Chapter 20

After studying this chapter, you should be able to:

• Explain the importance of gluconeogenesis in glucose homeostasis.
• Describe the pathway of gluconeogenesis, how irreversible enzymes of glycolysis are bypassed, and how glycolysis and gluconeogenesis are regulated reciprocally.
• Explain how plasma glucose concentration is maintained within narrow limits in the fed and fasting states.

Gluconeogenesis is the process of synthesizing glucose or glycogen from noncarbohydrate precursors. The major substrates are the glucogenic amino acids (Chapter 29), lactate, glycerol, and propionate. Liver and kidney are the major gluconeogenic tissues; the kidney may contribute up to 40% of total glucose synthesis in the fasting state and more in starvation. The key gluconeogenic enzymes are expressed in the small intestine, but it is unclear whether or not there is significant glucose production by the intestine in the fasting state.

A supply of glucose is necessary especially for the nervous system and erythrocytes. After an overnight fast, glycogenolysis (Chapter 19) and gluconeogenesis make approximately equal contributions to blood glucose; as glycogen reserves are depleted, so gluconeogenesis becomes progressively more important.

Failure of gluconeogenesis is usually fatal. Hypoglycemia causes brain dysfunction, which can lead to coma and death. Glucose is also important in maintaining the level of intermediates of the citric acid cycle even when fatty acids are the main source of acetyl-CoA in the tissues. In addition, gluconeogenesis clears lactate produced by muscle and erythrocytes, and glycerol produced by adipose tissue. In ruminants, propionate is a product of rumen metabolism of carbohydrates, and is a major substrate for gluconeogenesis.

Excessive gluconeogenesis occurs in critically ill patients in response to injury and infection, contributing to hyperglycemia which is associated with a poor outcome. Hyperglycemia leads to changes in osmolality of body fluids, impaired blood flow, intracellular acidosis and increased superoxide radical production (Chapter 45), resulting in deranged endothelial and immune system function and impaired blood coagulation. Excessive gluconeogenesis is also a contributory factor to hyperglycemia in type 2 diabetes because of impaired sensitivity of gluconeogenesis to downregulation in response to insulin.

Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis

Three nonequilibrium reactions in glycolysis (Chapter 18), catalyzed by hexokinase, phosphofructokinase and pyruvate kinase, prevent simple reversal of glycolysis for glucose synthesis (Figure 20–1). They are circumvented as follows.

Figure 20–1

Major pathways and regulation of gluconeogenesis and glycolysis in the liver. Entry points of glucogenic amino acids after transamination are indicated by arrows extended from circles (see also Figure 17–4). The key gluconeogenic enzymes are enclosed in double-bordered boxes. The ATP required for gluconeogenesis is supplied by the oxidation of fatty acids. Propionate is of quantitative importance only in ruminants. Arrows with wavy shafts signify allosteric effects; dash-shafted arrows, covalent modification by reversible phosphorylation. ...

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