gluconeogenes

Gluconeogenesis is a metabolic pathway that generates glucose from non-carbohydrate precursors. It primarily occurs in the liver, with a significant contribution from the kidneys during prolonged fasting; small amounts can occur in enterocytes of the small intestine.

Substrates include lactate, glycerol, and glucogenic amino acids such as alanine, aspartate, and glutamate. Lactate is produced by anaerobic glycolysis in muscle and erythrocytes (the Cori cycle). Glycerol comes from lipolysis in adipose tissue. These non-carbohydrate sources are converted through a series of enzyme-catalyzed reactions to glucose.

Core steps bypass the irreversible glycolytic steps. Pyruvate carboxylase and PEP carboxykinase convert pyruvate to phosphoenolpyruvate, bypassing the pyruvate kinase step. Fructose-1,6-bisphosphatase bypasses phosphofructokinase-1, and glucose-6-phosphatase converts glucose-6-phosphate to glucose, the final shared step in the liver and kidney. In the liver, glucose-6-phosphatase is located in the endoplasmic reticulum.

Energy cost: The pathway is energy-intensive, requiring about 4 ATP equivalents and 2 GTP per glucose synthesized.

Regulation: Gluconeogenesis is inhibited by insulin and activated by glucagon and cortisol via cAMP signaling. AMP and acetyl-CoA modulate key steps (acetyl-CoA activates pyruvate carboxylase, AMP inhibits fructose-1,6-bisphosphatase). Regulation ensures balance with glycolysis and overall energy status.

Physiological role: It maintains blood glucose during fasting, supporting the brain, red blood cells, and other glucose-dependent tissues. Dysregulation can contribute to metabolic disturbances, though defects in gluconeogenesis are uncommon; severe hypoglycemia may occur with deficiencies in key enzymes.