Hypoglycemia

HYPOGLYCEMIA

Hypoglycemia is characterized by 1) central nervous system (CNS) symptoms, including confusion, aberrant behavior, or coma; 2) a simultaneous blood glucose level equal to or less than 40 mg/dl; and 3) symptoms being resolved within minutes following the administration of glucose (Figure 23.13). Hypoglycemia is a medical emergency because the CNS has an absolute requirement for a continuous supply of bloodborne glucose to serve as fuel for energy metabolism. Transient hypoglycemia can cause cerebral dysfunction, whereas severe, prolonged hypoglycemia causes brain death. Therefore, it is not surprising that the body has multiple overlapping mechanisms to prevent or correct hypoglycemia. The most important hormone changes in combating hypoglycemia are elevated glucagon and the catecholamines, combined with the diminished release of insulin.

Figure 23.13 A. Actions of some of the glucoregulatory hormones in response to low blood glucose. B. Glycemic thresholds for the various responses to hypoglycemia. [Note: Normal fasted blood glucose is 70-99 mg/100 ml.] + = weak stimulation; ++ = moderate stimulation; +++ = strong stimulation; 0 = no effect; ACTH = adrenocorticotropic hormone.

A. Symptoms of hypoglycemia

The symptoms of hypoglycemia can be divided into two categories. Adrenergic symptoms, such as anxiety, palpitation, tremor, and sweating, are mediated by catecholamine release (primarily epinephrine) regulated by the hypothalamus in response to hypoglycemia. Adrenergic symptoms typically occur when blood glucose levels fall abruptly. The second category of hypoglycemic symptoms is neuroglycopenic. Neuroglycopenia (that is, the impaired delivery of glucose to the brain) results in impairment of brain function, causing headache, confusion, slurred speech, seizures, coma, and death. Neuroglycopenic symptoms often result from a gradual decline in blood glucose, often to levels below 40 mg/dl. The slow decline in glucose deprives the CNS of fuel, but fails to trigger an adequate adrenergic response.

B. Glucoregulatory systems

Humans have two overlapping glucose-regulating systems that are activated by hypoglycemia: 1) the pancreatic α cells, which release glucagon, and 2) receptors in the hypothalamus, which respond to abnormally low concentrations of blood glucose. The hypothalamic glucoreceptors can trigger both the secretion of catecholamines (mediated by the autonomic nervous system) and release of adrenocorticotropic hormone (ACTH) and growth hormone by the anterior pituitary (see Figure 23.13). [Note: ACTH increases cortisol synthesis and secretion in the adrenal cortex.] Glucagon, the catecholamines, cortisol, and growth hormones are sometimes called the “counterregulatory” hormones because each opposes the action of insulin on glucose use.

1. Glucagon and epinephrine: Secretion of these hormones is most important in the acute, short-term regulation of blood glucose levels. Glucagon stimulates hepatic glycogenolysis and gluconeogenesis. Epinephrine promotes glycogenolysis and lipolysis, inhibits insulin secretion, and inhibits the insulin-mediated uptake of glucose by peripheral tissues. Epinephrine assumes a critical role in hypoglycemia when glucagon secretion is deficient, for example, in the late stages of type 1 diabetes mellitus. The prevention or correction of hypoglycemia fails when the secretion of both glucagon and epinephrine is deficient.

2. Cortisol and growth hormone: These hormones are less important in the short-term maintenance of blood glucose concentrations. They do, however, play a role in the long-term (transcriptional) management of glucose metabolism.

C. Types of hypoglycemia

Hypoglycemia may be divided into four types: 1) insulin-induced, 2) postprandial (sometimes called reactive hypoglycemia), 3) fasting hypoglycemia, and 4) alcohol-related.

1. Insulin-induced hypoglycemia: Hypoglycemia occurs frequently in patients with diabetes who are receiving insulin treatment, particularly those striving to achieve tight control of blood glucose levels. Mild hypoglycemia in fully conscious patients is treated by oral administration of carbohydrate. Unconscious patients are typically given glucagon subcutaneously or intramuscularly (Figure 23.14).

