What is hypoglycemia? |

Causes and Symptoms

The condition known as hypoglycemia exists when the concentration of glucose in the bloodstream is too low to meet bodily needs for fuel, particularly those of the brain. Ordinarily, physiological compensatory mechanisms are called into play when the circulating concentration of glucose falls below about 3.5 millimoles. Activation of the sympathetic nervous system and the secretion of glucagon are especially important in promoting glycogenolysis and gluconeogenesis. Symptoms of sympathetic nervous activation normally become apparent with glucose concentrations that are less than about 3 millimoles. Brain function is usually demonstrably abnormal at glucose concentrations below about 2 millimoles; sustained hypoglycemia in this range can lead to permanent brain damage.

Some of the symptoms of hypoglycemia occur as by-products of activation of the sympathetic nervous system. These symptoms include trembling, pallor, palpitations and rapid heartbeat, sweating, abdominal discomfort, and feelings of anxiety and/or hunger. These symptoms are not dangerous in themselves; in fact, they may be considered to be beneficial, as they alert the individual of the need to obtain food. Meanwhile, the sympathetic nervous system signals compensatory mechanisms. The manifestations of abnormal brain function during hypoglycemia include blunting of higher cognitive functions, disturbed mentation, confusion, loss of normal control of behavior, headache, lethargy, impaired vision, abnormal speech, paralysis, neurologic deficits, coma, and epileptic seizures. The individual is usually unaware of the appearance of these symptoms, which can present real danger. For example, episodes of hypoglycemia have occurred while individuals were driving motor vehicles, which can lead to serious injury and death. After recovery from hypoglycemia, the patient may have no memory of the episode.

There are two major categories of hypoglycemia: fasting and reactive. The most serious, fasting hypoglycemia, represents impairment of the mechanisms responsible for the production of glucose when food is not available. These mechanisms include the functions of cells in the liver and brain that monitor the availability of circulating glucose. Additionally, there is a coordinated hormonal response involving the secretion of glucagon, growth hormone, and other hormones and the inhibition of the secretion of insulin. The normal consequences of these processes include the addition of glucose to the circulation, primarily from glycogenolysis, as well as a slowing of the rate of utilization of circulating glucose by many tissues of the body, especially the liver, skeletal and cardiac muscle, and fat. Even after days without food, the body normally avoids hypoglycemia through breakdown of stored proteins and activation of gluconeogenesis. There is considerable redundancy in the systems that maintain glucose concentration, so the occurrence of hypoglycemia often reflects the presence of defects in more than one of these mechanisms.

The other category of hypoglycemia, reactive hypoglycemia, includes disorders in which there is disproportionately prolonged and/or great activity of the physiologic systems that normally cause storage of the glucose derived from ingested foods. When a normal person eats a meal, the passage of food through the stomach and intestines elicits a complex and well-orchestrated neural and hormonal response, culminating in the secretion of insulin from the beta cells of the islets of Langerhans in the
pancreas. The insulin signals the cells in muscle, adipose tissue, and the liver to stop producing glucose and to derive energy from glucose obtained from the circulation. Glucose in excess of the body’s immediate needs for fuel is taken up and stored as glycogen or is utilized for the manufacture of proteins. Normally, the signals for the uptake and storage of glucose reach their peak of activity simultaneously with the entry into the circulation of glucose from the food undergoing digestion. As a result, the concentration of glucose in the circulation fluctuates only slightly. In individuals with reactive hypoglycemia, however, the entry of glucose from the digestive tract and the signals for its uptake and storage are not well synchronized. When signals for the cellular uptake of glucose persist after the intestinally derived glucose has dissipated, hypoglycemia can result. Although the degree of hypoglycemia may be severe and potentially dangerous, recovery can take place without assistance if the individual’s general nutritional state is adequate and the systems for activation of glycogenolysis and gluconeogenesis are intact.

Diagnosis and Treatment

The diagnostic evaluation of an individual who is suspected of having hypoglycemia begins with verification of the condition. Evaluation of a patient’s symptoms can be confusing. On one hand, the symptoms arising from the sympathetic nervous system and those of neuroglycopenia may occur in a variety of nonhypoglycemic conditions. On the other hand, persons with recurrent hypoglycemia may have few or no obvious symptoms. Therefore, it is most important to document the concentration of glucose in the blood.

To establish the diagnosis of fasting hypoglycemia, the patient is kept without food for periods of time, up to seventy-two hours, with frequent monitoring of the blood glucose. Should hypoglycemia occur, blood is taken for measurements of the key regulatory neurosecretions and hormones, including insulin, glucagon, growth hormone, cortisol, and epinephrine, as well as general indices of the function of the liver and kidneys. If there is suspicion of an abnormality in an enzyme involved in glucose production, the diagnosis can be confirmed by measurement of the relevant enzymatic activity in circulating blood cells or, if necessary, in a biopsy specimen of the liver.

