Hepatic Glycogenolysis and Gluconeogenesis

Regulation of hepatic glucose production is basic to the maintenance of glucose homeostasis. Although the kidney is capable of glycogen synthesis, glycogenolysis, and gluconeogenesis, it does not contribute a great deal to net glucose production in adults except during prolonged fasting or metabolic acidosis. No information is available to determine the quantitative contribution of renal glucose production to glucose homeostasis in children.

Four enzymes are important in gluconeogenesis from three-carbon substrates such as lactate and pyruvate. Glucose-6-phosphatase hydrolyzes glucose-6-phosphate to glucose and is the final enzymatic step by which the liver and kidney release free glucose derived from either glycogenolysis or gluconeogenesis except for a small fraction, which theoretically can be derived from debrancher enzyme activity.

Fructose-1,6-bisphosphatase catalyzes hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, bypassing the energy-yielding enzyme phosphofructokinase. This enzyme has an important regulatory role in hepatic gluconeogenesis.

A second and perhaps more important regulatory site for hepatic gluconeogenesis exists between pyruvate and phosphoenolpyruvate and involves two enzymes of gluconeogenesis (pyruvate carboxylase and phosphoenolpyruvate carboxykinase) and one enzyme of glycolysis, pyruvate kinase. Pyruvate carboxylase is a mitochondrial enzyme that catalyzes conversion of pyruvate to oxaloacetate by the addition of carbon dioxide. Pyruvate carboxylase is biotin and manganese dependent and has very low activity in the absence of acetyl-coenzyme A, its positive modulator. Thus, only when the availability of acetyl-coenzyme A is increased (fasting or poorly controlled diabetes), can increased amounts of pyruvate be converted to oxaloacetate, the first step in gluconeogenesis. Phosphoenolpyruvate carboxykinase is present in both the cytosol and mitochondria. Although these two enzymes are the first steps in hepatic gluconeogenesis, hormonal regulation of hepatic glucose production is thought to occur at the level of pyruvate kinase and phosphofructokinase.

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INSULIN Insulin is the predominant hormone regulating blood glucose, because it is the only hormone which acts to decrease endogenous glucose production and accelerate glucose use. Insulin stimulates (1) transmembrane movement of glucose into skeletal and cardiac muscle and adipose tissue as a result of the GLUT4 glucose transporter and (2) conversion of glucose to glycogen and triglyceride. At even low concentrations, insulin is a potent inhibitor of adipose tissue lipolysis and decreases the rate of proteolysis. The net effect of these actions on peripheral tissues is to accelerate glucose disappearance from the blood and decrease the supply of gluconeogenic substrates (glycerol and amino acids) presented to the liver. In concert with these peripheral actions, insulin stimulates hepatic glycogen synthesis, decreases glycogenolysis, and decreases release of glucose from hepatic gluconeogenesis. Insulin appears to activate glycogen synthetase and inhibit the phosphorylase system.