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Hypoglycemia

Hypoglycemia is a condition that occurs when the sugar levels in your blood are too low. Many people
think of hypoglycemia as something that only occurs in people with diabetes. However, it can also occur in
people who don’t have diabetes.
Hypoglycemia is different from hyperglycemia, which occurs when you have too much sugar in your
bloodstream. Hypoglycemia can happen in people with diabetes if the body produces too much insulin.
Insulin is a hormone that breaks down sugar so that you can use it for energy. You can also get
hypoglycemia if you have diabetes and you take too much insulin.
If you don’t have diabetes, hypoglycemia can happen if your body can’t stabilize your blood sugar levels. It
can also happen after meals if your body produces too much insulin. Hypoglycemia in people who don’t
have diabetes is less common than hypoglycemia that occurs in people who have diabetes or related
conditions.
Here's what you need to know about hypoglycemia that occurs without diabetes.

What are the symptoms of hypoglycemia?


Everyone reacts differently to fluctuations in their blood glucose levels. Some symptoms of hypoglycemia
may include:
 dizziness
 a feeling of extreme hunger
 a headache
 confusion
 an inability to concentrate
 sweating
 shaking
 blurred vision
 personality changes
You may have hypoglycemia without having any symptoms. This is known as hypoglycemia unawareness.

What are the causes of hypoglycemia?


Hypoglycemia is either reactive or non-reactive. Each type has different causes:

Reactive hypoglycemia
Reactive hypoglycemia occurs within a few hours after a meal. An overproduction of insulin causes reactive
hypoglycemia. Having reactive hypoglycemia may mean that you’re at risk for developing diabetes.

Non-reactive hypoglycemia
Non-reactive hypoglycemia isn't necessarily related to meals and may be due to an underlying disease.
Causes of non-reactive, or fasting, hypoglycemia can include:
 some medications, like those used in adults and children with kidney failure
 excess amounts of alcohol, which can stop your liver from producing glucose
 any disorder that affects the liver, heart, or kidneys
 some eating disorders, such as anorexia
 pregnancy
Although it's rare, a tumor of the pancreas can cause the body to make too much insulin or an insulin-like
substance, resulting in hypoglycemia. Hormone deficiencies can also cause hypoglycemia because
hormones control glucose levels.

Dumping syndrome
If you’ve had surgery on your stomach to alleviate the symptoms of gastroesophageal reflux disease, you
may be at risk for a condition known as dumping syndrome. In late dumping syndrome, the body releases
excess insulin in response to carbohydrate-rich meals. That can result in hypoglycemia and the related
symptoms.

Who can develop hypoglycemia without diabetes?


Hypoglycemia without diabetes can occur in both children and adults. You’re at an increased risk for
developing hypoglycemia if you:
 have other health problems
 are obese
 have family members with diabetes
 have had certain types of surgery on your stomach
 have prediabetes
Although having prediabetes increases your risk of diabetes, it doesn’t mean you’ll definitely develop type
2 diabetes. Diet and lifestyle changes can delay or prevent the progression from prediabetes to type 2
diabetes.
If your doctor diagnoses you with prediabetes, they’ll likely talk to you about lifestyle changes, such as
following a healthy diet and managing your weight. Losing 7 percent of your body weight and exercising for
30 minutes per day, five days per week has been shown to reduce the risk of type 2 diabetes by 58
percent.

How is hypoglycemia diagnosed?


Hypoglycemia can occur in a fasting state, meaning you’ve gone for an extended period without eating.
Your doctor may ask you to take a fasting test. This test can last as long as 72 hours. During the test, you’ll
have your blood drawn at different times to measure your blood glucose level.
Another test is a mixed-meal tolerance test. This test is for people experiencing hypoglycemia after eating.
Both tests will involve a blood draw at your doctor's office. The results are usually available within a day or
two. If your blood sugar level is lower than 50 to 70 milligrams per deciliter, you may have hypoglycemia.
That number can vary from one person to another. Some people's bodies naturally have lower blood sugar
levels. Your doctor will diagnose you based on your blood sugar levels.
Keep track of your symptoms and let your doctor know what symptoms you’re experiencing. One way to
do this is to keep a symptom diary. Your diary should include any symptoms you’re experiencing, what
you’ve eaten, and how long before or after a meal your symptoms occurred. This information will help
your doctor make a diagnosis.

How is hypoglycemia treated?


Your doctor will need to identify the cause of your hypoglycemia to determine the right long-term therapy
for you.
Glucose will help boost your blood sugar levels in the short term. One way to get additional glucose is to
consume 15 grams of carbohydrates. Orange juice or another fruit juice is an easy way to get extra glucose
into your bloodstream. These sources of glucose often briefly correct hypoglycemia, but then another drop
in blood sugar often follows. Eat foods that are high in high complex carbohydrates, such as pasta and
whole grains, to sustain your blood sugar levels after a period of hypoglycemia.
The symptoms of hypoglycemia can become so severe for some people that they interfere with daily
routines and activities. If you have severe hypoglycemia, you might need to carry glucose tablets or
injectable glucose.

What are the complications associated with hypoglycemia?


It’s important to control your hypoglycemia because it can cause long-term health problems. Your body
needs glucose to function. Without the right level of glucose, your body will struggle to perform its normal
functions. As a result, you may have difficulty thinking clearly and performing even simple tasks.
In severe cases, hypoglycemia can lead to seizures, neurological problems that may mimic a stroke, or even
loss of consciousness. If you believe you’re experiencing any of these complications, you or someone near
you should call 911 or you should go directly to the closest emergency room.

