REGULATION OF CARBOHYDRATE METABOLISM

The liver has the most complex metabolism of glucose compared with other organs. In it there are opposing processes: synthesis / breakdown of glycogen and glycolysis / gluconeogenesis.

Direction of glucose metabolism in the liver depends on the rhythm of meal.

Switching processes of synthesis and mobilization of glycogen in the liver occurs at the transition state of digestion in postabsorbtive period or dormancy mode on muscle work. In the switching of metabolic pathways in liver insulin, glucagon and adrenaline are involved, and in muscle - insulin and adrenaline. Their influence occurs through changes in the opposite direction activity of 2 key enzymes - glycogen synthase and glycogen phosphorylase. It is realized by their phosphorylation and dephosphorylation.

Insulin and glucagon are constantly present in the blood, but during the transition from absorptive state in postabsorbtive their relative concentration is changed. It is insulin-glucagon index(Fig. 21).

Fig. 21. Changing concentrations of glucose, insulin, glucagon after meals.

During the digestion insulin-glucagon index rises. Insulin stimulates glucose transport into muscular cells, changes activity of enzymes by phosphorylation and dephosphorylation, and amount of enzymes by induction of their synthesis. Insulin causes a lowering of blood glucose, increased glycogen content in muscles.

During the postabsorbtive period insulin-glucagon index decreases and the decisive factor is the effect of glucagon, which stimulate the degradation of glycogen in the liver. The mechanism of glucagon action involves a cascade of reactions that leads to the activation of glycogen phosphorylase. The result is an increase of glucose concentration in blood.

Biosynthesis and secretion of insulin and glucagon are controlled by glucose concentration primarily on the basis of feedback. Increased blood glucose causes an increase in insulin secretion and decrease glucagon secretion, the opposite - slowing down of insulin secretion and increasing of glucagon. This control of feedback type is one of the most important mechanisms for the regulation of blood glucose level.

Adrenaline increases the metabolism of carbohydrates in the body, increasing the degradation of glycogen in the muscles and inhibits the synthesis of glycogen from UDP-glucose. Adrenaline causes a sharp rise of glucose levels in blood.

Switching from glycolysis to gluconeogenesis and vice versa in liver is also happening with insulin and glucagon, and it is realized by means of:

- allosteric mechanisms;

- phosphorylation / dephosphorylation;

- induction / repression of key enzymes synthesis.

The regulation is aimed at irreversible stages of glycolysis and gluconeogenesis.

With a decrease in insulin-glucagon index synthesis of key enzymes of glycolysis is reduced, and enzymes of gluconeogenesis (phosphoenolpyruvate carboxykinase, fructose-6-phosphatase, glucose-6-phosphatase) is increased. So, gluconeogenesis is stimulated.

The direction of the reactions of glycolysis is regulated by glucose. During digestion the concentration of glucose in the blood increases to 10-20 micromoles/l and glucokinase activity is maximal. Glycolytic reaction is accelerated:

glucose → glucose-6-phosphate.

Insulin induces the synthesis of glucokinase and thus accelerates the phosphorylation of glucose.

Fructose-2,6-bisphosphate allosterically activates phosphofructokinase (glycolysis is increased) and inhibits the phosphatase fructose-1,6-bisphosphatase (gluconeogenesis is slowed down).

Fructose-2,6-bisphosphate is formed by phosphorylation of fructose-6-phosphate with the participation of the bifunctional enzyme. It has two domains with different enzymatic activity.

When it is in dephosphorylated form, it has kinase activity which is characteristic of the absorptive period (insulin-glucagon index is high). Glycolysis is increased.

In phosphorylated form it has phosphatase activity (prolonged starvation, insulin / glucagon index is low). The amount of fructose-2,6-bisphosphate is reduced, glycolysis is slowed down and switched on gluconeogenesis.

During digestion insulin activates protein phosphatase, which dephosphorylates pyruvate kinase, and converts it into active state. The conversion of phosphoenolpyruvate to pyruvate (glycolytic reaction) is accelerated during digestion and slowed down into postabsorbtiv period.

The reactions of gluconeogenesis:

pyruvate → oxaloacetate → phosphoenolpyruvate

can occur at any state of the organism.

During the digestion because of the acceleration of the initial stages of glycolysis the content of fructose-1,6-bisphosphate is increased, leading to activation of pyruvate kinase (glycolysis is increased).

After a meal rich in carbohydrates, insulin-glucagon index is increased, amount of glucokinase phosphofructokinase, pyruvate kinase (glycolytic enzymes) is increased. It stimulates the glycolytic pathway.

Glucose in liver cells is also used to energy supply of hepatocytes. The main consumers of ATP in the hepatocytes are the transmembrane transport of metabolites, synthesis of proteins, glycogen, fat, and gluconeogenesis.

ATP and AMP are allosteric effectors of some glycolytic enzymes: AMP activates phosphofructokinase and inhibits fructose-1,6-bisphosphatase, ATP inhibits pyruvate kinase. Thus, with the expenditure of ATP concentration of AMP is increased, glycolysis and ATP synthesis are activated, and gluconeogenesis is slowed down.