Chapter 28: Gluconeogenesis and Maintenance of Blood Glucose Levels

Because the brain and erythrocytes depend almost exclusively on glucose for energy, the liver and kidney must continuously synthesize glucose from noncarbohydrate substrates when dietary carbohydrate is unavailable. The chapter details how lactate, alanine, glycerol, and propionate serve as primary gluconeogenic precursors, recycled through metabolic cycles including the Cori cycle and glucose-alanine cycle that coordinate fuel availability across tissues. While most gluconeogenic reactions reverse glycolytic steps, three irreversible glycolytic reactions require dedicated gluconeogenic enzymes: pyruvate carboxylase and phosphoenolpyruvate carboxykinase bypass pyruvate kinase, fructose 1,6-bisphosphatase bypasses phosphofructokinase, and glucose 6-phosphatase bypasses glucokinase. Hormonal regulation represents a central theme, with insulin suppressing both pathways to promote fuel storage during fed states, while glucagon, cortisol, and epinephrine activate gluconeogenesis during fasting and stress. The chapter integrates clinical cases demonstrating metabolic disruptions: alcohol metabolism impairs gluconeogenesis by elevating the NADH-to-NAD ratio, corticosteroids inappropriately stimulate glucose production causing hyperglycemia, insulin overdose eliminates endogenous glucose synthesis triggering hypoglycemic crisis, and prolonged starvation reduces gluconeogenic demand as ketone bodies spare muscle protein. Diabetic ketoacidosis illustrates severe dysregulation where unchecked gluconeogenesis and ketogenesis cause dangerous hyperglycemia, osmotic diuresis, and metabolic acidosis. The chapter emphasizes reciprocal regulation preventing futile cycling between glycolysis and gluconeogenesis through coordinated enzyme inactivation and activation. During extended fasting beyond five to six weeks, blood glucose stabilizes at reduced levels as ketone body oxidation decreases cerebral glucose requirements. Exercise similarly depends on hepatic glucose output sustained through both glycogenolysis and gluconeogenesis. This integrated discussion reveals how dynamic metabolic coordination preserves glucose availability and cellular survival across diverse physiological states.