How to prevent hypoglycemia


Simple changes to your diet and eating schedule can resolve episodes of hypoglycemia, and they can also
prevent future episodes. Follow these tips to prevent hypoglycemia:
 Eat a balanced and stable diet that’s low in sugar and high in protein, fiber, and complex carbohydrates.
 It’s OK to eat good complex carbohydrates, such as sweet potatoes, but avoid eating processed, refined
carbohydrates.
 Eat small meals every two hours to help keep your blood sugar levels stable.
Snacks on the go
Apple slices and a handful of nuts are a good option for many people. You’ll get sugar from the apple, and
the protein from the nuts will help control your blood glucose levels.

Carry a snack
Always carry a snack with you. You can eat it to prevent hypoglycemia from happening. It's best to carry a
quick source of carbohydrates to boost your blood sugar levels. Protein will help keep sugar in your system
for a longer period as your body absorbs it.

Determine the cause


Meals and dietary changes aren't always long-term solutions. The most important thing you can do to treat
and prevent hypoglycemia is to determine why it's happening.
See your doctor to determine if there’s an underlying cause for your symptoms if you’re having recurrent
and unexplained episodes of hypoglycemia.

Hypoglycemia in Pregnancy
Glucose is the main source of energy for your body. Hypoglycemia is characterized by abnormal low
levels of blood sugar or blood glucose. Hypoglycemia often occurs with diabetes treatment.
However, nondiabetics can suffer from it due to a variety of medical ailments. Hypoglycemia is not a
disease in itself, but an indicator of some underlying disease. Hypoglycemia in pregnancy is quite
common, but should not be ignored.

Hypoglycemia During Pregnancy: How Low Is too Low?


Normally, the blood sugar level should range between 70 and 110 mg/dl. Traditionally hypoglycemia
refers to blood sugar level below 70 mg/dl. However, since during pregnancy the blood sugar levels
remain low, according to a report published in the May issue of "diabetes care" by the American
Diabetes Association and the Endocrine Society, during pregnancy a blood sugar level lower than 60
mg/dl can be referred to as hypoglycemia.

Possible Cause of Hypoglycemia During Pregnancy

1. With Diabetes
Type 1 or type 2 diabetics may take insulin to lower high blood sugar levels which could lead to
hypoglycemia. Besides, taking too much insulin, consuming less glucose or exercising excessively
may lead to hypoglycemia in pregnancy.

2. Without Diabetes
Hypoglycemia is very often during early months of pregnancy. This occurs due to metabolic changes
occurring as a result of loss of gluconeogenic substances (byproducts of digestion of protein) and
glucose to the growing fetus, which leads to low glucose levels in the mother.
 Medicines: Accidentally taking someone else’s drugs for diabetes is a possible cause. Medications
like quinine used to treat malaria may cause hypoglycemia in children or in patients suffering
from kidney failure
 Drinking alcohol excessively without eating
 Critical illnesses such as severe hepatitis
 A rare tumor of pancreas leading to insulin overproduction
 Hormonal deficiencies due to disorders of the pituitary or the adrenal glands
 Hypoglycemia may sometimes occur after having a meal due to overproduction of insulin,
referred to as postprandial or reactive hypoglycemia

How Harmful Is Hypoglycemia in Pregnancy?


Your brain and body need constant supply of glucose for its proper functioning. Various signs and
symptoms develop due to hypoglycemia during pregnancy.

1. General Harmful Effects


 Common symptoms: palpitations, pale skin, fatigue, anxiety, shakiness, hunger, sweating,
irritability, crying during sleep, and tingling around mouth.
 More severe symptoms: confusion or abnormal behavior, such as the female may be unable to
complete even routine tasks; disturbances of vision, such as blurred vision; seizures and loss of
consciousness. Severe hypoglycemia may make one appear intoxicated.
There are many other medical conditions that may produce these signs and symptoms. Hence, a
blood test to determine the blood glucose level when these signs and symptoms appear is the sure
shot way to know whether the cause is hypoglycemia or not.

2. Specific Harmful Effects for Pregnancy


Low blood sugar can have specific harmful effects on the pregnant female and her developing baby.
 Developmental abnormalities: According to a research published in the “Journal of the
Anatomical Society of India” in the year 2002, developmental abnormalities may develop due to
maternal hypoglycemia. The study conducted on rats found out that hypoglycemia can cause the
baby to have smaller size, optic nerve malformation, heart abnormalities, and abnormalities in
the development of retina.
 Low birth weight: According to the Oklahoma research published in “the Journal of the American
Osteopathic Association” in the year 2011, hypoglycemia in pregnancy is often associated with
low birth weight. In another study published in the journal “Psychiatry Research” in the year
2001, it was found that all developmental milestones such as teething, bladder control,
independent walking and sitting, and speech development were delayed in low birth weight
infants. Such infants also developed more behavioral and emotional issues during childhood and
adolescence.
 Long-term effects: According to the research published in “The Journal of Maternal-Fetal and
Neonatal Medicine” in the year 2000, hypoglycemia in pregnant women puts the unborn child at
increased risk of having cognitive deficits, hypertension, coronary artery disease and diabetes. It
may also lead to failure of pancreas during adulthood. According to a research done by Swiss
scientists and published in the “Journal of Pediatrics” in the year 1999, recurrent episodes of
hypoglycemia in infants (caused due to hypoglycemia in mother) may lead to issues with physical
growth such as decreased head circumference.
 Hypoglycemic unawareness: However, sometimes, persons with low blood glucose levels don’t
experience or notice the warning symptoms of hypoglycemia. In these causes, a dangerous
condition referred to as hypoglycemic unawareness develops. According to the ADA, this
condition is more common in those with type 1 and 2 diabetes for a long time or in pregnant
women. In its worst form, it can lead to loss of consciousness, coma or even death (rare).

