Hypoglycemia Clinical Trials, Diagnosis, and Treatment

Browse All Available Clinical Trials

Join Now to be Notified of New Clinical Trials

View Information and Clinical Trials for Other Conditions

Hypoglycemia

Hypoglycemia (hypoglycæmia in the UK) is a medical term referring to a pathologic state produced by a lower than normal amount of sugar (glucose) in the blood. The term hypoglycemia literally means "under-sweet blood" (Gr. hypo-, glykys, haima). Hypoglycemia can produce a variety of symptoms and effects but the principal problems arise from an inadequate supply of glucose as fuel to the brain, resulting in impairment of function (neuroglycopenia). Derangements of function can range from vaguely "feeling bad" to coma, and (rarely) permanent brain damage or death. Hypoglycemia can arise from many causes and can occur at any age. The most common forms of moderate and severe hypoglycemia occur as a complication of treatment of diabetes mellitus with insulin or oral medications. Hypoglycemia is usually treated by the ingestion or administration of glucose, or foods digestible to glucose.

Endocrinologists (specialists in disorders of glucose metabolism) typically consider the following criteria (referred to as Whipple's triad) as proving that an individual's symptoms can be attributed to hypoglycemia:

Symptoms known to be caused by hypoglycemia
Low glucose at the time the symptoms occur
Reversal or improvement of symptoms or problems when the glucose is restored to normal

However, not everyone has accepted these suggested diagnostic criteria, and even the level of glucose low enough to define hypoglycemia has been a source of controversy in several contexts. For many purposes, plasma glucose levels below 70 mg/dl or 3.9 mmol/L are considered hypoglycemic, but these issues are elaborated in more detail below.

Current Research

For current research articles click - here

Defining Hypoglycemia

No single glucose value alone serves to define the medical condition termed hypoglycemia for all people and purposes. Throughout the 24 hour cycles of eating, digestion, and fasting, blood plasma glucose levels are generally maintained within a range of 70-140 mg/dl (3.9-7.8 mmol/l) for healthy humans. Although 60 or 70 mg/dl (3.3 or 3.9 mmol/l) is commonly cited as the lower limit of normal glucose, different values (typically below 40, 50, 60, or 70 mg/dl) have been defined as low for different populations, clinical purposes, or circumstances.

The precise level of glucose considered low enough to define hypoglycemia is dependent on (1) the measurement method, (2) the age of the person, (3) presence or absence of effects, and (4) the purpose of the definition. While there is no disagreement as to the normal range of blood sugar, debate continues as to what degree of hypoglycemia warrants medical evaluation or treatment, or can cause harm.

This article expresses glucose in milligrams per deciliter (mg/dl or mg/100 ml) as is customary in the United States, while millimoles per litre (mmol/l or mM) are the SI (International System) units used in most of the rest of the world. Glucose concentrations expressed as mg/dl can be converted to mmol/l by dividing by 18. For example, a glucose concentration of 90 mg/dl is 5 mmol/l or 5 mM.

Measurement Method

Blood glucose levels discussed in this article are venous plasma or serum levels measured by standard, automated glucose oxidase methods used in medical laboratories. For clinical purposes, plasma and serum levels are similar enough to be interchangeable. Arterial plasma or serum levels are slightly higher than venous levels, and capillary levels are typically in between. This difference between arterial and venous levels is small in the fasting state but is amplified and can be greater than 10% in the postprandial state. On the other hand, whole blood glucose levels (e.g., by fingerprick meters) are about 10%-15% lower than venous plasma levels.[5] Furthermore, available fingerstick glucose meters are only warranted to be accurate to within 15% of a simultaneous laboratory value under optimal conditions, and home use in the investigation of hypoglycemia is fraught with misleading low numbers. In other words, a meter glucose reading of 39 mg/dl could be properly obtained from a person whose laboratory serum glucose was 53 mg/dl; even wider variations can occur with "real world" home use.

Two other factors significantly affect glucose measurement: hematocrit and delay after phlebotomy. The disparity between venous and whole blood concentrations is greater when the hematocrit is high,[9] as in newborn infants, or adults with polycythemia. High neonatal hematocrits are particularly likely to confound glucose measurement by meter. Second, unless the specimen is drawn into a fluoride tube or processed immediately to separate the serum or plasma from the cells, the measurable glucose will be gradually lowered by in vitro metabolism of the glucose at a rate of approximately 7 mg/dl/hr, or even more in the presence of leukocytosis.

Age Differences

Surveys of healthy children and adults show that plasma glucoses below 60 mg/dl (3.3 mM) or above 100 mg/dl (5.6 mM) are found in less than 5% of samples after an overnight fast. In infants and young children up to 10% have been found to be below 60 mg/dl after an overnight fast.[citation needed] As the duration of fasting is extended, plasma glucose levels can fall further, even in healthy people. In other words, many healthy people can occasionally have glucose levels in the hypoglycemic range without symptoms or disease.

The normal range of newborn blood sugars continues to be debated. Surveys and experience have revealed blood sugars often below 40 mg/dl (2.2 mM), rarely below 30 mg/dl (1.7 mM),[citation needed] in apparently healthy full-term infants on the first day of life. It has been proposed that newborn brains are able to use alternate fuels when glucose levels are low more readily than adults. Experts continue to debate the significance and risk of such levels, though the trend has been to recommend maintenance of glucose levels above 60-70 mg/dl after the first day of life. In ill, undersized, or premature newborns, low blood sugars are even more common, but there is a consensus that sugars should be maintained at least above 50 mg/dl (2.8 mM) in such circumstances. Some experts advocate 70 mg/dl as a therapeutic target, especially in circumstances such as hyperinsulinism where alternate fuels may be less available.

