gluconeogenesis

Gluconeogenesis is a metabolic pathway that generates glucose from non-carbohydrate precursors, such as lactate, glycerol, and glucogenic amino acids. It helps maintain blood glucose during fasting or prolonged exercise when dietary sugar is limited. The liver supplies most of the glucose in the bloodstream, with contribution from the kidney cortex and, to a lesser extent, the small intestine. The pathway largely mirrors glycolysis but includes bypass reactions to overcome irreversible steps.

Primary substrates include lactate (via the Cori cycle), glycerol (from adipose tissue lipolysis), and glucogenic amino acids such as alanine and glutamine. Carbon skeletons from these substrates are converted through a sequence of reactions in mitochondrial and cytosolic compartments, ultimately yielding glucose-6-phosphate that can be released into the blood after dephosphorylation.

Key enzymatic bypasses distinguish gluconeogenesis from glycolysis. Pyruvate carboxylase in mitochondria converts pyruvate to oxaloacetate, which is transported to the cytosol and converted to phosphoenolpyruvate by PEP carboxykinase. The pathway then proceeds through several steps to fructose-1,6-bisphosphatase and finally glucose-6-phosphatase in the endoplasmic reticulum, producing free glucose released by glucose-6-phosphate phosphatase. These bypasses avoid the irreversible glycolytic steps catalyzed by pyruvate kinase and phosphofructokinase-1.

Regulation is driven by hormones and energy status. Glucagon and epinephrine activate cAMP signaling to stimulate gluconeogenic enzymes, while insulin suppresses them. Nutrient availability, acetyl-CoA, and NADH levels influence enzyme activity (notably fructose-1,6-bisphosphatase and PEPCK). Gluconeogenesis is essential for glucose homeostasis during fasting; excessive hepatic glucose production can contribute to hyperglycemia in diabetes.