How to Deal With Hypoglycemia in Pregnancy


1. Dietary Method
Recommended treatment for hypoglycemia during pregnancy includes eating 15 g of carbohydrates
or sugar, such as a piece of hard candy, ½ a cup of sugary drink (juice or regular soda), or 3 tables or
gels of glucose. This treatment should be repeated till the blood glucose level becomes normal.

2. Hormonal Injection
Alternatively, a female may be prescribed a glucagon kit to use at home as the injection of this
hormone can increase the level of blood sugar, which stimulates the liver to produce more sugar
and send it into the blood.

3. Emergency Treatment
You can self-treat most of the episodes of hypoglycemia. However, in severe cases where one is
unable to drink or eat, it may become necessary to seek emergency treatment. If a female becomes
unconscious due to hypoglycemia, do not put anything into her mouth and call 911. In case you or
someone else in the family is trained to inject glucagon and if it’s available you can inject it.

How to Prevent Hypoglycemia in Pregnancy


1. With Diabetes: The management plan of diabetes should be followed carefully. It is important to
always carry a fast-acting carbohydrate with you, including juice or glucose tablets. Individuals
suffering from hypoglycemia unawareness should monitor glucose continuously.
2. Without Diabetes: Nondiabetics who develop recurring episodes of low blood sugar should eat
small meals frequently throughout the day. However, you should work with your physician to
identify and treat the cause of hypoglycemia as a long term measure.

What is non-diabetic hypoglycemia?


Hypoglycemia is the condition when your blood glucose (sugar) levels are too low. It happens to people
with diabetes when they have a mismatch of medicine, food, and/or exercise. Non-diabetic hypoglycemia,
a rare condition, is low blood glucose in people who do not have diabetes.
There are two kinds of non-diabetic hypoglycemia:
 Reactive hypoglycemia, which happens within a few hours of eating a meal
 Fasting hypoglycemia, which may be related to a disease
DID YOU KNOW?
You can have symptoms of hypoglycemia, but unless your blood glucose level is actually low when you
have symptoms, you don’t have hypoglycemia.
Glucose is the main source of energy for your body and brain. It comes from what we eat and drink.
Insulin, a hormone, helps keep blood glucose at normal levels so your body can work properly. Insulin’s job
is to help glucose enter your cells where it’s used for energy. If your glucose level is too low, you might not
feel well.
What causes non-diabetic hypoglycemia?
The two kinds of non-diabetic hypoglycemia have different causes. Researchers are still studying the
causes of reactive hypoglycemia. They know, however, that it comes from having too much insulin in the
blood, leading to low blood glucose levels.
TYPE OF
NON-
DIABETIC
HYPOGLYCE
MIA POSSIBLE CAUSES

 Having pre-diabetes or being at risk for diabetes, which can lead to trouble making the
Reactive right amount of insulin
hypoglycemia  Stomach surgery, which can make food pass too quickly into your small intestine
 Rare enzyme deficiencies that make it hard for your body to break down food

 Medicines, such as
o salicylates (a type of pain reliever)
o sulfa drugs (an antibiotic)
o pentamidine (to treat a serious kind of pneumonia)
o quinine (to treat malaria)
 Alcohol, especially with binge drinking
 Serious illnesses, such as those affecting the liver, heart, or kidneys
 Low levels of certain hormones, such as cortisol, growth hormone, glucagon, or
Fasting epinephrine
hypoglycemia  Tumors, such as a tumor in the pancreas that makes insulin or a tumor that makes a
similar hormone called IGF-II

What are the symptoms of non-diabetic hypoglycemia?


The symptoms include being
 Hungry
 Shaky
 Sleepy
 Anxious
 Dizzy
 Confused or nervous
 Sweaty
 Irritable
Some people have trouble speaking and also feel weak.
Talk with your doctor if you have symptoms of hypoglycemia, even if you only have one episode.
How is non-diabetic hypoglycemia diagnosed?
Your doctor can diagnose non-diabetic hypoglycemia by reviewing your symptoms, doing a physical exam,
looking at your risk for diabetes, and checking your blood glucose level. Your doctor will also see whether
you feel better after you eat or drink to raise your glucose to a normal level.
Checking your blood glucose to see if it is actually low (about 55 mg/dL or less) when you’re having
symptoms is an important part of diagnosis. Your doctor will check your blood glucose level and may order
other tests. A personal blood glucose meter is not accurate enough for diagnosis.
For fasting hypoglycemia, you may have your blood glucose checked every few hours during a fast lasting
several days. For reactive hypoglycemia, you might have a test called a mixed-meal tolerance test (MMTT).
For the MMTT, you first have a special drink containing protein, fats, and sugar. The drink raises your blood
glucose, causing your body to make more insulin. Then your blood glucose level is checked a number of
times over the next five hours.
Both tests check to see if your blood glucose levels drop too low. Your doctor might also check your blood
for insulin levels or other substances.
What is the treatment for non-diabetic hypoglycemia?
Treatment depends on the cause of your hypoglycemia. For example, if you have a tumor, you may need
surgery. If medicine is causing your hypoglycemia, you need to change medicines.
For immediate treatment of low blood glucose, make sure you eat or drink 15 grams carbohydrate (in form
of juice, glucose tablets, or hard candy).
Ask your doctor or dietitian whether you need to change your diet. The following type of diet may help
you:
 Eating small meals and snacks throughout the day, eating about every three hours
 Having a variety of foods, including protein (meat and non-meat), dairy foods, and high-fiber foods such as
whole-grain bread, fruit, and vegetables
 Limiting high-sugar foods
Some doctors recommend a high-protein, low-carbohydrate diet but this type of diet has not proven to
help hypoglycemia.

