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Extra Edge
  1. Gluconeogenesis is the process of synthesizing glucose from noncarbohydrate precursors. It is of particular importance when carbohydrate is not available from the diet.
  2. Since glycolysis and gluconeogenesis share the same pathway but operate in opposite directions, their activities must be regulated reciprocally.
  1. Substrate : Glucogenic amino acid (amino acids that can be converted into glucose), lactate, pyruvate, propionate from odd carbon fatty acids and glycerol.
  2. Location:
    1. Liver is responsible for 85% of glucose that is made,
    2. During starvation or metabolic acidosis, kidney is capable of making glucose and may contribute to 50% glucose formed.
      Energetics: Conversion of 2 moles of pyruvate into 1 mole of glucose requires 4 moles of ATP, 2 moles GTP and 2 moles of NADH.  
  3. Conditions characterized by active gluconeogenesis:
    1. Prolonged fasting and starvation
    2. Periods of intense exercise, where lactate produced in muscle are transported to the liver to be converted into glucose, through the Cori cycle which is an active cycle during gluconeogenesis. The lactate from RBC is also converted by liver to glucose through Cori cycle.
    3. Diabetes mellitus, due to the lack of insulin, an inhibitory hormone for gluconeogenesis.  Also in diabetic persons glucogenic hormones (principally cortisol) act unopposed.
    4. Cushing’s syndrome – due to excessive production of cortisol from adrenal cortex.
    5. In patients treated by high doses of cortisone or ACTH. 
  4. Enzymes of gluconeogenesis:
    1. Pyruvate carboxylase
    2. Phosphoenol pyruvate carboxykinase
    3. Fructose 1,6 diphosphatase
    4. Glucose-6-phosphatase
These enzymes are present in liver and kidney, the 2 organs carrying out gluconeogenesis.  Major pathways and regulation of gluconeogenesis and glycolysis in liver is shown below:


Shuttle System

  1. Most of the NADH and FADH2, entering the mitochondrial electron transport chain arise from citric acid cyle and -oxidation of fatty acids, located in the mitochondria itself.
  2. NADH is also produced in the cytosol during glycolysis
  3. To get oxidized, NADH has to be transported into the mitochondria as respiratory chain (ETC) is located inside the mitochondria. Since, the inner mitochondrial membrane is not permeable to cytoplasmic NADH, there are special shuttle systems which carry reducing equivalents from cytosolic NADH (rather than NADH itself) into the mitochondria by an indirect route.
  4. Two such shuttle systems that can lead to transport of reducing equivalent from the cytoplasm into mitochondria are: -
  1. Malate Shuttle
  1. This is more common and universal shuttle used mainly in liver, kidney & heart.
  2. Oxidation of reduced NADH+ H+ in mitochondria yields 3 ATO (old)/ 2.5 ATP (new)
  3. When body utilized malate shuttle, net ATP production by glycolysis – TCA cycle per glucose molecule oxidized will be 38 ATP /32 ATP (new)
  4. The complexity of this system is d/t impermeability of mitochondrial membrane to O.A.A, which must react with glutamate & transaminase to aspartate and - ketoglutarate before transport through mitochondrial membrane & reconstitution to O.A.A in cytosol.
  1. Glycerophosphate Shuttle
  1. This is present in some tissue (e.g brain, white skeletal muscle) and absent in others (e.g. heart muscle)
  2. FADQ dependent so only 2 ATO (old) / 1.5 ATP (new are produced.
  3. When body utilizes this system, net ATP production is 36 ATP (old) / 30 ATP (new)

Glucose-alanine cycle
Because muscle is incapable of synthesizing urea, -amino groups of amino acids (i.e., ammonia) has be transported to liver, which is the major site of urea synthesis. Thus, glucose - alanine cycle serves two purposes:

  1. alanine helps in gluconeogenesis
  2. alanine also transports a-amino groups of amino acids to liver (i.e., excretion of ammonia). Alanine is the major amino-acid released from muscle to liver during fasting (or starvation) to transport ammonia (PGI97) as well as for gluconeogenesis.
Hormonal regulations of gluconeogenesis:
  1. Glucocorticoids (e.g. cortisol) are the most important stimulating hormones for gluconeogenesis. 
  2. These hormones act as inducers of pyruvate carboxylase, phosphoenol pyruvate carboxykinase, fructose 1,6 di phosphosphatase and glucose-1-phosphatase.
  3. Glucagon and epinephrine also stimulate gluconeogenesis but to a somewhat lesser extent than cortisol.
  4. Insulin on the other hand is an inhibitor for the key enzymes of gluconeogenesis. 

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