Figure 23.14 Reversal of insulin-induced hypoglycemia by administration of subcutaneous glucagon.

2. Postprandial hypoglycemia: This is the second most common form of hypoglycemia. It is caused by an exaggerated insulin release following a meal, prompting transient hypoglycemia with mild adrenergic symptoms. The plasma glucose level returns to normal even if the patient is not fed. The only treatment usually required is that the patient eats frequent small meals rather than the usual three large meals.

3. Fasting hypoglycemia: Low blood glucose during fasting is rare but is more likely to present as a serious medical problem. Fasting hypoglycemia, which tends to produce neuroglycopenic symptoms, may result from a reduction in the rate of glucose production by hepatic glycogenolysis or gluconeogenesis. Thus, low blood glucose levels are often seen in patients with hepatocellular damage or adrenal insufficiency or in fasting individuals who have consumed large quantities of ethanol (see below). Alternately, fasting hypoglycemia may be the result of an increased rate of glucose use by the peripheral tissues due to overproduction of insulin by rare pancreatic tumors. If left untreated, a patient with fasting hypoglycemia may lose consciousness and experience convulsions and coma. [Note: Certain inborn errors of metabolism, for example, defects in fatty acid oxidation, result in fasting hypoglycemia.]

4. Alcohol-related hypoglycemia: Alcohol is metabolized in the liver by two oxidation reactions (Figure 23.15). Ethanol is first converted to acetaldehyde by alcohol dehydrogenase. Acetaldehyde is subsequently oxidized to acetate by aldehyde dehydrogenase (ALDH). [Note: ALDH is inhibited by disulfiram, a drug that is used in the treatment of chronic alcoholism. The resulting rise in acetaldehyde results in flushing, tachycardia, hyperventilation, and nausea.] In each reaction, electrons are transferred to oxidized nicotinamide adenine dinucleotide (NAD⁺), resulting in an increase in the concentration of cytosolic NADH. The abundance of NADH favors the reduction of pyruvate to lactate and of oxaloacetate (OAA) to malate. Recall that pyruvate and OAA are intermediates in the synthesis of glucose. Thus, the ethanol-mediated increase in NADH causes these intermediates of gluconeogenesis to be diverted into alternate pathways, resulting in the decreased synthesis of glucose. This can precipitate hypoglycemia, particularly in individuals who have depleted their stores of liver glycogen. [Note: Decreased availability of OAA allows acetyl CoA to be diverted to ketone body synthesis in the liver and can result in alcoholic ketoacidosis.] Hypoglycemia can produce many of the behaviors associated with alcohol intoxication, such as agitation, impaired judgment, and combativeness. Therefore, alcohol consumption in vulnerable individuals (such as those who are fasted or have engaged in prolonged, strenuous exercise) can produce hypoglycemia that may contribute to the behavioral effects of alcohol. Becuase alcohol consumption can also increase the risk for hypoglycemia in patients using insulin, those in an intensive insulin treatment protocol are counseled about the increased risk of hypoglycemia that generally occurs many hours after alcohol ingestion. [Note: Chronic alcohol consumption can also result in alcoholic fatty liver due to increased hepatic synthesis of TAGs coupled with impaired formation or release of VLDLs. This occurs as a result of decreased fatty acid oxidation due to a fall in the NAD⁺/NADH ratio and increased lipogenesis due to the increased availability of fatty acids (decreased catabolism) and of glyceraldehyde 3-phosphate (the dehydrogenase is inhibited by the low NAD⁺/NADH ratio). With continued alcohol consumption, alcoholic fatty liver can progress first to alcoholic hepatitis and then to alcoholic cirrhosis (Figure 23.16).]

Figure 23.15 A. Normal gluconeogenesis in the absence of ethanol consumption. B. Inhibition of gluconeogenesis resulting from hepatic metabolism of ethanol. NAD(H) = nicotinamide adenine dinucleotide.

Figure 23.16 Effects of chronic alcohol consumption on liver morphology.