Hormonal Shift and Phase 1: Postabsorptive State (Up to 24 Hours)
Within the first 24 hours of the postabsorptive period, metabolism begins to change drastically. The primary trigger is a sharp drop in the insulin-to-glucagon ratio. Insulin concentration decreases by 10-to-15-fold, while counterregulatory hormones (glucagon and cortisol) increase.
These hormonal alterations activate cAMP-dependent protein kinase A in adipocytes via the adenylate cyclase system. Protein kinase A phosphorylates and activates hormone-sensitive triacylglycerol (TAG) lipase, initiating active lipolysis.
First-day outcomes:
- Liver glycogen reserves are completely depleted.
- Blood glucose drops to the lower limit of normal (approximately 60 mg/dL).
- Accelerated gluconeogenesis begins — de novo glucose synthesis from amino acids and glycerol.
Phase 2: Interorgan Metabolism (Up to One Week)
With glycogen stores exhausted, the body must solve two problems: maintaining normoglycemia for glucose-dependent tissues (brain, erythrocytes) and finding alternative fuel for other organs. Catabolism predominates over anabolism.
- Adipose tissue massively mobilizes triacylglycerols (TAGs). Fatty acids and glycerol are released into the blood.
- Skeletal muscle actively oxidizes fatty acids to Acetyl-CoA. Simultaneously, muscle proteins are degraded, and amino acids are transported to the liver. Protein synthesis is halted.
- Liver takes up free fatty acids and initiates accelerated ketogenesis (synthesis of ketone bodies). Concurrently, the liver produces glucose from incoming amino acids, glycerol, and lactate (supplied by anaerobic glycolysis in erythrocytes via the Cori cycle).
- Kidneys increase the excretion of nitrogenous waste products, primarily urea, resulting from intensive protein breakdown.
Due to active ketogenesis, blood ketone body concentrations rise sharply, and a characteristic acetone breath odor appears.
Phase 3: Adaptation and Protein Conservation (Several Weeks)
The primary threat during prolonged starvation is critical skeletal muscle mass loss (catabolism of one-third of total body protein is fatal). To survive, the overall metabolic rate slows down.
Energy provision pathways adapt:
- The rate of protein degradation and, consequently, gluconeogenesis from amino acids decreases significantly.
- The brain adapts to glucose deficiency and begins actively oxidizing ketone bodies.
- Muscles practically stop using ketone bodies, sparing them for the brain, and switch exclusively to utilizing fatty acids.
The nitrogen balance remains negative throughout all phases. The capacity of tissues to synthesize and utilize ketone bodies becomes a key survival factor. However, their full integration into the tricarboxylic acid (TCA) cycle requires oxaloacetate. During deep fasting, oxaloacetate can be formed exclusively from amino acids, making minimal protein breakdown inevitable.