Presence or Absence of Effects

Research in healthy adults shows that mental efficiency declines slightly but measurably as blood glucose falls below 65 mg/dl (3.6 mM) in many people. Hormonal defense mechanisms (adrenaline and glucagon) are activated as it drops below a threshold level (about 55 mg/dl for most people), producing the typical symptoms of shakiness and dysphoria. On the other hand, obvious impairment does not often occur until the glucose falls below 40 mg/dl, and up to 10% of the population may occasionally have glucose levels below 65 in the morning without apparent effects. Brain effects of hypoglycemia, termed neuroglycopenia, determine whether a given low glucose is a "problem" for that person, and hence some people tend to use the term hypoglycemia only when a moderately low glucose is accompanied by symptoms.

Even this criterion is complicated by the facts that hypoglycemic symptoms are vague and can be produced by other conditions, that people with persistently or recurrently low glucose levels can lose their threshold symptoms so that severe neuroglycopenic impairment can occur without much warning, and that many of our measurement methods (especially glucose meters) are imprecise at low levels.

Diabetic hypoglycemia represents a special case with respect to the relationship of measured glucose and hypoglycemic symptoms for several reasons. Although home glucose meter readings are sometimes misleading, the probability that a low reading accompanied by symptoms represents real hypoglycemia is higher in a person who takes insulin. Second, the hypoglycemia has a greater chance of progressing to more serious impairment if not treated, compared to most other forms of hypoglycemia that occur in adults. Third, because glucose levels are above normal most of the time in people with diabetes, hypoglycemic symptoms may occur at higher thresholds than in people who are normoglycemic most of the time. For all of these reasons, people with diabetes usually use higher meter glucose thresholds to determine hypoglycemia.

Purpose of Definition

For all of the reasons explained in the above paragraphs, deciding whether a blood glucose in the borderline range of 45-75 mg/dl (2.5-4.2 mM) represents clinically problematic hypoglycemia is not always simple. This leads people to use different "cutoff levels" of glucose in different contexts and for different purposes.

Pathophysiology

Like most animal tissues, brain metabolism depends primarily on glucose for fuel in most circumstances. A limited amount of glucose can be derived from glycogen stored in astrocytes, but it is consumed within minutes. For most practical purposes, the brain is dependent on a continual supply of glucose diffusing from the blood into the interstitial tissue within the central nervous system and into the neurons themselves.

Therefore, if the amount of glucose supplied by the blood falls, the brain is one of the first organs affected. In most people subtle reduction of mental efficiency can be observed when the glucose falls below 65 mg/dl (3.6 mM). Impairment of action and judgement usually becomes obvious below 40 mg/dl (2.2 mM). Seizures may occur as the glucose falls further. As blood glucose levels fall below 10 mg/dl (0.55 mM), most neurons become electrically silent and nonfunctional, resulting in coma. These brain effects are collectively referred to as neuroglycopenia.

The importance of an adequate supply of glucose to the brain is apparent from the number of nervous, hormonal and metabolic responses to a falling glucose. Most of these are defensive or adaptive, tending to raise the blood sugar via glycogenolysis and gluconeogenesis or provide alternative fuels.

Brief or mild hypoglycemia produces no lasting effects on the brain, though it can temporarily alter brain responses to additional hypoglycemia. Prolonged, severe hypoglycemia can produce lasting damage of a wide range. This can include impairment of cognitive function, motor control, or even consciousness. The likelihood of permanent brain damage from any given instance of severe hypoglycemia is difficult to estimate, and depends on a multitude of factors such as age, recent blood and brain glucose experience, concurrent problems such as hypoxia, and availability of alternative fuels. The vast majority of symptomatic hypoglycemic episodes result in no detectable permanent harm.

Signs and Symptoms

Hypoglycemic symptoms and manifestations can be divided into those produced by the counterregulatory hormones (adrenaline and glucagon) triggered by the falling glucose, and the neuroglycopenic effects produced by the reduced brain sugar.

Adrenergic Manifestations

Shakiness, anxiety, nervousness, tremor

Palpitations, tachycardia

Sweating, feeling of warmth

Pallor, coldness, clamminess

Dilated pupils

Glucagon Manifestations

Hunger, borborygmus

Nausea, vomiting, abdominal discomfort

Neuroglycopenic Manifestations

Abnormal mentation, impaired judgement

Nonspecific dysphoria, anxiety, moodiness, depression, crying

Negativism, irritability, belligerence, combativeness, rage

Personality change, emotional lability

Fatigue, weakness, apathy, lethargy, daydreaming, sleep

Confusion, amnesia, dizziness, delirium

Staring, "glassy" look, blurred vision, double vision

Automatic behavior, also known as automatism

Difficulty speaking, slurred speech

Ataxia, incoordination, sometimes mistaken for "drunkenness"

Focal or general motor deficit, paralysis, hemiparesis

Paresthesias, headache

Stupor, coma, abnormal breathing

Generalized or focal seizures

Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by severity of the hypoglycemia. In young children vomiting often accompanies morning hypoglycemia with ketosis. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.