Fasting hypoglycemia may be caused by any condition that inhibits the production of glucose or that causes an inappropriately great utilization of circulating glucose when food is not available. Insulin produces hypoglycemia through both of these mechanisms. Excessive circulating insulin ranks as one of the most important causes of fasting hypoglycemia, most cases of which result from the treatment of diabetes mellitus with insulin or with an oral drug of the sulfonylurea class. If the patient is known to be taking insulin or a sulfonylurea drug for diabetes, the cause of hypoglycemia is obvious; appropriate modification of the treatment should be made. Hypoglycemia caused by oral sulfonylureas is particularly troublesome because of the prolonged retention of these drugs in the body. The passage of several days may be required for recovery, during which time the patient needs continuous intravenous infusion of glucose.

Excessive insulin secretion may also result from increased numbers of pancreatic beta cells; the abnormal beta cells may be so numerous that they form benign or malignant
tumors, called insulinomas. The preferred treatment of an insulinoma is surgery, if feasible. When the tumor can be removed surgically, the operation is often curative. Unfortunately, insulinomas are sometimes difficult for the surgeon to find. Magnetic resonance imaging (MRI), computed tomography (CT) scanning, ultrasonography, or angiography may help localize the tumor. Some insulinomas are multiple and/or malignant, rendering total removal impossible. In these circumstances, hypoglycemia can be relieved by drugs that inhibit the secretion of insulin.

Malignant tumors arising from various tissues of the body may produce hormones that act like insulin with respect to their effects on glucose metabolism. In some cases, these hormones are members of the family of insulin-like growth factors, which resemble insulin structurally. Malnutrition probably has an important role in predisposing patients with malignancy to hypoglycemia, which tends to occur when the cancer is far advanced.

Fasting hypoglycemia can be caused by disorders affecting various parts of the endocrine system. One such disorder is adrenal insufficiency; continued secretion of cortisol by the adrenal cortex is required for maintenance of normal glycogen stores and of the enzymes of glycogenolysis and gluconeogenesis. Severe hypothyroidism also may lead to hypoglycemia. Impairment in the function of the anterior pituitary gland predisposes a patient to hypoglycemia through several mechanisms, including reduced function of the thyroid gland and adrenal cortices (which depend on pituitary secretions for normal activity) and reduced secretion of growth hormone. Growth hormone plays an important physiologic role in the prevention of fasting hypoglycemia by signaling metabolic changes that allow heart and skeletal muscles to derive energy from stored fats, thereby sparing glucose for the brain. Specific replacement therapies are available for
deficiencies of thyroxine, cortisol, and growth hormone.

Hypoglycemia has occasionally been reported as a side effect of treatment with medications other than those intended for treatment of diabetes. Drugs that have been implicated include sulfonamides, used for treatment of bacterial infections; quinine, used for treatment of falciparum malaria; pentamidine isethionate, given by injection for treatment of pneumocystosis; ritodrine, used for inhibition of premature labor; and propranolol or disopyramide, both of which are used for treatment of cardiac arrhythmias. Malnourished patients seem to be especially susceptible to the hypoglycemic effects of these medications, and management should consist of nutritional repletion in addition to discontinuation of the drug responsible. In children, aspirin or other medicines containing salicylates may produce hypoglycemia.

Alcohol hypoglycemia occurs in persons with low bodily stores of glycogen when there is no food in the intestine. In this circumstance, the only potential source of glucose for the brain is gluconeogenesis. When such an individual drinks alcohol, its metabolism within the liver prevents the precursors of glucose from entering the pathways of gluconeogenesis. This variety of fasting hypoglycemia can occur in persons who are not chronic alcoholics: It requires the ingestion of only a moderate amount of alcohol, on the order of three mixed drinks. Treatment involves the nutritional repletion of glycogen stores and the limitation of alcohol intake.

Severe infections, including overwhelming bacterial infection and malaria, can produce hypoglycemia by mechanisms that are not well understood. Patients with very severe liver damage can develop fasting hypoglycemia, because the pathways of glycogenolysis and gluconeogenesis in the liver are by far the major sources of circulating glucose in the fasted state. In such cases, the occurrence of hypoglycemia usually marks a near-terminal stage of liver disease. Uremia, the syndrome produced by kidney failure, can also lead to fasting hypoglycemia.

Some types of fasting hypoglycemia occur predominantly in infants and children. Babies in the first year of life may have an inappropriately high secretion of insulin. This problem occurs especially in newborn infants whose mothers had increased circulating glucose during pregnancy. Children from two to ten years of age may develop ketotic hypoglycemia, which is probably related to insufficient gluconeogenesis. These disorders tend to improve with time. Fasting hypoglycemia is also an important manifestation of a variety of inherited disorders of metabolism characterized by the abnormality or absence of one of the necessary enzymes or cofactors of glycogenolysis and gluconeogenesis or of fat metabolism (which supplies the energy for gluconeogenesis). Most of these disorders become evident in infancy or childhood. If there is a hereditary or acquired deficiency of an enzyme of glucose production, the problem can be circumvented by provision of a continuous supply of glucose to the affected individual.