ABSTRACT
Hypoglycemia (glucose <55 mg/dL) is uncommon in people without diabetes. Whipple’s triad (low plasma
glucose concentration, clinical signs/symptoms consistent with hypoglycemia, and resolution of signs or
symptoms when the plasma glucose concentration increases) should be documented in patients prior to
embarking on evaluation. Medications should be reviewed. Critical illnesses, malnutrition, hormone
deficiencies especially adrenal insufficiency, and nonislet cell tumors secreting IGF-II need be considered in
those who are ill. Hypoglycemia can also follow bariatric surgery. In apparently healthy individuals,
endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or insulin autoimmune
conditions are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Tests
performed during hypoglycemia can establish the cause in those whom illness or medications are not the
cause. Testing may be done at the time of spontaneous development of symptoms. If this is not possible, it
can be done in the setting of a prolonged supervised fast or during a mixed meal test. Endogenous
hyperinsulinism is supported by insulin ≥3 uU/mL, c-peptide ≥0.2 nmol/L, proinsulin ≥5 pmol/L, beta-
hydroxybutyrate ≤2.7 mmol/L and undetectable sulfonylurea/meglitinide in the setting of hypoglycemia.
Use of glucagon tolerance tests, c-peptide suppression tests, anti-insulin antibody testing and continuous
glucose monitoring are discussed. Treatment of hypoglycemia is tailored to the etiology. Accurate diagnosis
is needed to direct medical and/or surgical treatment for non-diabetic hypoglycemia. For complete coverage
of this and all related areas of Endocrinology, please visit our FREE on-line web-
textbook, www.endotext.org.
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INTRODUCTION
Hypoglycemia is uncommon in people who are not being treated for diabetes, and may be due to varied or
multiple etiologies. Different causes of hypoglycemia should be considered in patients who are apparently
healthy compared to those who are ill. Whipple’s triad (low plasma glucose concentration, clinical signs or
symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the plasma glucose
concentration increases) should be documented prior to embarking on evaluation (1-3). Appropriate blood
tests performed at the time of hypoglycemia can establish the etiology in those for whom illness or
medications are not a readily apparent cause. Testing should be done at the time of spontaneous
development of symptoms when feasible. If this is not possible, testing can be done in the setting of a
prolonged supervised fast or during a mixed meal test as described in this review. Additional diagnostic tests
are also discussed. Treatment of hypoglycemia should be tailored to its cause and may include dietary,
medical and/or surgical therapies.
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PHYSIOLOGY
Glucose is the solitary source of energy for the brain under normal conditions (4). In order to maintain
proper brain function, plasma glucose must be maintained within a relatively narrow range. Redundant
counter-regulatory mechanisms are in place to prevent or correct hypoglycemia. As glucose levels decline,
major defense mechanisms include a decrease in insulin secretion, an increase in glucagon secretion, and an
increase in epinephrine secretion. Increased cortisol and growth hormone secretion occur in prolonged
hypoglycemia. If these defenses fail and plasma glucose levels continue to fall then symptoms prompting
food ingestion will develop. Symptoms typically develop at a plasma glucose of 55 mg/dl (3.0 mmol/liter) in
otherwise healthy individuals (5-6). At glucose levels of 55 mg/dl (3.0 mmol/l) and lower, insulin secretion
is normally almost completely suppressed. Lower plasma glucose levels occur in healthy individuals without
symptoms or signs during extended fasting when there is use of alternative fuels such as ketones (1).
Because of this variability there is not a single plasma glucose concentration that defines hypoglycemia. In
type 1 and longstanding type 2 diabetes the counter-regulatory responses to hypoglycemia are frequently
impaired and shift to lower thresholds (1,7-8), but have not been as well studied in patients with chronic
hypoglycemia in the absence of diabetes..
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SIGNS AND SYMPTOMS


Low blood glucose concentrations lead to sympathoadrenergic activation and neuroglycopenia (9-12).
Awareness of hypoglycemia is mainly due to the perception of neurogenic symptoms (12). Symptomatic
hypoglycemia is diagnosed clinically using Whipple’s triad: symptoms of hypoglycemia, plasma glucose
concentration <55 mg/dl (3.0 mmol/l), and resolution of those symptoms after the plasma glucose
concentration is raised. The most common symptoms of hypoglycemia are listed in Table 1. The presence of
neuroglycopenic symptoms in patients without diabetes are strongly suggestive of a hypoglycemic disorder
(1). Conversely, there is a low likelihood of a hypoglycemia disorder in those with the presence of
neurogenic symptoms in the absence of a low plasma glucose concentration (13). Capillary blood glucose
measurements should not be used in the evaluation of hypoglycemia due to poor accuracy (1). Symptoms of
hypoglycemia may be absent in patients with hypoglycemia unawareness which is thought to be due to
decreased sympathetic response due to recurrent hypoglycemia, prior exercise or sleep (1,7-9).

