Gluconeogenesis

Gluconeogenesis is the synthesis of new glucose from non-carbohydrate sources — chiefly lactate, glycerol from fat breakdown, and glucogenic amino acids such as alanine. It occurs primarily in the liver (with a smaller contribution from the kidney) and becomes the body's main source of blood glucose once glycogen stores are depleted during fasting, sustaining tissues like red blood cells and much of the brain's fuel supply.

The pathway is roughly glycolysis run in reverse, but three glycolytic steps are irreversible and must be bypassed by four unique enzymes: pyruvate carboxylase (pyruvate to oxaloacetate, in the mitochondria, requiring biotin), PEP carboxykinase (oxaloacetate to phosphoenolpyruvate), fructose-1,6-bisphosphatase (the key rate-limiting step), and glucose-6-phosphatase (found in the liver, which is why muscle cannot release free glucose). The Cori cycle links exercising muscle to the liver: muscle exports lactate, and the liver converts it back to glucose.

Hormones set the direction of flux. Glucagon, cortisol, and epinephrine promote gluconeogenesis during fasting and stress, while insulin suppresses it after a meal. Notably, fatty acids cannot be converted to glucose in humans — acetyl-CoA is not a gluconeogenic substrate — though the glycerol backbone of triglycerides is. Odd-chain fatty acids are the exception, yielding propionyl-CoA.

USMLE Step 1 and the MCAT both test gluconeogenesis alongside glycolysis: know the four bypass enzymes, the rate-limiting step, the fasting-state hormonal logic, and why acetyl-CoA cannot become glucose. The CSCS exam touches the pathway in sports nutrition, where gluconeogenesis helps maintain blood glucose during prolonged training.