The postabsorptive state usually starts about four hours after a meal and lasts until the next meal is eaten. During this time, the digestive system stops absorbing nutrients, and the body uses stored energy reserves to maintain stable blood glucose levels.

Initially, glycogen stored in the liver is broken down to release glucose into the bloodstream, while glycogen in the muscles is broken down to supply glucose for energy directly within the muscle cells. As glycogen stores diminish, lipolysis in adipose tissue is stimulated, breaking down triglycerides into fatty acids and glycerol. Fatty acids are transported to tissues such as muscle, which can oxidize them for energy, while glycerol enters the bloodstream and is used by the liver for gluconeogenesis. In prolonged fasting states, some tissue proteins are catabolized to release amino acids, which also serve as substrates for gluconeogenesis in the liver.

The liver and kidneys initiate gluconeogenesis, synthesizing glucose from non-carbohydrate sources, including amino acids and glycerol. This process becomes critical as glycogen reserves are exhausted, ensuring glucose supply for glucose-dependent tissues. To conserve glucose for the brain and red blood cells, which rely predominantly on glucose for energy, other tissues switch to alternative fuel sources, such as fatty acids and, over time, ketone bodies (produced from fatty acids in the liver), further sparing glucose for essential functions. After prolonged starvation (~3 days), ketone bodies become the main source of energy for the brain.

In response to a drop in blood glucose, the pancreas releases glucagon, which stimulates glycogen breakdown (glycogenolysis) and promotes gluconeogenesis to ensure a continuous supply of glucose into the bloodstream.