Table 1Symptoms of Hypoglycemia

Neurogenic Neuroglycopenic

Sweating Behavioral changes


Warmth Visual changes
Anxiety Confusion/difficulty speaking
Tremor Dizziness/lightheadedness
Nausea Lethargy
Palpitations Seizure
Tachycardia Loss of consciousness
Hunger Coma

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DIFFERENTIAL DIAGNOSIS
In individuals with hypoglycemia in the absence of diabetes mellitus the differential diagnosis is broad
(Table 2). Multiple etiologies may be present concurrently. Different causes of hypoglycemia should be
considered in patients who are apparently healthy compared to those who are ill. Drugs, critical illnesses,
hormone deficiencies, and nonislet cell tumors should be considered in those who are ill or taking
medications. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-
cell disorders, or insulin autoimmune conditions are possible, as are accidental, surreptitious or factitious
causes of hypoglycemia. Hypoglycemia in patients who have had bariatric surgery is increasingly
recognized as the frequency of these operations has grown. Artifactual hypoglycemia can occur if blood
samples are improperly handled (lack of antiglycolytic agent in the collection tube) and there is a delay in
processing.
Drugs are the most common cause of hypoglycemia (Table 3) (1). Drug-induced hypoglycemia is more
common in older patients with underlying comorbidities and in those taking glucose lowering medications
(14-16). Hypoglycemia in the setting of critical illness is not unusual. Sepsis, hepatic, renal or cardiac failure
and hormone deficiencies (cortisol, glucagon and epinephrine) are other causes of hypoglycemia. Non-islet
cell tumors and endogenous hyperinsulinism (such as insulinoma, noninsulinoma pancreatogenous
hypoglycemia, and autoimmune hypoglycemia) are rare causes of hypoglycemia (1). Accidental,
surreptitious or malicious hypoglycemia due to administration of insulin or insulin secretagogues need also
to be considered.
Insulinomas primarily cause hypoglycemia in the fasting state, but may cause symptoms in the postprandial
period as well. The incidence is 1/250,000 patient-years. Less that 10% are malignant, multiple or present in
patients with multiple endocrine neoplasia type 1 (MEN-1) syndrome (1).
Noninsulinoma pancreatogenous hypoglycemia typically causes hypoglycemia in the postprandial state.
These patients have diffuse islet involvement with nesidioblastosis (islet hypertrophy, hyperplasia and
enlarged and hyperchromatic β-cell nuclei) (17). Some patients who have had bariatric surgery for the
treatment of obesity, most commonly Roux-en-Y gastric bypass surgery, will develop hypoglycemia. This
may be due to pancreatic islet nesidioblastosis, a preexisting insulinoma, or may be due to reactive
hypoglycemia related to abnormal transport of food to the small intestine or abnormal secretion of other
glucoregulatory hormones (18-24). The incidence of hypoglycemia following Roux-en-Y gastric bypass
surgery is unknown.
Antibodies to insulin or the insulin receptor are rare causes of hypoglycemia (1,13). Antibodies to native
insulin occur primarily in patients of Japanese and Korean descent (25). Patients with autoimmune
hypoglycemia may have other autoimmune disease or exposure to sulfhydryl containing drugs (26). Late
postprandial hypoglycemia occurs as insulin secreted in response to the meal disassociates from antibodies
(1). Diagnosis is made with documentation of elevated insulin antibody levels in the absence of exposure to
exogenous insulin.

Table 2Causes of Hypoglycemia in Adults


Drugs- see Table 3
Hepatic, renal or cardiac failure
Sepsis, trauma, burns
Malnutrition
Hormonal deficiencies (cortisol, glucagon, epinephrine)
Nonislet cell tumors (IGF-II secreting tumors)
Insulinoma (insulin-secreting tumors)
Noninsulinoma pancreatogenous hypoglycemia (NIPHS)
Post gastric bypass hypoglycemia
Insulin antibodies
Insulin receptor antibodies
Accidental, surreptitious or malicious hypoglycemia
Adapted from: Cryer, PE, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009.

Table 3Drugs Associated with Hypoglycemia


Insulin
Insulin secretagogues
Alcohol
Cibenzoline
Glucagon (during endoscopy)
Indomethacin
Pentamidine
Quinine
Artesunate/artemisin/artemether
Chloroquineoxaline sulfonamide
IGF-1
Lithium
Propoxyphine/dextropropoxyphene
The following are supported by very low quality evidence:
Angiotensin converting enzyme inhibitors
Angiotensin receptor antagonists
Β-Adrenergic receptor antagonists
Fluoroquinolones
Mifepristone
Disopyramide
Trimethoprim-sulfamethoxazole
Heparin
6-Mercaptopurine
Adapted from: Cryer, PE, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009.
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DIAGNOSTIC TESTS
The most recent clinical practice guidelines for the evaluation and management of adult hypoglycemic
disorders were published by the Endocrine Society in 2009 (1). The testing approach is also discussed in the
Endotext chapter on pancreatic-islet function testing (27).
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Initial Evaluation
Evaluation should be conducted in patients in whom Whipple’s triad (low plasma glucose concentration,
clinical signs or symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the
plasma glucose concentration increases) is documented. Patients with hypoglycemia typically present with a
history of “spells” concerning for hypoglycemia, or have an incidental low plasma glucose measurement.
The first step is to review the patient’s history in detail, including type of symptoms, timing of episodes, and
relation to food ingestion, comorbid conditions, medications and social history.
Consideration for hormone deficiencies and nonislet cell tumors should be given. When adrenal
insufficiency is considered, a Cortrosyn stimulation test should be performed. If the cause of hypoglycemia
is not apparent then further laboratory testing is indicated. Capillary blood glucose measurements should not
be used in the diagnosis of hypoglycemic disorders due to their poor accuracy in these situations.
If possible, testing should be done during a time of symptomatic hypoglycemia. Simultaneous measurements
of plasma glucose, insulin, c-peptide, proinsulin, and beta-hydroxybutyrate and a screen for oral
hypoglycemic agents (sulfonylureas and meglitinide) should be performed (Table 4). Glucagon, 1 mg IV,
should then be administered with careful follow up of the glucose response every 10 minutes for 30 minutes.
These tests distinguish between hypoglycemia due to hyperinsulinism (endogenous and exogenous) and
other causes.
If testing cannot be performed during a spontaneous episode of hypoglycemia, either a fast of up to 72 hours
or a mixed meal test done in a monitored setting followed by administration of glucagon is the most useful
diagnostic strategy as described below. The choice of test is based on the circumstances in which
hypoglycemia is most likely to occur.
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The 72-Hour Fast