In newborns, hypoglycemia can produce irritability, jitters, myoclonic jerks, cyanosis, respiratory distress, apneic episodes, sweating, hypothermia, somnolence, hypotonia, refusal to feed, and seizures or "spells". Hypoglycemia can resemble asphyxia, hypocalcemia, sepsis, or heart failure.

In both young and old patients, the brain may habituate to low glucose levels, with a reduction of noticeable symptoms despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed hypoglycemia unawareness and is a significant clinical problem when improved glycemic control is attempted. Another aspect of this phenomenon occurs in type I glycogenosis, when chronic hypoglycemia before diagnosis may be better tolerated than acute hypoglycemia after treatment is underway.

Nearly always, hypoglycemia severe enough to cause seizures or unconsciousness can be reversed without obvious harm to the brain. Cases of death or permanent neurological damage occurring with a single episode have usually involved prolonged, untreated unconsciousness, interference with breathing, severe concurrent disease, or some other type of vulnerability. Nevertheless, brain damage or death has occasionally resulted from severe hypoglycemia.

Determining the Cause

Hundreds of conditions can cause hypoglycemia. Common causes by age are listed below. While many aspects of the medical history and physical examination may be informative, the two best guides to the cause of unexplained hypoglycemia are usually.

The Circumstances
A critical sample of blood obtained at the time of hypoglycemia, before it is reversed.

The Circumstances of Hypoglycemia Provide Most of the Clues to Diagnosis

Circumstances include the age of the patient, time of day, time since last meal, previous episodes, nutritional status, physical and mental development, drugs or toxins (especially insulin or other diabetes drugs), diseases of other organ systems, family history, and response to treatment. When hypoglycemia occurs repeatedly, a record or "diary" of the spells over several months, noting the circumstances of each spell (time of day, relation to last meal, nature of last meal, response to carbohydrate, and so forth) may be useful in recognizing the nature and cause of the hypoglycemia.

An especially important aspect is whether the patient is seriously ill with another problem. Severe disease of nearly all major organ systems can cause hypoglycemia as a secondary problem. Hospitalized patients, especially in intensive care units or those prevented from eating, can suffer hypoglycemia from a variety of circumstances related to the care of their primary disease. Hypoglycemia in these circumstances is often multifactorial or even iatrogenic. Once identified, these types of hypoglycemia are readily reversed and prevented, and the underlying disease becomes the primary problem.

Apart from determining nutritional status and identifying whether there is likely to be an underlying disease more serious than hypoglycemia, the physical examination of the patient is only occasionally helpful. Macrosomia in infancy usually indicates hyperinsulinism. A few syndromes and metabolic diseases may be recognizable by clues such as hepatomegaly or micropenis.

Response to treatment, especially the amount of carbohydrate needed to reverse or prevent recurrence of hypoglycemia, may provide important clues as well. When 15-30 grams of sugar or starch are given by mouth, a low blood glucose will usually rise by 18-36 mg/dl (1-2 mmol/l) within 5-10 minutes, relieving hypoglycemic symptoms within 10 minutes. It may take longer to recover from severe hypoglycemia with unconsciousness or seizure even after restoration of normal blood glucose. When a person has not been unconscious, failure of carbohydrate to reverse the symptoms in 10-15 minutes increases the likelihood that hypoglycemia was not the cause of the symptoms. When severe hypoglycemia has persisted in a hospitalized patient, the amount of glucose required to maintain satisfactory blood glucose levels becomes an important clue to the underlying etiology. Glucose requirements above 10 mg/kg/minute in infants, or 6 mg/kg/minute in children and adults are strong evidence for hyperinsulinism. In this context this is referred to as the glucose infusion rate (GIR). Finally, the blood glucose response to glucagon given when the glucose is low can also help distinguish among various types of hypoglycemia. A rise of blood glucose by more than 30 mg/dl (1.70 mmol/l) suggests insulin excess as the probable cause of the hypoglycemia.

In Less Obvious Cases, a "Critical Sample" May Provide the Diagnosis

In the majority of children and adults with recurrent, unexplained hypoglycemia, the diagnosis may be determined by obtaining a sample of blood during hypoglycemia. If this critical sample is obtained at the time of hypoglycemia, before it is reversed, it can provide information that would otherwise require a several-thousand-dollar hospital admission and unpleasant starvation testing. Perhaps the most common inadequacy of emergency department care in cases of unexplained hypoglycemia is the failure to obtain at least a basic sample before giving glucose to reverse it.

Part of the value of the critical sample may simply be the proof that the symptoms are indeed due to hypoglycemia. More often, measurement of certain hormones and metabolites at the time of hypoglycemia indicates which organs and body systems are responding appropriately and which are functioning abnormally. For example, when the blood glucose is low, hormones which raise the glucose should be rising and insulin secretion should be completely suppressed.

The following is a brief list of hormones and metabolites which may be measured in a critical sample. Not all tests are checked on every patient. A "basic version" would include insulin, cortisol, and electrolytes, with C-peptide and drug screen for adults and growth hormone in children. The value of additional specific tests depends on the most likely diagnoses for an individual patient, based on the circumstances described above. Many of these levels change within minutes, especially if glucose is given, and there is no value in measuring them after the hypoglycemia is reversed. Others, especially those lower in the list, remain abnormal even after hypoglycemia is reversed, and can be usefully measured even if a critical specimen is missed. Although interpretation in difficult cases is beyond the scope of this article, for most of the tests, the primary significance is briefly noted.

