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.

Endocrine System

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.

Also Check

Pancreatic arterial glucose concentration is the primary but not sole determinant of insulin release. A number of substrates, including free fatty acids, ketone bodies, and some amino acids, can either directly stimulate insulin release from the β cell or potentiate the effect of glucose on hormone secretion. Oral ingestion of fat and glucose provokes secretion of enteric factors that themselves augment or facilitate insulin release. During fasting, plasma concentration of insulin decreases to less than 5 uU·mL^-1 in children. Concentrations greater than this in association with blood glucose concentrations less than 2.8 mmol/L (50 mg·dL^-1) are distinctly abnormal. Systemic insulin concentrations are substantially lower than the concentration in the portal vein, reflecting both transhepatic removal (approximately 50% is removed in one transhepatic passage) and dilution in the total vascular space.

COUNTERREGULATORY HORMONES The actions of cortisol, glucagon, epinephrine, and growth hormone oppose the hypoglycemic effects of insulin. These hormones increase the ambient blood glucose concentration by (1) inhibiting glucose uptake by muscle (epinephrine, cortisol, and growth hormone), (2) increasing the availability of endogenous gluconeogenic amino acids by increasing muscle proteolysis (cortisol), (3) activating lipolysis and providing increased free fatty acids as a source of energy and glycerol for gluconeogenesis (epinephrine, glucagon, growth hormone, and cortisol), (4) inhibiting insulin secretion from the pancreas (epinephrine), (5) acutely activating glycogenolytic and gluconeogenic enzymes (epinephrine and glucagon), and (6) chronically inducing gluconeogenic enzyme synthesis (glucagon and cortisol).

Pascal J. Vanelderen MD, Resident, Filiep M. Soetens MD, Staff Anesthesiologist, Maurits A. Soetens MD, Staff Anesthesiologist, Herman J. Janssen PhD, Professor and Andre’ M. De Wolf MDc, Professor

Department of Anesthesiology, Sint-Elisabeth Hospital, 2300 Turnhout, Belgium
Department of Physics, Limburgs Universitair Centrum, 3590 Diepenbeek, Belgium

REFERENCES

HAYMOND MW: Hypoglycemia in infants and children. Endocrinol Metab Clin North Am 18:211-252, 1989

HAYMOND MW , SUNEHAG A: Controlling the sugar bowl: regulation of glucose homeostasis in children. Endocrinol Metab Clin North Am 28:663-694, 1999

KATZ LE , FERRY RJ JR , STANLEY CA , COLLETT-SOLBERG PF , BAKER L , COHEN P: Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor. J Clin Endocrinol Metab 84:3117-24, 1999

SCHWITZGEBEL VM , GITELMAN SE: Neonatal hyperinsulinism. Clin Perinatol, 25:1015-1038, 1998

STANLEY CA , LIEU YK , HSU BY , et al: Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352-1357, 1998