The gold standard test in the evaluation of hypoglycemia is the 72-hour supervised fast. The purpose of the
fast is twofold. The first is to diagnose hypoglycemia as the cause of the patient's symptoms. The second is
an attempt to determine the etiology of the hypoglycemia. Due to the risk of hypoglycemia, patients should
be admitted to the hospital to undergo the fast in a monitored setting. The fast can be initiated in a carefully
monitored outpatient facility, with the patient entering the hospital if the fast is not terminated prior to the
closing of the site.
During a 72 hour fast, patients are allowed no food but can consume non-caloric caffeine-free beverages.
The onset of the fast is the time of the last food consumption. During the fast all non-essential medications
should be discontinued. Simultaneous insulin, c-peptide and glucose samples are obtained at the beginning
of the fast and every 4-6 hours. When the plasma glucose falls to <60 mg/dl, specimens should be taken
every 1-2 hours under close supervision. Patients should continue activity when they are awake. The fast
continues until the plasma glucose falls below 45 (2.5 mmol/l) [plasma glucose less than 55 mg/dl (3.0
mmol/l) is an alternative end point if Whipple’s triad has been previously documented] and symptoms of
neuroglucopenia develop. At this time insulin, glucose, c-peptide, oral insulin secretagogues, proinsulin and
beta-hydroxybutyrate levels are obtained and the fast is terminated (1). Additional samples for insulin
antibodies, anti-insulin receptor antibodies, IGF-1/IGF-2 and plasma cortisol, glucagon or growth hormone
can also be obtained if a non-islet cell tumor, autoimmune etiology, or hormone deficiency is suspected.
Follow up with a glucagon tolerance test is frequently done to aid in diagnosis [Glucagon, 1 mg IV,
administered with careful follow up of the glucose response every 10 minutes for 30 minutes. Further details
regarding the glucagon tolerance test are below]. Patients are fed at the conclusion of the fast.
The diagnosis of endogenous hyperinsulinism is supported if insulin, c-peptide and proinsulin levels are
inappropriately elevated in the setting of hypoglycemia (Table 4). Beta-hydroxybutyrate <2.7 mmol/l, and
an increase in plasma glucose ≥25 mg/dl (1.4 mmol/liter) after IV glucagon indicate mediation of the
hypoglycemia by either insulin (endogenous or exogenous) or an IGF excess (1). It has been suggested that
an amended insulin:glucose ratio, which subtracts 30 mg/dL (1.7 mmol/L) from the measured glucose, may
be helpful in ruling out suspected insulinomas, but this remains controversial (28-29)
In patients with laboratory assessments consistent with endogenous hyperinsulinism, negative screening for
oral hypoglycemic agents (sulfonylureas/meglitinide) and negative insulin antibodies are suggestive of an
insulinoma, noninsulinoma pancreatogenous hypoglycemia (NIPHS), or post gastric bypass hypoglycemia.

Table 4
Distinguishing Causes of Symptomatic Hypoglycemia [glucose < 55 mg/dl (3.0 mmol/l)] After a
Prolonged Fast

Insulin C-peptide Proinsulin Oral hypoglycemic Interpretation


(µU/ml) (nmol/L) (pmol/L) medication

»3 <0.2 <5 No Exogenous insulin

≥3 ≥0.2 ≥5 No Endogenous insulina

≥3 ≥0.2 ≥5 Yes Oral hypoglycemic (drug-


induced)

a
Insulinoma, noninsulinoma pancreatogenous hypoglycemia (NIPHS), post gastric bypass hypoglycemia.

Adapted from: Cryer, PE, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009
Approximately 75% of patients with insulinomas are diagnosed after a 24 hour fast and 90-94% at 48 hours.
Although some experts advocate conducting the prolonged fast for only 48 hours others disagree, arguing
that prolonging the fast up to 72 hours minimizes misdiagnosis and maximizes the probability of diagnosing
an insulinoma (30-31).
Limitations of the prolonged fast:
 Normal subjects, especially young women, can occasionally have plasma glucose levels of <40
mg/dl (2.2 mmol/l)
 Rare insulinomas suppress their release of insulin in response to hypoglycemia
 Insulin levels can sometimes be artificially elevated in the presence of anti-insulin antibodies.
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Glucagon Tolerance Test