Glucose: needed to document actual hypoglycemia

Insulin: any detectable amount is abnormal during hypoglycemia, but physician must know assay characteristics

Cortisol: should be high during hypoglycemia if pituitary and adrenals are functioning normally

Growth hormone: should rise after hypoglycemia if pituitary is functioning normally

Electrolytes and total carbon dioxide: electrolyte abnormalities may suggest renal or adrenal disease; mild acidosis is normal with starvation hypoglycemia; usually no acidosis with hyperinsulinism

Liver enzymes: elevation suggests liver disease

Ketones: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism or fatty acid oxidation disorder

Beta-hydroxybutyrate: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism or fatty acid oxidation disorder

Free fatty acids: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism; high with low ketones suggests fatty acid oxidation disorder

Lactic acid: high levels suggest sepsis or an inborn error of gluconeogenesis such as glycogen storage disease

Ammonia: if elevated suggests hyperinsulinism due to glutamate dehydrogenase deficiency, Reye syndrome, or certain types of liver failure

C-peptide: should be undetectable; if elevated suggests hyperinsulinism; low c-peptide with high insulin suggests exogenous (injected) insulin

Proinsulin: detectable levels suggest hyperinsulinism; levels disproportionate to a detectabe insulin level suggest insulinoma

Ethanol: suggests alcohol intoxication

Toxicology screen: can detect many drugs causing hypoglycemia, especially for sulfonylureas

Insulin antibodies: if positive suggests repeated insulin injection or antibody-mediated hypoglycemia

Urine organic acids: elevated in various characteristic patterns in several types of organic aciduria

Carnitine, free and total: low in certain disorders of fatty acid metabolism and certain types of drug toxicity and pancreatic disease

Thyroxine and TSH: low T4 without elevated TSH suggests hypopituitarism or malnutrition

Acylglycine: elevation suggests a disorder of fatty acid oxidation

Epinephrine: should be elevated during hypoglycemia

Glucagon: should be elevated during hypoglycemia

IGF-1: low levels suggest hypopituitarism or chronic malnutrition

IGF-2: low levels suggest hypopituitarism; high levels suggest non-pancreatic tumor hypoglycemia

ACTH: should be elevated during hypoglycemia; unusually high ACTH with low cortisol suggests Addison's disease

Alanine or other plasma amino acids: abnormal patterns may suggest certain inborn errors of amino acid metabolism or gluconeogenesis

Further Diagnostic Steps

When suspected hypoglycemia recurs and a critical specimen has not been obtained, the diagnostic evaluation may take several paths.

When general health is good, the symptoms are not severe, and the person can fast normally through the night, experimentation with diet (extra snacks with fat or protein, reduced sugar) may be enough to solve the problem. If it is uncertain whether "spells" are indeed due to hypoglycemia, some physicians will recommend use of a home glucose meter to test at the time of the spells to confirm that glucoses are low. This approach may be most useful when spells are fairly frequent or the patient is confident that he or she can provoke a spell. The principal drawback of this approach is the high rate of false positive or equivocal levels due to the imprecision of the currently available meters: both physician and patient need an accurate understanding of what a meter can and cannot do to avoid frustrating and inconclusive results.

In cases of recurrent hypoglycemia with severe symptoms, the best method of excluding dangerous conditions is often a diagnostic fast. This is usually conducted in the hospital, and the duration depends on the age of the patient and response to the fast. A healthy adult can usually maintain a glucose level above 50 mg/dl (2.8 mM) for 72 hours, a child for 36 hours, and an infant for 24 hours. The purpose of the fast is to determine whether the person can maintain his or her blood glucose as long as normal, and can respond to fasting with the appropriate metabolic changes. At the end of the fast the insulin should be nearly undetectable and ketosis should be fully established. The patient's blood glucose levels are monitored and a critical specimen is obtained if the glucose falls. Despite its unpleasantness and expense, a diagnostic fast may be the only effective way to confirm or refute a number of serious forms of hypoglycemia, especially those involving excessive insulin.

A traditional method for investigating suspected hypoglycemia is the oral glucose tolerance test, especially when prolonged to 3, 4, or 5 hours. Although quite popular in the United States in the 1960s, repeated research studies have demonstrated that many healthy people will have glucose levels below 70 or 60 during a prolonged test, and that many types of significant hypoglycemia may go undetected with it. This combination of poor sensitivity and specificity has resulted in its abandonment for this purpose by physicians experienced in disorders of glucose metabolism.

Causes

There are several ways to classify hypoglycemia. The following is a list of the more common causes and factors which may contribute to hypoglycemia grouped by age, followed by some causes that are relatively age-independent. See causes of hypoglycemia for a more complete list grouped by etiology.

Hypoglycemia in Newborn Infants

Hypoglycemia is a common problem in critically ill or extremely low birthweight infants. If not due to maternal hyperglcemia, in most cases it is multifactorial, transient and easily supported. In a minority of cases hypoglycemia turns out to be due to significant hyperinsulinism, hypopituitarism or an inborn error of metabolism and presents more of a management challenge.