There are several other rare causes of fasting hypoglycemia. A few individuals have had circulating antibodies that caused hypoglycemia by interacting with the patient’s own insulin or with receptors for insulin on the patient’s cells. Although the autonomic (involuntary) nervous system has an important role in signaling recovery from hypoglycemia, diseases affecting this branch of the nervous system do not usually produce hypoglycemia; presumably, hormonal mechanisms can substitute for the missing neural signals.

Reactive hypoglycemia can occur with an unusually rapid passage of foodstuffs through the upper intestinal tract, such as may occur after partial or total removal of the stomach. Persons predisposed to maturity-onset diabetes may also have reactive hypoglycemia, probably because of the delay in the secretion of insulin in response to a meal. Finally, reactive hypoglycemia need not indicate the presence of any identifiable disease and may occur in otherwise normal individuals.

Diagnosis of reactive hypoglycemia is made difficult by the variability of symptoms and of glucose concentrations from day to day. Adding to the diagnostic uncertainty, circulating glucose normally rises and falls after meals, especially those rich in carbohydrates. Consequently, entirely normal and asymptomatic individuals may sometimes have glucose concentrations at or below the levels found in persons with reactive hypoglycemia. Therefore, the
glucose tolerance test, in which blood samples are taken at intervals for several hours after the patient drinks a solution containing 50 to 100 grams of glucose, is quite unreliable and should not be employed for the diagnosis of reactive hypoglycemia. Proper diagnosis of reactive hypoglycemia depends on careful correlation of the patient’s symptoms with the circulating glucose level, preferably measured on several occasions after ingestion of ordinary meals. Some persons develop symptoms such as weakness, nausea, sweating, and tremulousness after meals, but without a significant reduction of circulating glucose. This symptom complex should not be confused with hypoglycemia.

When rapid passage of food through the stomach and upper intestine causes reactive hypoglycemia, the administration of drugs that slow intestinal transit may be helpful. When reactive hypoglycemia has no evident pathological cause, the patient is usually advised to take multiple small meals throughout the day instead of the usual three meals and to avoid concentrated sweets. These dietary modifications can help avoid hypoglycemia by reducing the stimulus to secrete insulin.

Two rare inherited disorders of metabolism can produce reactive hypoglycemia after the ingestion of certain foods. In hereditary fructose intolerance, the offending nutrient is fructose, a sugar found in fruits as well as ordinary table sugar. In
galactosemia, the sugar responsible for hypoglycemia is galactose, a major component of milk products. Management of these conditions, which usually become apparent in infancy or childhood, consists of avoidance of the foods responsible.

Perspective and Prospects

Fasting hypoglycemia is uncommon, except in the context of treatment of diabetes mellitus. The most serious public health problem associated with hypoglycemia is that it limits the therapeutic effectiveness of insulin and sulfonylurea drugs. Evidence suggests that elevation of the circulating glucose concentration (hyperglycemia) is responsible for much of the disability and premature death among patients withdiabetes. In many of these patients, therapeutic regimens consisting of multiple daily injections of insulin or continuous infusion of insulin through a small needle placed under the skin can reduce the average circulating glucose to normal. Frequent serious hypoglycemia is the most important adverse consequence of such regimens. Persons with diabetes seem to be at especially high risk for dangerous hypoglycemia for two reasons. First, there is often a failure of the warning systems that ordinarily cause uncomfortable symptoms when the circulating glucose concentration declines, a situation termed hypoglycemic unawareness. As a consequence, when a patient with diabetes attempts to control his or her blood sugar with more frequent injections of insulin, there may occur unheralded episodes of hypoglycemia that can lead to serious alterations in mental activity or even loss of consciousness. Many patients with diabetes also have hypoglycemic unresponsiveness, an impaired ability to recover from episodes of hypoglycemia. Also, diabetes can interfere with the normal physiologic responses that cause the secretion of glucagon in response to a reduction of circulating glucose, thus eliminating one of the most important defenses against hypoglycemia. If both hypoglycemic unawareness and hypoglycemic unresponsiveness could be reversed, intensive treatment of diabetes would become safer and more widely applicable.

Reactive hypoglycemia, although seldom a clue to serious disease, has attracted public attention because of its peculiarly annoying symptoms. These symptoms, which reflect activation of the sympathetic nervous system, resemble those of fear and anxiety. The symptoms are not specific, and many patients with these complaints do not have hypoglycemia.

In summary, hypoglycemia indicates defective regulation of the supply of energy to the body. When severe or persistent, hypoglycemia can lead to serious behavioral disorder, obtunded consciousness, and even brain damage. Fasting hypoglycemia may be a clue to significant endocrine disease. Reactive hypoglycemia, while annoying, usually responds to simple dietary measures. The study of hypoglycemia has led to many important insights into the regulation of energy metabolism.

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