Directional Shifts

The majority of enzymes catalyze reversible reactions, and their action is highly dependent on the concentration of the reactants involved. An increase in the concentration of one reactant will drive the reaction in the direction that results in the breakdown of that reactant so as to achieve homeostasis. An example of a directional shift is the interconversion of glucose 1-phosphate and glucose 6-phosphate. During glucogenolysis, the concentration of glucose 1-phosphate increases and the reaction is driven towards the production of glucose 6-phosphate. During glycogen synthesis and gluconeogenesis, the concentration of glucose 6-phosphate increases and the reaction is driven towards the production of glucose 1-phosphate and, subsequently, towards the formation of glycogen.

Regulation of Gene Expression

Regulation of gene expression enables the human body to respond to changes in nutrient concentration. During increased availability of a specific nutrient, there is no need to express the genes encoding for enzymes involved in the metabolism of that nutrient. Gene expression is highly regulated by hormones, which respond to the concentration of nutrients in the blood. Selective expression of specific genes plays a major role in the regulation of carbohydrate metabolism.

Hormonal and nutrient concentrations affect several regulatory domains of genes that encode for enzymes involved in anabolic and catabolic pathways. High insulin and glucose concentrations increase mRNA levels and the transcription rates of the glycolytic enzymes and decrease those of the gluconeogenic enzymes. Glucagon has the opposite effect to insulin.

Glycogen Synthesis and Breakdown

The regulatory mechanism of glycogen synthesis and breakdown involves two counteracting enzymes: glycogen synthase and glycogen phosphorylase (Figure 4). Insulin activates glycogen synthase and therefore increases glycogen synthesis in the liver and muscle. When blood glucose levels decrease, glucagon inhibits glycogen synthase and activates glycogen phosphorylase in order to break down gly-cogen in the liver. Epinephrine also activates glyco-gen breakdown both in the liver and in skeletal muscle.

Peripheral Uptake of Glucose by Skeletal Muscle and Adipose Tissue

Glucose enters the target tissues by facilitated diffusion through a family of transporters known as glucose transporters (GLUTs). Five different iso-forms of GLUTs have been isolated and characterized, GLUT1 to GLUT5. GLUT4 is mainly present in skeletal and cardiac muscle and in brown adipose tissue and differs significantly from the other iso-forms in that it is stimulated by insulin. The other GLUTs do not require the action of insulin for glucose transport. GLUT1 and GLUT3 are responsible for glucose transport in most body tissues and are found in the brain, kidney, placenta, red blood cells, and fetal tissue. GLUT2 exists mainly in the liver and pancreas, and GLUT5 is responsible for glucose and fructose transport in the small intestine.

The GLUTs are encoded by different genes, and the regulation of their expression is highly tissue specific. GLUT4 is highly regulated by insulin, and its concentration is significantly increased in the presence of this hormone. As a result of the increase in GLUT4 concentration, there is increased glucose uptake by the adipose tissue and skeletal muscle.

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