Transient neonatal hypoglycemia
- Prematurity, intrauterine growth retardation, perinatal asphyxia
- Maternal hyperglcemia due to diabetes or iatrogenic glucose administration
- Sepsis
- Prolonged fasting (e.g., due to inadequate breast milk or condition interfering with feeding)
Congenital hypopituitarism
Congenital hyperinsulinism, several types, both transient and persistent
Inborn errors of carbohydrate metabolism such as glycogen storage disease

Hypoglycemia in Young Children

Single episodes of hypoglycemia due to gastroenteritis or fasting, but recurrent episodes nearly always indicate either an inborn error of metabolism, congenital hypopituitarism, or congenital hyperinsulinism

Prolonged fasting
- Diarrheal illness in young children, especially rotavirus gastroenteritis
Idiopathic ketotic hypoglycemia
Isolated growth hormone deficiency, hypopituitarism
Insulin excess
- Hyperinsulinism due to several congenital disorders of insulin secretion
- Insulin injected for type 1 diabetes
Gastric dumping syndrome (after gastrointestinal surgery)
Other congenital metabolic diseases; some of the common include
- Maple syrup urine disease and other organic acidurias
- Type 1 glycogen storage disease
- Disorders of fatty acid oxidation
- Medium chain acylCoA dehydrogenase deficiency (MCAD)
Accidental ingestions
- Sulfonylureas, propranolol and others
- Ethanol (mouthwash, "leftover morning-after-the-party drinks")

Hypoglycemia in Older Children and Young Adults

By far the most common cause of severe hypoglycemia in this age range is insulin injected for type 1 diabetes. Circumstances should provide clues fairly quickly for the new diseases causing severe hypoglycemia. All of the congenital metabolic defects, congenital forms of hyperinsulinism, and congenital hypopituitarism are likely to have already been diagnosed or are unlikely to start causing new hypoglycemia at this age. Body mass is large enough to make starvation hypoglycemia and idiopathic ketotic hypoglycemia quite uncommon. Recurrent mild hypoglycemia may fit a reactive hypoglycemia pattern, but this is also the peak age for idiopathic postprandial syndrome, and recurrent "spells" in this age group can be traced to orthostatic hypotension or hyperventilation as often as demonstrable hypoglycemia.

Insulin-induced hypoglycemia
- Insulin injected for type 1 diabetes
- Factitious insulin injection (Munchausen syndrome)
- Insulin-secreting pancreatic tumor
- Reactive hypoglycemia and idiopathic postprandial syndrome
Addison's disease
Sepsis

Hypoglycemia in Older Adults

The incidence of hypoglycemia due to complex drug interactions, especially involving oral hypoglycemic agents and insulin for diabetes rises with age. Though much rarer, the incidence of insulin-producing tumors also rises with advancing age. Most tumors causing hypoglycemia by mechanisms other than insulin excess occur in adults.

Insulin-induced hypoglycemia
- Insulin injected for diabetes
- Factitious insulin injection (Munchausen syndrome)
- Excessive effects of oral diabetes drugs, beta-blockers, or drug interactions
- Insulin-secreting pancreatic tumor
- Alimentary (rapid jejunal emptying with exaggerated insulin response)
  - After gastrectomy dumping syndrome or bowel bypass surgery or resection
- Reactive hypoglycemia and idiopathic postprandial syndrome
Tumor hypoglycemia, Doege-Potter syndrome
Acquired adrenal insufficiency
Acquired hypopituitarism

Treatment and Prevention

Management of hypoglycemia involves immediately raising the blood sugar to normal, determining the cause, and taking measures to prevent future episodes.

Reversing Acute Hypoglycemia

The blood glucose can be raised to normal within minutes by taking (or receiving) 10-20 grams of carbohydrate. It can be taken as food or drink if the person is conscious and able to swallow. This amount of carbohydrate is contained in about 3-4 ounces (100-120 ml) of orange, apple, or grape juice, about 4-5 ounces (120-150 ml) of regular (non-diet) soda, about one slice of bread, about 4 crackers, or about 1 serving of most starchy foods. Starch is quickly digested to glucose (unless the person is taking acarbose), but adding fat or protein retards digestion. Symptoms should begin to improve within 5 minutes, though full recovery may take 10-20 minutes. Overfeeding does not speed recovery and if the person has diabetes will simply produce hyperglcemia afterwards.

If a person is suffering such severe effects of hypoglycemia that they cannot (due to combativeness) or should not (due to seizures or unconsciousness) be given anything by mouth, glucose can be given by intravenous infusion or the glucose can be rapidly raised by an injection of glucagon. Further details of glucagon use are provided in the article on diabetic hypoglycemia.

One situation where starch may be less effective than glucose or sucrose is when a person is taking acarbose. Since acarbose and other alpha-glucosidase inhibitors prevents starch and other sugars from being broken down into monosaccharides that can be absorbed by the body, patients taking these medications should consume monosaccharide-containing foods such as glucose tablets, honey, or juice to reverse hypoglycemia.

Prevention

The most effective means of preventing further episodes of hypoglycemia depends on the cause.

The risk of further episodes of diabetic hypoglycemia can often be reduced by lowering the dose of insulin or other medications, or by more meticulous attention to blood sugar balance during unusual hours, higher levels of exercise, or alcohol intake.