The glucagon tolerance test serves as a supplemental study to aid in determining the etiology of
hypoglycemia. Following an overnight fast (or at the conclusion of the prolonged fast), 1 mg of glucagon is
injected intravenously over 2 minutes. Plasma glucose and insulin levels are measured at baseline, and either
10, 20, and 30 minutes after glucagon, or at 3, 5, 10, 15, 20, and 30 minutes after glucagon injection.
In normal patients, maximum insulin response occurs rapidly and usually does not exceed 100 uU/ml (peak
insulin 61+19 uU/ml at 3-15 minutes), and the serum glucose levels peak at 20-30 minutes (140 +24 mg/dl)
(32).
Insulinoma patients demonstrate an exaggerated insulin response to glucagon, with values often exceeding
160 uU/ml within 15-30 minutes of the injection (peak insulin 93-343 uU/ml at 15 minutes) (32). In the
hypoglycemic patient at the conclusion of the prolonged fast, an increase in plasma glucose of >25 mg/dl
(1.4 mmol/l) post-glucagon suggests an insulin-mediated etiology (13).
Patients with malnutrition or hepatic disease may be unable to have a hyperglycemic response to glucagon
due to depleted hepatic glycogen stores. Insulin responses in these subjects may be increased but not to the
degree seen in subjects with an insulinoma. Drugs such as diazoxide, hydrochlorothiazide and
diphenylhydantoin can cause false negative results (32). Patients with non islet cell tumors such as
hemangiopericytomas and meningeal sarcomas can have similar glucose elevations (30 mg/dl) as subjects
with insulinomas following glucagon injection (33).
Another limitation of the glucagon stimulation test is the failure of some insulinoma patients to hypersecrete
insulin following glucagon injection. This problem was reported in 8% of patients with insulinomas in one
study (32). In addition, patients with cirrhosis with portocaval anastomosis can have peak insulin levels that
are indistinguishable from subjects with insulinomas. Obese subjects and patients with acromegaly can also
have exaggerated peak insulin responses, as can patients treated with sulfonylurea drugs and aminophylline.
An additional disadvantage of this test is the danger of causing hypoglycemia after 90-180 min (34), as well
as inducing nausea and vomiting. Because of the possibility of severe hypoglycemia, a physician needs to be
present during the test.
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Mixed Meal Testing


For patients with hypoglycemic symptoms several hours after meals, a mixed meal test may be performed.
This test has not been well standardized. This test is typically done after an overnight fast. Patients eat a
meal similar to one that provokes their symptoms. If this is not possible then a commercial mixed meal may
be used. Patients are then observed for several hours. Samples for plasma glucose, insulin, c-peptide, and
proinsulin are collected prior to the meal and every 30 minutes thereafter, for 5 hours. If symptoms occur
prior to the end of the test then additional samples for the above are collected prior to administration of
carbohydrates. If Whipple’s triad is demonstrated, testing for oral hypoglycemic drugs and testing for insulin
antibodies should be done. Interpretation of test results is the same as for the 72-hour fast or spontaneous
hypoglycemia (Table 4).

Continuous Glucose Monitoring


Continuous glucose monitoring (CGM) devices measure interstitial glucose concentrations and are used by
individuals with diabetes to help guide treatment. In patients who have had Roux-en-Y gastric surgery, use
of CGM was reported to detect more hypoglycemia than the mixed meal tolerance test (35-36). Whereas
these devices may be helpful in detecting hypoglycemia in selected patients, their use is not recommended
for the diagnosis of hypoglycemic disorders in people without diabetes.

Anti-Insulin Antibodies
Autoimmune hypoglycemia is a rare condition whereby antibodies, either directed against insulin or against
the insulin receptor, are responsible for hypoglycemia. Autoimmune hypoglycemia due to insulin-antibodies
should be suspected when the hypoglycemia is associated with high insulin levels (usually >100 uU/ml) and
incompletely suppressed C-peptide levels. Insulin levels are rarely >100 uU/ml in the presence of
hypoglycemia due to an insulinoma. Although these elevated insulin levels can be observed with exogenous
insulin administration, the associated c-peptide levels are usually extremely low. Autoimmune
hypoglycemia is most often seen in people of Japanese descent, but has been described in other populations
(37). Autoimmune hypoglycemia may also be due to antibodies to the insulin receptor. These patients will
have mildly elevated insulin levels (thought to be due to decreased clearance of insulin) and suppressed c-
peptide levels, and may have other autoimmune conditions (26). Insulin antibody testing does not need to be
done at the time of hypoglycemia.

C-Peptide Suppression Test


C-peptide and insulin are secreted in equimolar concentrations in the pancreas, making c-peptide levels a
good marker of endogenous insulin secretion. The c-peptide suppression test can be used to test for an
insulinoma or to provide supplemental diagnostic information, especially if the results of a supervised fast
are not definitive. The c-peptide suppression test must be carefully administered, since the patient is given
intravenous insulin to induce hypoglycemia. The advantage of the test is that it is of much shorter duration
than the supervised fast.
The c-peptide suppression test is performed following an overnight fast. The procedure is to infuse regular
insulin, 0.125 U/kg body weight, intravenously over 60 minutes. Blood samples are obtained from the
contralateral arm at 0, 30, 60, 90, and 120 minutes for determination of insulin, c-peptide, and plasma
glucose levels. An abnormal result is a lower percentage decrease of c-peptide at 60 minutes compared to
normative data appropriately adjusted for the patient's body mass index and age (38). For example, an
abnormal result for a 45 year old with a BMI of 25-29 kg/m2 would be <61% suppression of c-peptide at 60
minutes (39). An alternative method (Regular insulin 0.075 IU/kg hr infused intravenously over 2 hours)
using a different classification plot has been proposed (40) but few data using it have been published.
Limitations of this test include the fact that some patients with a documented insulinoma have normal c-
peptide levels including normal percent decrease in c-peptide levels. There is also the danger of inducing
severe hypoglycemia. In addition, little data concerning the reliability, sensitivity and safety of this test are
published.

