal of Pharmacy & Bioallied Sciences | volume = 12 | issue = 2 | pages = 102–111 | date = 2020 | pmid = 32742108 | pmc = 7373113 | doi = 10.4103/jpbs.JPBS_7_20 | doi-access = free }}</ref><ref name=":16">{{cite journal | vauthors = Mian Z, Hermayer KL, Jenkins A | title = Continuous Glucose Monitoring: Review of an Innovation in Diabetes Management | journal = The American Journal of the Medical Sciences | volume = 358 | issue = 5 | pages = 332–339 | date = November 2019 | pmid = 31402042 | doi = 10.1016/j.amjms.2019.07.003 | s2cid = 199047204 }}</ref> Insulin pumps help to prevent high glucose spikes, and help prevent inappropriate insulin dosing.<ref name=":4" /><ref name=":16" /><ref name=":0">{{Cite web|title=Continuous Glucose Monitoring {{!}} NIDDK|url=https://www.niddk.nih.gov/health-information/diabetes/overview/managing-diabetes/continuous-glucose-monitoring|access-date=25 January 2022|website=National Institute of Diabetes and Digestive and Kidney Diseases|language=en-US|archive-date=12 January 2022|archive-url=https://web.archive.org/web/20220112193835/https://www.niddk.nih.gov/health-information/diabetes/overview/managing-diabetes/continuous-glucose-monitoring|url-status=live}}</ref> [[Medicine:Continuous glucose monitor|Continuous glucose monitor]]s 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 [[Chemistry:Cortisol|cortisol]] in [[Medicine:Addison's disease|Addison's disease]] or lack of [[Biology:Growth hormone|growth hormone]] in [[Medicine:Hypopituitarism|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 [[Physics:Radiation therapy|radiotherapy]] or [[Medicine:Chemotherapy|chemotherapy]] to reduce the size of the [[Medicine:Neoplasm|tumor]].<ref name="Jameson_2018" /><ref name="Cry2009" /> In some cases, those with non-B cell tumors may have [[Medicine:Hormone therapy|hormone therapy]] with [[Biology:Growth hormone|growth hormone]], [[Chemistry:Glucocorticoid|glucocorticoid]], or [[Chemistry:Octreotide|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 [[Biology:Alpha-glucosidase inhibitor|alpha-glucosidase inhibitor]], [[Chemistry:Diazoxide|diazoxide]], or [[Chemistry:Octreotide|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 [[Medicine:Insulinoma|insulinoma]]s 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, [[Chemistry:Diazoxide|diazoxide]] or [[Chemistry:Octreotide|octreotide]] may be used.<ref name="Cry2009" />

== Epidemiology ==
Hypoglycemia is common in people with [[Medicine:Type 1 diabetes|type 1 diabetes]], and in people with [[Medicine:Type 2 diabetes|type 2 diabetes]] taking [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Meglitinide|glinides]], or [[Chemistry:Sulfonylurea|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 rate|mortality]], hypoglycemia causes death in 6–10% of type 1 diabetics.<ref name="Jameson_2018" />{{Verify source|date=June 2022}}

In those with [[Medicine:Type 2 diabetes|type 2 diabetes]], hypoglycemia is less common compared to [[Medicine:Type 1 diabetes|type 1 diabetics]], because medications that treat type 2 diabetes like [[Chemistry:Metformin|metformin]], glitazones, [[Biology:Alpha-glucosidase inhibitor|alpha-glucosidase inhibitor]]s, glucagon-like peptide 1 agonists, and [[Biology:Dipeptidyl-peptidase IV family|dipeptidyl peptidase IV]] inhibitors, do not cause hypoglycemia.<ref name="NIH2008" /><ref name="Jameson_2018" /> Hypoglycemia is common in type 2 diabetics who take [[Chemistry:Insulin (medication)|insulin]], [[Chemistry:Meglitinide|glinides]], or [[Chemistry:Sulfonylurea|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 [[Biography:Frederick Banting|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">{{cite web|title=Collip discovers hypoglycemia|url=https://tacomed.com/chapter-7-standardization/collip-discovers-hypoglycemia/|website=Treating Diabetes|access-date=18 June 2017|url-status=dead|archive-url=https://web.archive.org/web/20170908182717/https://tacomed.com/chapter-7-standardization/collip-discovers-hypoglycemia/|archive-date=8 September 2017}}</ref>

==Etymology==
The word ''hypoglycemia'' is [[Social:American and British English spelling differences#ae and oe|also spelled]] ''hypoglycaemia'' or ''hypoglycæmia''. The term means 'low blood sugar' from [[Social:Greek language|Greek]] ὑπογλυκαιμία, from ὑπο- ''hypo-'' 'under' + γλυκύς ''glykys'' 'sweet' + αἷμᾰ ''haima'' 'blood'.

== References ==
{{Reflist}}

== External links ==
* [http://www.mayoclinic.com/health/hypoglycemia/ds00198/ Hypoglycemia at the Mayo Clinic]
* [https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hypoglycemia American Diabetes Association]
* {{cite web | url = https://medlineplus.gov/hypoglycemia.html | publisher = U.S. National Library of Medicine | work = MedlinePlus | title = Hypoglycemia }}

{{Medical resources
 | DiseasesDB     = 6431
 | ICD11          = {{ICD11|5A21}}, {{ICD11|KB60.4}}, {{ICD11|5A45}}, {{ICD11|8D8D}}, {{ICD11|5A41}}
 | ICD10          = {{ICD10|E16.0}}–{{ICD10|E16.2}}
 | ICD9           = {{ICD9|250.8}}, {{ICD9|251.0}}, {{ICD9|251.1}}, {{ICD9|251.2}}, {{ICD9|270.3}}, {{ICD9|775.6}}, {{ICD9|962.3}}
 | ICDO           =
 | OMIM           =
 | MedlinePlus    = 000386
 | eMedicineSubj  = emerg
 | eMedicineTopic = 272
 | eMedicine_mult = {{eMedicine2|med|1123}} {{eMedicine2|med|1939}} {{eMedicine2|ped|1117}}
 | MeshID         = D007003
}}
{{Blood tests}}

[[Category:Medical emergencies]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Disorders causing seizures]]

{{Sourceattribution|Hypoglycemia}}