Many of the inborn errors of metabolism require avoidance or shortening of fasting intervals, or extra carbohydrates. For the more severe disorders, such as type 1 glycogen storage disease, this may be supplied in the form of cornstarch every few hours or by continuous gastric infusion.

Several treatments are used for hyperinsulinemic hypoglycemia, depending on the exact form and severity. Some forms of congenital hyperinsulinism respond to diazoxide or octreotide. Surgical removal of the overactive part of the pancreas is curative with minimal risk when hyperinsulinism is focal or due to a benign insulin-producing tumor of the pancreas. When congenital hyperinsulinism is diffuse and refractory to medications, near-total pancreatectomy may be the treatment of last resort, but in this condition is less consistently effective and fraught with more complications.

Hypoglycemia due to hormone deficiencies such as hypopituitarism or adrenal insufficiency usually ceases when the appropriate hormone is replaced.

Hypoglycemia due to dumping syndrome and other post-surgical conditions is best dealt with by altering diet. Including fat and protein with carbohydrates may slow digestion and reduce early insulin secretion. Some forms of this respond to treatment with a glucosidase inhibitor, which slows starch digestion.

Reactive hypoglycemia with demonstrably low blood glucose levels is most often a predictable nuisance which can be avoided by consuming fat and protein with carbohydrates, by adding morning or afternoon snacks, and reducing alcohol intake.

Idiopathic postprandial syndrome without demonstrably low glucose levels at the time of symptoms can be more of a management challenge. Many people find improvement by changing eating patterns (smaller meals, avoiding excessive sugar, mixed meals rather than carbohydrates by themselves), reducing intake of stimulants such as caffeine, or by making lifestyle changes to reduce stress. See the following section of this article.

Hypoglycemia as American Folk Medicine

Hypoglycemia is also a term of contemporary American folk medicine which refers to a recurrent state of symptoms of altered mood and subjective cognitive efficiency, sometimes accompanied by adrenergic symptoms, but not necessarily by measured low blood glucose. Symptoms are primarily those of altered mood, behavior, and mental efficiency. This condition is usually treated by dietary changes which range from simple to elaborate.

This condition therefore overlaps with the definition and forms of hypoglycemia described in the remainder of this article but is not entirely congruent. When low glucose levels can be measured, this condition is what is usually described by physicians as idiopathic reactive hypoglycemia. When glucose levels are not low enough to distinguish the patient's glucose from normal levels, this type of "hypoglycemia" does not carry the same risks of coma or brain damage as measurable hypoglycemia that meets the Whipple criteria. A variety of terms have been used in the medical literature: functional hypoglycemia, idiopathic postprandial syndrome, pseudohypoglycemia, nonhypoglycemia, and "hypoglycemia". The terms range from favorable to pejorative and reflect the range of attitudes of physicians as much as the nature of the condition.

Advising people on management of this condition is a significant "sub-industry" of alternative medicine. More information about this form of "hypoglycemia", with far more elaborate dietary recommendations, is available on the internet and in health food stores. Most of these websites and books describe a conflated mixture of reactive hypoglycemia and idiopathic postprandial syndrome but do not recognize a distinction. The value of these recommendations is unproven.

(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Hypoglycemia)

Findings From Current Research

Development and Validation of a New Measure to Evaluate Psychological Resistance to Insulin Treatment

Authors: Petrak F, Stridde E, Leverkus F, Crispin AA, Forst T, Pfützner A.

Department for Psychosomatic Medicine and Psychotherapy, LWL-Clinic Dortmund/Ruhr-University of Bochum, Dortmund, Germany.

Objective: To develop a psychometric questionnaire to measure psychological barriers to insulin treatment in patients with type 2 diabetes. Research Design and Methods: Scale development was based on principal component analyses in two cross-sectional studies of insulin-naïve patients with type 2 diabetes. The structure of the questionnaire was developed in the first sample of 448 patients and subsequently cross-validated in an independent sample of 449 patients. Results: Analyses in the first sample yielded five components that accounted for 74.5% of the variance based on 14 items and led to the following subscales: Fear of injection and self-testing, Expectations regarding positive insulin-related outcomes, Expected hardship from insulin treatment, Stigmatization by insulin injections, and Fear of hypoglycemia. In addition, an overall sum score of all values was calculated. The structure of the questionnaire was cross-validated in the second sample with almost identical component loadings and an explained variance of 69.4%. An additional confirmatory factor analysis also indicated an acceptable to good model fit with RMSEA = 0.04 and CFI = 0.97. Coefficients of reliability (Cronbach's alphas 0.62 to 0.85 and 0.78 for overall sum score) were acceptable, considering the very small number of items for each scale. Conclusions: The Barriers to Insulin Treatment Questionnaire (BIT) appears to be a reliable and valid measure of psychological insulin resistance in patients with type 2 diabetes. This short instrument is easy to administer and may be used by both clinicians and researchers to assess the psychological barriers to insulin treatment.

Journal: Diabetes Care. 2007 Jun 15
Adapted from PubMed; click here to access full journal article.

Regional Brain Volume Differences Associated with Hyperglycemia and Severe Hypoglycemia in Youth with Type 1 Diabetes

Authors: Perantie DC, Wu J, Koller JM, Lim A, Warren SL, Black KJ, Sadler M, White NH, Hershey T.

Departments of Psychiatry, Washington University School of Medicine.

