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A 14-year-old high school girl who is extremely conscious about her appearance has gone  near fasting for two days to fit in to a dress she intentionally brought a size smaller than her actual size for a dance party. Which of the following organs/tissues contributes to the glucose that is being synthesized through gluconeogenesis?

A) Spleen

B) Red blood cells

C) Skeletal muscle

D) Liver

E) Brain

The correct answer is- D) Liver.

Gluconeogenesis is the process of converting non-carbohydrate precursors to glucose or glycogen.

Gluconeogenesis meets the needs of the body for glucose when sufficient carbohydrate is not available from the diet or glycogen reserves. A supply of glucose is necessary especially for the nervous system and erythrocytes. Failure of gluconeogenesis is usually fatal.

Liver and kidney are the major gluconeogenic tissues.

Substrates of Gluconeogenesis

The major substrates are-

  1. The glucogenic amino acids,
  2. Lactate
  3. Glycerol, and
  4. Propionate.

These noncarbohydrate precursors of glucose are first converted into pyruvate or enter the pathway at later intermediates such as oxaloacetate and Dihydroxyacetone phosphate (figure-1).

Pathway of gluconeogensis


Figure-1- Reactions of gluconeogenesis. Three irreversible reactions of glycolysis are substituted by alternative reactions. Pyruvate carboxylase, Phospho enol pyruvate carboxy kinase, Fructose 1,6 bisphosphatase and glucose-6-Phosphatase enzymes are unique to pathway of gluconeogenesis. Lactate enters as pyruvate, glycerol as Dihydroxy acetone-phosphate, propionate as Succinyl co A, and the intermediates of TCA cycle distal to α-Keto glutarate are glucogenic. Acetyl co A  is not glucogenic but it is a positive modulator of pyruvate carboxylase enzyme.

Role of kidney

Although the liver has the critical role of maintaining blood glucose homeostasis and therefore, is the major site of gluconeogenesis, the kidney also 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. The glutamine is then transported to the kidneys where the reverse reactions occur. Glutamate is first produced from hydrolysis of Glutamine by glutaminase, which is then further catabolized  liberating ammonia and producing α-ketoglutarate which can enter the TCA cycle and the carbon atoms diverted to gluconeogenesis via oxaloacetate.

Role of kidney in gluconeogenesis

Figure-2- Role of kidney in gluconeogenesis

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.









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