Alcohol-related hypoglycemia occurs when alcohol is metabolized in the liver through two oxidation reactions. The first reaction involves alcohol dehydrogenase converting ethanol to acetaldehyde, followed by aldehyde dehydrogenase oxidizing acetaldehyde to acetate. It is important to note that the drug disulfiram, used in treating chronic alcoholism, inhibits aldehyde dehydrogenase, leading to an increase in acetaldehyde levels which can cause flushing, tachycardia, hyperventilation, and nausea.

During these reactions, the oxidized form of nicotinamide adenine dinucleotide (NAD+) accepts electrons, resulting in an increased ratio of the reduced form (NADH) to NAD+. This abundance of NADH promotes the reduction of pyruvate to lactate and oxaloacetate (OAA) to malate. Pyruvate and OAA are substrates involved in glucose synthesis. Consequently, the increase in NADH levels caused by ethanol metabolism diverts these gluconeogenic precursors into alternate pathways, ultimately leading to a decrease in glucose synthesis. This can trigger hypoglycemia, particularly in individuals who have depleted their liver glycogen stores.

Moreover, decreased availability of OAA leads to the diversion of acetyl CoA to ketone body synthesis in the liver, resulting in alcoholic ketosis and potentially ketoacidosis. Hypoglycemia can produce symptoms resembling alcohol intoxication, including agitation, impaired judgment, and combativeness. Therefore, vulnerable individuals, such as those who are fasting or have engaged in prolonged strenuous exercise, may experience alcohol-induced hypoglycemia, contributing to the behavioral effects of alcohol. Additionally, patients using insulin are at an increased risk of hypoglycemia after alcohol consumption.

Chronic alcohol consumption can also lead to alcoholic fatty liver due to increased hepatic synthesis of triglycerides (TAG) and impaired formation or release of very low-density lipoprotein (VLDL). This occurs as a result of decreased fatty acid oxidation caused by a decrease in the NAD+/NADH ratio. Additionally, increased lipogenesis occurs due to the higher availability of fatty acids (decreased catabolism) and glyceraldehyde 3-phosphate (as the dehydrogenase is inhibited by the low NAD+/NADH ratio). If alcohol consumption continues, alcoholic fatty liver can progress to alcoholic hepatitis and eventually alcoholic cirrhosis.

In summary, alcohol metabolism in the liver can lead to alcohol-related hypoglycemia, where the increase in NADH levels diverts gluconeogenic precursors and decreases glucose synthesis. This can have behavioral effects similar to alcohol intoxication. Chronic alcohol consumption can also result in alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis due to various metabolic disturbances.
Alcohol-related hypoglycemia: Alcohol (ethanol) is metabolized in the liver by two oxidation reactions (Fig. 23.15). Ethanol is first converted to acetaldehyde by zinc-containing 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 ratio of the reduced form (NADH) to NAD+. The abundance of NADH favors the reduction of pyruvate to lactate and of oxaloacetate (OAA) to malate. Recall from p. 118 that pyruvate and OAA are substrates in the synthesis of glucose. Thus, the ethanol-mediated increase in NADH causes these gluconeogenic precursors 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 (see p. 195) and can result in alcoholic ketosis that may result in 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. Because alcohol consumption can also increase the risk for hypoglycemia in patients using insulin, those in an intensive insulin treatment protocol (see p. 340) are counseled about the increased risk of hypoglycemia that generally occurs many hours after alcohol ingestion.
B. Inhibition of gluconeogenesis resulting from hepatic metabolism of ethanol. NAD(H) = nicotinamide adenine dinucleotide.
Chronic alcohol consumption can also result in alcoholic fatty liver because of increased hepatic synthesis of TAG coupled with impaired formation or release of VLDL. This occurs as a result of decreased FA oxidation because of a fall in the NAD+/NADH ratio and increased lipogenesis because of the increased availability of FA (decreased catabolism) and of glyceraldehyde 3-phosphate (the dehydrogenase is inhibited by the low NAD+/NADH ratio; see p. 101). With continued alcohol consumption, alcoholic fatty liver can progress first to alcoholic hepatitis and then to alcoholic cirrhosis.
V. CHAPTER SUMMARY