Objective: Despite interest in the effects of type 1 diabetes on the developing brain, structural brain volumes in youth with this disease have not been previously examined. This study is the first to quantify regional brain volume differences in a large sample of youth with diabetes. Research Design and Methods: Magnetic resonance images (MRI) were acquired from youth with diabetes (n=108) and healthy sibling controls (HC; n=51) aged 7-17 years. History of severe hypoglycemia was assessed by parent interview and included seizure, loss of consciousness, or requiring assistance to treat. Hemoglobin A1c (HbA1c) values since diagnosis were obtained from medical records; median HbA1c was weighted by duration of disease. Voxel-based morphometry (SPM5) was used to determine the relationships of prior hypoglycemia and hyperglcemia to regional gray and white matter volumes across the whole brain. Results: No significant differences were found between diabetic and HC groups in gray or white matter. However, within the diabetic group, a history of severe hypoglycemia was associated with smaller gray matter volume in the left superior temporal region. Greater exposure to hyperglcemia was associated with smaller gray matter volume in the right cuneus and precuneus, smaller white matter volume in a right posterior parietal region, and larger gray matter volume in a right prefrontal region. Conclusions: Qualitatively different relationships were found between hypoglycemia and hyperglycemia and regional brain volumes in youth with type 1 diabetes. Future studies should investigate whether these differences relate to cognitive function and how these regions are affected by further exposure.

Journal: Diabetes Care. 2007 Jun 15
Adapted from PubMed; click here to access full journal article.

Effect of Fasting on Young Adults who have Symptoms of Hypoglycemia in the Absence of Frequent Meals

Authors: Alkén J, Petriczko E, Marcus C.

Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden.

Background and Objectives:Among otherwise healthy adults, there is a subgroup of individuals who develop symptoms of hypoglycemia during episodes of food restriction. The aim of the present study was to investigate whether such individuals develop hypoglycemia or react abnormally in other metabolic aspects during a 24-hour fast.Subjects and Methods:Ninety medical students were asked if they wanted to participate. Sixteen were selected; none dropped out. A 24-hour fast was performed at a hospital ward. Blood samples and questionnaires were taken at eight specific times.Result:During the fast, the sensitive group reported significantly higher scores on 'irritation' and 'shakiness'. However, no hypoglycemia occurred and the lowest detected blood glucose concentration was 3.7 mmol/l. There were no differences between the groups in plasma glucose, cortisol, growth hormone (GH), insulin, beta-hydroxybutyrate (beta-OH) and lactate levels. The blood pressures and heart rates were also similar.Conclusions:Adults, despite subjective signs of hypoglycemia, can fast without any metabolic or endocrine derangement.European Journal of Clinical Nutrition advance online publication, 16 May 2007; doi:10.1038/sj.ejcn.1602785.

Journal: Eur J Clin Nutr. 2007 May 16
Adapted from PubMed; click here to access full journal article.

Type 1 Diabetes: Exercise and Hypoglycemia

Authors: Briscoe VJ, Tate DB, Davis SN.

Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, 715 Preston Research Building, Nashville, TN 37232-6303, USA

The Diabetes Control and Complications Trial demonstrated that tight control of diabetes management greatly reduces the risk of microvascular complications of diabetes. Unfortunately, tight control of blood glucose can also result in hypoglycemia, especially in patients with type 1 diabetes mellitus (T1DM). It is now widely recognized that antecedent hypoglycemia can blunt neuroendocrine, autonomic nervous system (ANS), and metabolic counterregulatory responses to subsequent hypoglycemia. Thus, blunted counterregulatory defenses against falling plasma glucose levels are a major risk factor for hypoglycemia in people with diabetes. This risk is also complicated by a difference in responses between males and females. Because of the qualitative similarity of neuroendocrine, ANS, and metabolic responses to hypoglycemia and exercise, we developed studies to determine whether neuroendocrine and ANS counterregulatory dysfunction play a role in the pathogenesis of exercise-related hypoglycemia in T1DM. Results from these studies have shown that neuroendocrine (catecholamine and glucagon), ANS (muscle sympathetic nerve activity), and metabolic (lipolysis and glucose kinetics) responses are blunted during exercise after antecedent hypoglycemia, and that there is a sexual dimorphism in responses. Similarly, antecedent episodes of exercise can blunt counterregulatory responses during subsequent hypoglycemia, thereby creating reciprocal feed-forward vicious cycles that increase the risk of hypoglycemia during either stress.

Journal: Appl Physiol Nutr Metab. 2007 Jun;32(3):576-82.
Adapted from PubMed; click here to access full journal article.

Hyperglycemia Management in the Hospital Setting

Authors: Hassan E.

Pharmacotherapy Services, VISICU, 217 E. Redwood Street, Suite 1900, Baltimore, Maryland 21202. ehassan@visicu.com.

