Gluconeogenesis

Gluconeogenesis, literally the making of new glucose, is how the body produces glucose when none is arriving from food and glycogen stores are running low. It takes place mainly in the liver, with the kidneys contributing more during long fasts. Its raw materials include lactate from muscles and red blood cells, glycerol released from stored fat, and amino acids such as alanine from the breakdown of protein. Humans cannot make glucose from even-chain fatty acids, because their carbon enters metabolism as acetyl CoA, which cannot be turned back into pyruvate.

The pathway is largely glycolysis in reverse, but three steps of glycolysis release so much energy that they cannot simply run backward. Gluconeogenesis bypasses them with other enzymes: pyruvate is converted to oxaloacetate and then to phosphoenolpyruvate, fructose-1,6-bisphosphatase takes the place of phosphofructokinase, and glucose-6-phosphatase frees glucose in the last step. Using separate enzymes lets the cell control the two pathways independently. Building glucose this way costs energy, paid in ATP and GTP.

The brain and red blood cells need a steady glucose supply, so gluconeogenesis is vital during fasting and starvation. Glucagon and cortisol switch it on and insulin holds it back. In the Cori cycle, lactate from hard-working muscle travels to the liver, which rebuilds it into glucose for the muscle to use again.