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Q.1-What is the cause of Alcohol induced hypoglycemia?

Answer- Alcohol-related hypoglycemia is due to hepatic glycogen depletion combined with alcohol-mediated inhibition of gluconeogenesis. It is most common in malnourished alcohol abusers, but can occur in anyone who is unable to ingest food after an acute alcoholic episode followed by gastritis and vomiting.

The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a cytosolic enzyme that catalyzes the conversion of alcohol to acetaldehyde (Figure-1). This enzyme is located mainly in the liver, but small amounts are found in other organs such as the brain and stomach.

During conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from alcohol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH.

Much of the acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (AcDH). The product of this reaction is acetate (Figure-1), which can be further metabolized to CO2 and water, or used to form acetyl-CoA. As a net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. The excess NADH production appears to contribute to the metabolic disorders that accompany chronic alcoholism.

The NADH produced in the cytosol by ADH must be reduced back to NAD+. The reduction in NAD+ Impairs the flux of glucose through glycolysis at the glyceraldehyde-3-phosphate dehydrogenase reaction, thereby limiting energy production. Additionally, there is an increased rate of hepatic lactate production due to the effect of increased NADH on the direction of the hepatic lactate dehydrogenase (LDH) reaction. This reversal of the LDH reaction in hepatocytes diverts pyruvate from gluconeogenesis leading to a reduction in the capacity of the liver to deliver glucose to the blood.

In addition to the negative effects of the altered NADH/NAD+ ratio on hepatic gluconeogenesis, fatty acid oxidation is also reduced as this process requires NAD+ as a cofactor. In fact the opposite is true, fatty acid synthesis is increased and there is an increase in triacylglyceride production by the liver. In the mitochondria, the production of acetate from acetaldehyde leads to increased levels of acetyl-CoA. Since the increased generation of NADH also reduces the activity of the TCA cycle, the acetyl-CoA is diverted to fatty acid synthesis. The reduction in cytosolic NAD+ leads to reduced activity of glycerol-3-phosphate dehydrogenase (in the glycerol 3-phosphate to DHAP direction) resulting in increased levels of glycerol 3-phosphate which is the backbone for the synthesis of the triacylglycerides. Both of these two events lead to fatty acid deposition in the liver, leading to fatty liver syndrome.



Figure-1- showing metabolism of alcohol and conversion of pyruvate to lactate

Q.-2 Premature and low-birth-weight babies are more susceptible to hypoglycemia, what could be the possible cause for this?

Answer- Premature and low-birth-weight babies are more susceptible to hypoglycemia, since they have little adipose tissue to provide alternative fuels such as free fatty acids or ketone bodies during the transition from fetal dependency to the free-living state. The enzymes of gluconeogenesis may not be completely functional at this time, and gluconeogenesis is any way dependent on a supply of free fatty acids for energy. Little glycerol, which would normally be released from adipose tissue, is available for gluconeogenesis, but that is not sufficient to fulfill the energy needs. Small for date babies have inadequate glycogen stores as well, so at the time of need there is diminished outpouring of glucose. The situation worsens further due to prematurity since the glycogen stores are laid in the last months of pregnancy. Hence a premature baby has diminished stores and frequently undergoes hypoglycemia.

Q.3- What is the role played by kidneys in gluconeogenesis?

Answer- Although the liver has the critical role of maintaining blood glucose homeostasis and therefore, is the major site of gluconeogenesis, the kidney plays an important role. During periods of severe hypoglycemia that occur under conditions of hepatic failure, the kidney can provide glucose to the blood via renal gluconeogenesis. In the renal cortex, glutamine is the preferred substance for gluconeogenesis.

Glutamine is produced in high amounts by skeletal muscle during periods of fasting as a means to export the waste nitrogen resulting from amino acid catabolism. Through the actions of transaminases, a mole of waste ammonia is transferred to α-ketoglutarate via the glutamate dehydrogenase catalyzed reaction yielding glutamate. Glutamate is then a substrate for glutamine synthetase, which incorporates another mole of waste ammonia generating glutamine .The glutamine is then transported to the kidneys where the reverse reactions occur liberating the ammonia and producing α-ketoglutarate which can enter the TCA cycle and the carbon atoms diverted to gluconeogenesis via oxaloacetate. This process serves two important functions. The ammonia (NH3) that is liberated spontaneously ionizes to ammonium ion (NH4+) and is excreted in the urine effectively buffering the acids in the urine. In addition, the glucose that is produced via gluconeogenesis can provide the brain with critically needed energy.

 Q.4-   What is the biochemical basis for-

 a) Hypoglycemia in- Babies of diabetic mothers

 b) Maternal hypoglycemia during pregnancy

Answer- a) Babies of diabetic mothers- The growing fetus of a diabetic mother is exposed to maternal hyperglycemia which leads to hyperplasia of pancreatic islet cells. After delivery the baby fails to suppress the excessive insulin secretions and develops hypoglycemia.

b) Maternal or fetal hypoglycemia may also be observed during pregnancy, fetal glucose consumption increases and there is a risk of maternal and possibly fetal hypoglycemia, particularly if there are long intervals between meals or at night.

Q.5- What is the biochemical basis for Hypoglycemia in conditions of impaired fatty acid oxidation ?

Answer- Impaired fatty acid oxidation can be due to

1) Deficiency or inactivation of any of the enzyme of fatty acid oxidation pathway.

2) Carnitine deficiency (Carnitine is a transporter for transportation of fatty acids from the cytoplasm to mitochondria where the actual oxidation takes place).

3) Deficiency of coenzyme, as in chronic alcoholism

Impaired fatty acid oxidation results in hypoglycemia due to three main reasons-

a) There is an imbalance between demand and supply of fuels. There is no fatty acid oxidation, the requirement for Glucose increases

b) Acetyl Co A, the end product of fatty acid oxidation acts as a positive modifier for pyruvate carboxylase enzyme (Figure-2). In  conditions of impaired fatty acid oxidation, there is less activity of pyruvate carboxylase, less oxaloacetate  and hence less glucose production.

c) The energy evolved from fatty acid oxidation is used for glucose production in conditions of fasting or starvation, but in conditions of impaired fatty acid oxidation, non availability of sufficient energy causes inhibition of the pathway resulting in hypoglycemia.

Figure-2 -Acetyl Co A acts a  negative modifier for Pyruvate dehydrogenase complex (PDH) while a positive modifier for Pyruvate carboxylase. In conditions of excess production of  Acetyl co A  (as during fasting,starvation or diabetes mellitus, there is excessive fatty acid oxidation) PDH complex is inhibited, while pyruvate carboxylase is stimulated to provide more glucose.

Q.6-Why do nutritionists recommend  very low carbohydrate diets  to reduce body weight, What is the biochemical basis ?

Answer- Very low carbohydrate diets, providing only 20 g per day of carbohydrate or less (compared with a desirable intake of 100–120 g/day), but permitting unlimited consumption of fat and protein, have been promoted as an effective regime for weight loss, although such diets are counter to all advice on a prudent diet for health. Since there is a continual demand for glucose, there will be a considerable amount of gluconeogenesis from amino acids; the associated high ATP cost must then be met by oxidation of fatty acids. Endogenous adipose stores are depleted with the resultant weight loss.

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