Purpose. Recommendations for target blood glucose concentrations; factors that can complicate glycemic control; considerations that determine the aggressiveness of therapy to manage blood glucose levels; the role of oral antihyperglycemic drug therapy, sliding-scale insulin, continuous intravenous (i.v.) insulin infusions, and basal-bolus insulin therapy; the pharmacodynamics of various insulin products; computer decision support systems; and discharge planning for hospitalized patients with hyperglcemia are described. SUMMARY: Target blood glucose concentrations depend on whether patients are critically ill or not. Factors that can complicate glycemic control include the severity of illness, medications, and inconsistent dietary intake. The expected course of treatment, anticipated length of stay, and preadmission glycemic control influence the aggressiveness of therapy to manage hyperglcemia. The usefulness of oral antihyperglycemic agents for managing in-hospital hyperglycemia is limited by difficulty titrating the dosage and promptly achieving target blood glucose concentrations. Sliding-scale insulin is not recommended because it is ineffective and potentially dangerous. Continuous i.v. insulin therapy or intermittent subcutaneous (s.c.) basal-bolus plus correction injections is preferred. Basal-bolus plus correction insulin therapy usually involves a single daily dose of insulin glargine at bedtime to prevent gluconeogenesis and ketogenesis, bolus injections of a rapid-acting insulin shortly before or after meals to meet prandial requirements, and correction bolus injections of rapid-acting insulin as needed for blood glucose elevations before or between meals. Hypoglycemia is the primary limiting factor for achieving optimal glycemic control with insulin therapy. Computer decision support systems can help reduce the risk of insulin infusion rate calculation errors and standardize insulin therapy. Communication with the primary care physician in the outpatient setting is an important part of discharge planning. CONCLUSION: Sliding-scale insulin is not effective. Continuous i.v. insulin therapy or intermittent s.c. basal-bolus plus correction injections is preferred. Proactive management of hyperglcemia using these methods is needed to achieve and maintain glycemic control in hospitalized patients.

Journal: Am J Health Syst Pharm. 2007 May 15;64(10 Suppl 6):S9-S14
Adapted from PubMed; click here to access full journal article.

Management of Inpatient Hyperglycemia: Assessing Perceptions and Barriers to Care Among Resident Physicians

Authors: Cook CB, McNaughton DA, Braddy CM, Jameson KA, Roust LR, Smith SA, Roberts DL, Thomas SL, Hull BP.

Division of Endocrinology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.

OBJECTIVE: To develop insight into resident physician attitudes about inpatient hyperglcemia and determine perceived barriers to optimal management. METHODS: As part of a planned educational program, a questionnaire was designed and administered to determine the opinions of residents about the importance of inpatient glucose control, their perceptions about what glucose ranges were desirable, and the problems they encountered when trying to manage hyperglycemia in hospitalized patients. RESULTS: Of 70 resident physicians from various services, 52 completed the survey (mean age, 31 years; 48% men; 37% in first year of residency training). Most respondents indicated that glucose control was "very important" in critically ill and perioperative patients but only "somewhat important" in non-critically ill patients. Most residents indicated that they would target a therapeutic glucose range within the recommended levels in published guidelines. Most residents also said they felt "somewhat comfortable" managing hyperglcemia and hypoglycemia and using subcutaneous insulin therapy, whereas most residents (48%) were "not at all comfortable" with use of intravenous administration of insulin. In general, respondents were not very familiar with existing institutional policies and preprinted order sets relating to glucose management. The most commonly reported barrier to management of inpatient hyperglycemia was lack of knowledge about appropriate insulin regimens and how to use them. Anxiety about hypoglycemia was only the third most frequent concern. CONCLUSION: Most residents acknowledged the importance of good glucose control in hospitalized patients and chose target glucose ranges consistent with existing guidelines. Lack of knowledge about insulin treatment options was the most commonly cited barrier to ideal management. Educational programs should emphasize inpatient treatment strategies for glycemic control.

Journal: Endocr Pract. 2007 Mar-Apr;13(2):117-24.
Adapted from PubMed; click here to access full journal article.

The Effects of Hypo- and Hyperglycaemia on the Hypoxic Ventilatory Response in Humans.

Authors: Ward DS, Voter WA, Karan S.

University of Rochester.

Animal and tissue studies have indicated that the carotid bodies are sensitive to glucose concentrations within the physiological range. This glucose sensitivity may modulate the ventilatory response to hypoxia, with hyperglycaemia suppressing the hypoxic response and hypoglycaemia stimulating it. This study was designed to determine if, in humans, hypo- and hyperglycaemia modulate the hypoxic ventilatory response. In 11 normal research participants, glucose levels were clamped at 2.8 and 11.2 mmol l-1 for 30 minutes. At the start and end of each clamp, blood was drawn for hormone measurement and the isocapnic hypoxic ventilatory response was measured. Because generation of reactive oxygen species may be a common pathway for the interaction between glucose and oxygen levels, the experiments were repeated with and without pretreatment for one week with vitamins C and E. Hypoglycaemia caused an increase in the counter-regulatory hormones, a 54% increase in isocapnic ventilation, and a 108% increase in the hypoxic ventilatory response. Contrary to the hypothesis, hyperglycaemia resulted in small but significant increases in both ventilation and the hypoxic ventilatory response. Antioxidant vitamin pre-treatment altered neither response. In conclusion, the stimulant effect of hypoglycaemia on the hypoxic ventilatory response is consistent with a direct effect on the carotid body, but an indirect effect through the activation of the counter-regulatory response cannot be excluded. The mechanisms behind the mild stimulating effect of hyperglycaemia remain to be elucidated.

Journal: J Physiol. 2007 May 3
Adapted from PubMed; click here to access full journal article.

Join Now - Become a free member and get notified about studies in your area when they become available.

Browse Our Current Studies - Look over all of our current studies being conducted throughout the United States.

View Information and Clinical Trials for Other Conditions - Access all of our health-related content.