Imaging
When endogenous hyperinsulininemic hypoglycemia is present, imaging studies are performed. These may
include computed tomography, magnetic resonance imaging (MRI), and/or transabdominal and endoscopic
ultrasonography. Imaging studies are successful in identifying approximately 75% of insulinomas (41).
Intraoperative pancreatic ultrasonography may also be used to localize small insulinomas not otherwise
found with other imaging modalities. Insulinomas are often less than 1.0 cm, so negative imaging does not
exclude the diagnosis (42-46).

Selective Pancreatic Calcium Stimulation with Hepatic Venous Sampling


In patients with endogenous hyperinsulinemic hypoglycemia, it is sometimes difficult to distinguish between
insulinoma and noninsulinoma pancreatogenous hypoglycemia. When noninvasive imaging studies are
negative or equivocal, selective arterial calcium injections with measurements of hepatic venous insulin
levels can be used to help differentiate insulinoma from diffuse nesidioblastosis (18, 47-53).
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TREATMENT
Immediate treatment should be focused on reversing the hypoglycemia. If the patient is able to ingest
carbohydrates 15 to 20 grams of glucose should be given every 15 minutes until the hypoglycemia has
resolved. If the patient is unable to ingest carbohydrates, or if the hypoglycemic episode is severe, parenteral
glucose should be administered. In a healthcare setting intravenous dextrose is used. Twenty-five gram
boluses of 50% dextrose are given until the hypoglycemia has resolved. If needed, an infusion of 10% or
20% dextrose can be used to sustain euglycemia in patients with recurrent episodes of hypoglycemia. In the
outpatient setting, glucagon, given as an intramuscular injection, is used to correct hypoglycemia. Glucose
gel and other forms of oral glucose should be used in impaired patients with caution and only in
circumstances where no alternative is available, as they pose an aspiration risk.
Long-term treatment should be tailored to the specific hypoglycemic disorder, taking into account the
burden of hypoglycemia on well-being and patient preferences. Offending medications should be
discontinued and underlying illnesses treated, whenever possible.
Surgical Treatment
Surgical resection can be curative for insulinomas. Most patients with successful surgical removal will have
good long term outcomes (54, 55). Surgery can also alleviate hypoglycemia in nonislet cell tumors, even if
the cancer cannot be cured. Radiotherapy and chemotherapy can also be used in nonislet cell tumors. Partial
pancreatectomy can be considered in patients with noninsulinoma pancreatogenous hypoglycemia. Results
of selective arterial calcium stimulation testing can be used to guide the area(s) of resection when partial
pancreatectomy is needed.

Dietary Treatment
In noninsulinoma pancreatogenous hypoglycemia, including patients with post Roux-en-Y gastric bypass
hypoglycemia, dietary interventions may be helpful. Frequent feedings and a low carbohydrate diet are
common recommendations (22-24, 56-57). Low carbohydrate diets are broadly defined in the literature, with
the macronutrient content from carbohydrates ranging from 2% to 30% (57-58). In post Roux-en-Y gastric
bypass hypoglycemia, restriction of carbohydrates, and avoidance of high glycemic index foods and simple
sugars are recommended. In severe cases gastrostomy tube feeding is sometimes needed.

Medical Treatment
Medical treatment with α-glucosidase inhibitors, calcium channel blockers, diazoxide,or octreotide can be
used if resection is not possible in patients with hyperinsulinism, or as a temporizing measure (Table 5).
Alpha glucosidase inhibitors (such as acarbose) delay the digestion of ingested carbohydrates, resulting in
lower blood glucose concentrations after meals. This medication may be useful in lessening the
hyperinsulinism in post Roux-en-Y gastric bypass hypoglycemia. It is typically prescribed as 50 mg three
times daily with meals (23, 57, 59).
Calcium channel blockers mediate hypoglycemia by inhibiting glucose stimulated insulin secretion from the
pancreatic beta-cells; verapamil 80 mg twice daily has been reported in the literature, but other agents such
as diltiazem and nifedipine have been used as well (23, 59).
Diazoxide inhibits insulin secretion by opening the ATP-dependent potassium channel of the beta cell in the
pancreas. Diazoxide is given orally as 3-8 mg/kg/day divided every 8-12 hours up to 1200 mg/day.
Diazoxide may cause edema, dizziness, nausea and hirsutism, and the dose should be reduced in the
presence of renal insufficiency (23, 60-61)
Somatostatin analogs (such as octreotide) inhibit insulin secretion when given in high doses, but may not be
as effective as diazoxide Octreotide is given as a subcutaneous injection 100 mcg twice daily up to 1500
mcg daily (23, 62).

Table 5Medication Treatment Options for Serious Hypoglycemia

Medication Class Name Route Dosage

Alpha-glucosidase inhibitor/Carbohydrate digestion and Acarbose Oral 50 mg TID with


glucose absorption delayed meals

Calcium channel blocker/Insulin secretion inhibitor Verapamil Oral 80 mg BID

Vasodilator/Insulin secretion inhibitor Diazoxide Oral 3-8 mg/kg/day


Somatostatin analog/Insulin secretion inhibitor Octreotide Subcutaneous 100 mcg BID

Autoimmune hypoglycemic conditions may be treated with either glucocorticoids or immunosuppressants,


but these disorders may be self-limited. Providing glucose by ingestion of uncooked cornstarch or
intragastric glucose infusion may be necessary in some patients.