Gluconeogenesis And Nitrogen Balance

Gluconeogenesis

Creating glucose when body is low on energy. This will maintain blood glucose levels and preserves proteins which would otherwise be broken down for energy. 90% of gluconeogenesis occurs in the liver, 10% in the kidney. This process costs 4 ATP, 2 GTP, and 2 NADH.

This process runs glycolysis backwards. However, the three irreversible steps of glycolysis must be circumvented to do so.

Bypass 1: Pyruvate Kinase

This step occurs in the mitochondria with recently formed pyruvate. This is converted into oxaloacetate (OAA) via pyruvate carboxylase. Biotin is required as a cofactor for this reaction. Because oxaloacetate is a TCA intermediate, this process is anaplerotic (increasing TCA factors). The OAA can then be exported via the Malate-Aspartate Shuttle.

Once the OAA is in the cytosol, it is converted to phosphoenolpyruvate (PEP), the intermediate above the irreversible pyruvate kinase step.

NOTE: During this step, pyruvate kinase is inhibited by alanine and also by phosphorylate via PKA.

Alternative pathway

OAA can be converted directly to phosphoenolpyruvate (PEP), but this will not regenerate NADH and will require input from the oxidation of lactate to pyruvate.

Bypass 2: Phosphofructokinase (PFK-1)

This step can by reversed by the conversion of fructose-1,6 bisphosphate (F1,6BP) to fructose-6-phosphate (F6P) via Fructose 1,6 bisphosphatase (FBP-1).

Regulation

This step is metered by intermediates which allows the body to control the rate of gluconeogenesis.

The conversion of F6P to F1,6BP in glycolysis also yields some F2,6BP via PFK-2, which is an activator of PFK-1 and an inhibitor of FPB-1. However, in low glucose states, fructose bisphosphatase-2 (FBP-2) will be active which will decrease the amount of F2,6BP produced, slowing down glycolysis.

PFK-1: Continues glycolysis
FPB-1: Reverses glycolysis

PFK-2: Produces F2,6BP (promotes PFK-1/inhibits FPB-1 → continues glycolysis)
FBP-2: Catabolizes F2,6BP (inhibits PFK-1/promotes FPB-1 → reverses glycolysis)

Bypass 3: Hexokinase

G6P can be converted to glucose via glucose-6-phosphotatse.

Clinical pearl: Diabetic Ketoacidosis

Hyperglycemia is the hallmark of DKA which is indicated by a blood glucose < 250 mg/dl. Therefore, the body will ramp up glucose production. Ketones will also be produced, which appear in blood and urine.

Other indicators:

Low bicarbonate (<15 mEq/L) will result in acidosis (pH < 7.35).
Potassium deficit
High blood urea nitrogen (BUN)

Amino acid catabolism

This is when glycogen is depleted and lactic acid is not being produced (abject starvation). The carbon skeletons from glucogenic amino acids can be used as material for gluconeogenesis.

Glucogenic amino acids: Alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, methionine, proline, serine, valine
Glucogenic and ketogenic amino acids (PITTT): Isoleucine, phenylalanine, tryptophan, tyrosine, threonine
Ketogenic amino acids: Lysine, leucine

Aminotransferase

Will move the amino group from a glucogenic amino acid to alpha-ketoglutarate (AKG), forming a glutamate and an alpha-keto acid. AKG is the rate limiting factor in this reaction and requires use of Vitamin B6. Glutamate can then be deaminated back to alpha-ketoglutarate via glutamate dehydrogenase.

Leftover nitrogen (ammoniums) are transferred to pyruvate, forming alanine, which can then be safely transported to the liver. There, it is converted to urea and excreted. This is referred to as the glucose-alanine cycle.