GluconeogenesisEdit

Gluconeogenesis is a central metabolic pathway that builds glucose from non-carbohydrate sources when dietary carbohydrate is scarce or energy demands persist. The liver is the principal site of this process, with the kidney contributing during prolonged fasting or certain physiological states. By supplying glucose, gluconeogenesis helps keep brain and red blood cells fueled and maintains overall blood glucose levels within a narrow range. It is not simply the reverse of glycolysis; instead, it uses a set of bypass reactions that circumvent thermodynamically unfavorable steps in glycolysis and enable glucose synthesis under demanding conditions. liver kidney glucose glycolysis

Substrates and sources Gluconeogenesis draws on several substrates that arise from different tissue processes. Lactate, produced by anaerobic metabolism in skeletal muscle and erythrocytes, is transported to the liver and converted back to glucose via the Cori cycle. Glycerol, released during triglyceride breakdown in adipose tissue, provides another major non-carbohydrate carbon source. Glucogenic amino acids—especially alanine and glutamine—feed into the pathway after transamination. These substrates collectively enable glucose production during fasting, prolonged exercise, and other states of limited dietary carbohydrate. lactate Cori cycle glycerol alanine glutamine amino acids blood glucose

Pathway architecture and bypass steps Gluconeogenesis is often described as glycolysis running in reverse, but it is more accurately viewed as a separate pathway with three key bypasses that bypass irreversible steps in glycolysis:

  • Pyruvate to phosphoenolpyruvate (PEP) bypass: Pyruvate is carboxylated to oxaloacetate by mitochondrial pyruvate carboxylase, consuming ATP, and then oxaloacetate is converted to PEP by cytosolic PEP carboxykinase (PEPCK), which uses GTP. This two-step sequence is a critical entry point for glucose synthesis. pyruvate carboxylase PEP carboxykinase oxaloacetate pyruvate GTP

  • Fructose-1,6-bisphosphatase bypass: The conversion of fructose-1,6-bisphosphate to fructose-6-phosphate occurs via the enzyme fructose-1,6-bisphosphatase, releasing phosphate and circumventing the glycolytic step catalyzed by phosphofructokinase-1. fructose-1,6-bisphosphatase glycolysis

  • Glucose-6-phosphatase bypass: Glucose-6-phosphate is dephosphorylated to glucose by glucose-6-phosphatase, a key terminal step that allows glucose to exit liver cells. glucose-6-phosphatase glucose

These bypasses collectively enable gluconeogenesis to proceed under energetically unfavorable conditions. The overall process is energetically demanding, typically described as consuming several high-energy phosphate equivalents per glucose synthesized (often summarized as about 6 high-energy phosphate equivalents, including ATP and GTP), reflecting the substantial energy investment required to produce new glucose molecules. glycolysis glucose-6-phosphatase

Tissues and cellular localization The liver dominates gluconeogenesis in the fed and fasting states, providing a robust source of glucose for the whole body. During extended fasting, the kidneys also contribute a meaningful amount of glucose, particularly through the cortex of the nephron. The process occurs in distinct cellular compartments: several steps take place in mitochondria, others in the cytosol, and the shuttle systems move intermediates between compartments to support continuous flux. liver kidney mitochondria cytosol

Regulation: hormonal and metabolic control Gluconeogenesis is tightly regulated to balance energy homeostasis, nutrient availability, and hormonal signals. Hormones such as glucagon and epinephrine activate signaling cascades that promote gluconeogenic gene expression and enzymatic activity, while insulin acts to suppress the pathway in fed states. Cortisol also supports gluconeogenesis, particularly during stress or fasting. At the enzymatic level, key control points include pyruvate carboxylase and PEP carboxykinase, as well as fructose-1,6-bisphosphatase and glucose-6-phosphatase. Substrate availability (lactate, glycerol, amino acids) and cellular energy status (ATP, AMP) further influence flux through the pathway. glucagon epinephrine insulin cortisol AMP-activated protein kinase FOXO1 CREB

Metabolic regulation in health and disease In healthy individuals, gluconeogenesis helps maintain blood glucose during fasting and supports metabolic flexibility. In metabolic disorders, regulation can become dysregulated. For example, in type 2 diabetes mellitus, hepatic gluconeogenesis can contribute to fasting and postprandial hyperglycemia due to impaired hormonal signaling and altered transcriptional control of gluconeogenic genes. Treatments that modulate hepatic glucose production—such as metformin and other agents targeting hepatic signaling pathways—aim to reduce excess glucose output while preserving physiological needs. type 2 diabetes mellitus metformin hepatic glucose production

Clinical and nutritional considerations Gluconeogenesis intersects with nutrition, energy balance, and metabolic health. It is particularly relevant during prolonged fasting, low-carbohydrate diets, and periods of intense exercise, where the liver and kidney collectively ensure a steady glucose supply. The interplay with adipose tissue (via glycerol release) and muscle (via lactate generation) highlights the integrated nature of glucose production within whole-body metabolism. Related pathways—such as glycogenolysis, glycolysis, and ketogenesis—together determine how the body adapts to different energy and nutrient states. ketogenesis glycogenolysis glycolysis liver

See also - glycolysis - liver - kidney - glucose - glucose-6-phosphatase - pyruvate carboxylase - PEP carboxykinase - fructose-1,6-bisphosphatase - Cori cycle - glucose-alanine cycle - lactate