Gluconeogenesis Overview

Study Notes

Gluconeogenesis Lecture Notes

Gluconeogenesis is the process of forming glucose from non-carbohydrate precursors.
Key tissues requiring glucose include brain, red blood cells, kidney medulla, eye lens, cornea, testes, and exercising muscle.
Liver glycogen, a postprandial glucose source, can meet these needs for only 10-18 hours without dietary carbohydrates.
During prolonged fasting, gluconeogenesis takes place using precursors like lactate, pyruvate, glycerol (from triacylglycerols), and α-keto acids (from glucogenic amino acids).
Gluconeogenesis requires both mitochondrial and cytosolic enzymes.
During an overnight fast, approximately 90% of gluconeogenesis occurs in the liver, while the kidney supplies 10%.
During prolonged fasting, the kidney becomes a major glucose-producing organ, contributing approximately 40% of total glucose production.
Gluconeogenic precursors are molecules that can synthesize glucose.
Precursors include intermediates of glycolysis and the tricarboxylic acid (TCA) cycle.
Glycerol, lactate, and α-keto acids from glucogenic amino acids are important gluconeogenic precursors.
Glycerol is released during the hydrolysis of triacylglycerols in adipose tissue and delivered to the liver.
Lactate is released into the bloodstream by exercising skeletal muscle and cells lacking mitochondria (e.g., red blood cells).
The Cori cycle involves converting blood-borne glucose to lactate in exercising muscle, which then diffuses into the blood, and the liver takes up this lactate, reconverting it to glucose and releasing it back into the circulation.
Muscle cramps during strenuous exercise may result from lactate accumulation.
Amino acids derived from hydrolyzed tissue proteins are significant glucose sources during fasting.
α-keto acids, such as α-ketoglutarate, are derived from glucogenic amino acid metabolism.
These α-keto acids enter the TCA cycle, forming oxaloacetate (OAA), a direct precursor of phosphoenolpyruvate (PEP).
Key enzymes involved in gluconeogenesis include PEP-carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase.
Glucagon, a hormone from pancreatic α cells, stimulates gluconeogenesis by activating fructose-1,6-bisphosphatase and increasing PEP-carboxykinase gene transcription.
Insulin, conversely, causes decreased transcription of the mRNA for these enzymes.
Availability of gluconeogenic precursors, particularly glucogenic amino acids, significantly impacts hepatic glucose synthesis.
Insulin inhibits the mobilization of amino acids from tissue protein.
Acetyl CoA accumulation during fasting (due to increased lipolysis and fatty acid β-oxidation) activates pyruvate carboxylase.
AMP inhibits fructose 1,6-bisphosphatase.