Prolonged fasting is a chronic low-insulin, high-glucagon state. The brain adapts to this by using ketone bodies as an energy substrate. There is also a decrease in thyroid hormone levels and, clinically, lethargy. Early in the fasting period, free fatty acid concentrations increase in plasma and they become a major energy source. At the same time oxaloacetate is being directed towards gluconeogenesis and its low concentration in the mitochondria tends to limit TCA cycle activity (see Chapter 13). Consequently, large amounts of acetyl CoA produced by β-oxidation of fatty acids in the liver enter ketogenesis instead of the TCA cycle. There is an increase in the concentration of plasma ketone bodies, which are oxidized in the muscle. Alanine and glutamine released from muscle serve as substrates for gluconeogenesis. During prolonged fasting, gluconeogenesis in the kidney becomes a significant source of endogenous glucose . The body minimizes the use of proteins as a gluconeogenic substrate by becoming almost totally dependent on fat as an energy source (Fig. 20.14). The amount of the GLUT-4 in the adipose tissue and muscle decreases. As the plasma concentrations of ketone bodies continue to rise, the brain uses them as a fuel. Some brain tissue also switches from the complete oxidation of glucose to CO2, to glycolysis. As the produced lactate enters the Cori cycle operating between the brain and the liver, the requirement for endogenous glucose production decreases; this spares muscle protein.
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