Gluconeogenesis

Gluconeogenesis is the metabolic process by which the liver — and, during prolonged fasting, the kidney — synthesizes glucose de novo from non-carbohydrate precursors: primarily lactate, glycerol, and glucogenic amino acids such as alanine and glutamine. The pathway runs largely in reverse of glycolysis but bypasses its three irreversible steps via four specific enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase, and glucose-6-phosphatase. Glucagon and cortisol activate the pathway; insulin suppresses it. In healthy adults fasting overnight, gluconeogenesis accounts for roughly 50% of hepatic glucose output, rising to ~93% after 42 hours as glycogen stores are exhausted (Landau et al., 1996). Blood glucose therefore remains in the normal range during ketogenic diets or prolonged fasting, sustained by adipose-derived glycerol and muscle-derived alanine even without dietary carbohydrate. In aging research, upregulation of PEPCK in *C. elegans* intestinal cells extends lifespan under dietary restriction, and its inhibition abolishes this benefit (Onken et al., 2020, *PLoS Genetics*) — though whether the mechanism translates to mammals remains associational rather than causal.