Question

Alcohol consumption on an empty stomach results in hypoglycemia and ow blood pH levels.

There are also significant changes to certain metabolites (increased intracellular ratios of lactate

to pyruvate, of glycerol-3-phophate to dihydroxyacetone phosphate, of glutamate to alphaketoglutarate).

(a) Why does symptoms of hypoglycemia and blood acidosis seen only in hungry individuals

consuming alcohol and not in well-fed individuals consuming alcohol? (5 points)

(b) What is the biochemical explanation behind altered metabolite ratios? (5 points)

Answer 1

a) Metabolic acidosis occurs when the pH of blood falls below 7.35 and plasma bicarbonate is below 22mmol/L. Metabolic acidosis is due to lactic acidosis, ketoacidosis and acetic acidosis. Hypoglycemia is when the blood glucose levels falls in blood.

Liver is the organ that is responsible for storage of glucose as glycogen. When glucose levels in blood drop, glycogen is broken down in liver to release glucose. Alcohol limits the ability of the liver to release glucose. This impairment of liver lasts for several hours after consumption of alcohol. Although alcoholic drinks such as beer, wine have sugars in them, due to impairment of the liver, glucose cannot be released in the blood.

When a person has taken food, glucose present in blood enters the blood. This glucose is acted upon by insulin and taken up by cells. It takes about 2-4 hours for glucose to be metabolized before glucose levels start declining and glucagon activates glycogen breakdown. The liver impairment will be reinstated by the time blood sugar levels reduce. However, if a person has not eaten at the time of imbibing alcohol, the blood glucose levels are already low due to action of insulin. Further, the liver cannot breakdown glycogen in presence of increasing glucagon. This will cause further decline in blood sugar causing hypoglycemia.

Alcohol is metabolized in liver to acetaldehyde with reduction of NAD+ to NADH. This result in high NADH: NAD ratios. When NADH: NAD ratios are high, pyruvate is converted to lactic acid in liver. When glucose levels decline in starved individuals, there is more mobilization of fats from adipose tissues for energy generation. Lipids are broken down to acetyl CoA, which normally should enter TCA cycle. However, as the NADH:NAD ratios are high, TCA cycle slows down. Thus, there is formation of ketone bodies instead from acetyl CoA. The body will use acetate, a end product of alcohol metabolism as fuel and therefore ketoacids and lactic acid will accumulate in blood. This will cause blood acidosis. In fed individuals, glucose is still available for energy generation. Hence, ketoacids are not formed in blood.

b) Alcohol dehydrogenase reaction involves the reduction of NAD to NADH, when ethanol metabolizes to acetaldehyde in liver. Acetaldehyde is oxidised in hepatic mitochondria to acetic acid, which then forms acetyl coenzyme A (acetyl CoA). The increased NADH: NAD ratios affect liver mitochondrial metabolic activity. This raised NADH/NAD ratio affects glycogen metabolism in liver. Insulin production decreases and glucagon levels rise.

High NADH: NAD ratios inhibit gluconeogenesis as pyruvate is converted to lactate, which then enters the liver. As gluconeogenesis is inhibited and there is less glucose present in blood of starved individual, fats are mobilized from adipose tissue for energy generation. Fatty acids are oxidized to acetyl CoA. This acetyl CoA rather than entering TCA cycle, forms ketone bodies, which are released in blood. Increased lactate and ketoacids will cause acidosis.

Lactate is increased as pyruvate is used for conversion to lactate. Hence, lactate: pyruvate ratios are altered. Due to altered NADH: NAD+ ratio, DHAP is not converted to G-3-P. G-3-P breakdown to 1,3 Bis phosphoglycerate requires NAD+. Conversion of glutamate to alpha ketoglutarate involves glutamate dehydrogenase. This enzyme requires NAD+ to be oxidized to NADH. Due to high NADH: NAD ratios, the enzyme is inhibited. The glutamate levels will rise, as amino acids are broken down to glutamate and keto acids by transaminases for energy generation.

In fed individuals, glucose is available for energy generation. Hence, fatty acid metabolism or amino acid metabolism is not increased considerably in these individual due to alcohol consumption. Glucose is converted to pyruvate, which is broken down for energy formation. Hence, keto acids are not formed. This will not result in severe acidosis that is seen in starved individuals.