Cortisol, a hormone produced by the body, has various effects on glucose metabolism. It enhances the expression of phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme in liver gluconeogenesis. However, it decreases glucose uptake in skeletal muscle and adipose tissue by inhibiting GLUT4. During periods of low insulin-glucagon ratio, cortisol promotes glucose sparing by facilitating the release of free fatty acids (FFAs) through the action of catecholamines on lipolysis. This provides an additional energy source. Moreover, cortisol inhibits protein synthesis and increases proteolysis, particularly in skeletal muscle, which supplies carbon for hepatic gluconeogenesis.

In Fig. 43.10, the normal role of cortisol in response to stress is contrasted with its effects under chronically elevated cortisol levels due to pathological conditions. These two states have distinct metabolic effects, especially concerning lipid metabolism. In stress, cortisol works synergistically with catecholamines and glucagon to promote a metabolic response characterized by lipolysis, gluconeogenesis, ketogenesis, and glycogenolysis. It also collaborates with catecholamines to induce an appropriate cardiovascular response. However, in pathological conditions with excessive cortisol production, it synergizes with insulin in the presence of elevated glucose levels and hyperinsulinemia to promote lipogenesis and the accumulation of abdominal/visceral adipose tissue.

Cortisol's impact on blood glucose is further reinforced by its positive effects on the cardiovascular system. It increases the expression of adrenergic receptors, contributing to cardiac output and blood pressure. Cortisol also stimulates the synthesis of erythropoietin, leading to an increase in red blood cell production. Deficiency of cortisol can result in anemia, while excessive cortisol levels can lead to polycythemia.

Stress often triggers inflammation and immune responses. While these responses are essential for maintaining homeostasis, they can be detrimental and even fatal if not properly regulated. Cortisol, along with epinephrine and norepinephrine, helps maintain immune balance by suppressing the production of proinflammatory cytokines and promoting the production of anti-inflammatory cytokines.

During the interdigestive period, stress can occur, such as when an elderly person slips on ice and dislocates their hip. This triggers various metabolic responses aimed at meeting the increased energy demands and maintaining adequate blood glucose levels for conscious and deliberate actions. These metabolic responses are supported by cardiovascular responses induced by sympathoadrenal output and optimized by cortisol, which enhances adrenergic receptor function. Additionally, cortisol provides energy for the initial inflammatory and immune responses to stress while protecting the individual from the potential harm of uncontrolled inflammation.
Fig. 43.10 ). Cortisol enhances gene expression of the key hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Cortisol also decreases GLUT4-mediated glucose uptake in skeletal muscle and adipose tissue. During the interdigestive period (low insulin-glucagon ratio), cortisol promotes glucose sparing by potentiating the effects of catecholamines on lipolysis, thereby making FFAs available as energy sources. Cortisol inhibits protein synthesis and increases proteolysis, especially in skeletal muscle, thereby providing a rich source of carbon for hepatic gluconeogenesis.
Fig. 43.10 also contrasts the normal role of cortisol in response to stress and the effects of chronically elevated cortisol as a result of pathological conditions. As discussed later, there are important differences in the overall metabolic effects of cortisol between these two states, particularly with respect to lipid metabolism. During stress, cortisol synergizes with catecholamines and glucagon to promote a lipolytic, gluconeogenic, ketogenic, and glycogenolytic metabolic response while synergizing with catecholamines to promote an appropriate cardiovascular response. During chronically elevated cortisol secondary to pathological overproduction, cortisol synergizes with insulin in the context of elevated levels of glucose (from increased appetite) and hyperinsulinemia (from elevated glucose and glucose intolerance) to promote lipogenesis and truncal (abdominal/ visceral) adiposity.
Cortisol reinforces its effects on blood glucose by its positive effects on the cardiovascular system. Cortisol has permissive actions on catecholamines by increasing adrenergic receptor expression and thereby contributes to cardiac output and blood pressure. Cortisol stimulates erythropoietin synthesis and hence increases red blood cell production. Anemia occurs when cortisol is deficient, and polycythemia occurs when cortisol levels are excessive.
Inflammation and immune responses are often part of the response to stress. However, inflammation and immune responses have the potential for significant harm and may cause death if they are not held in homeostatic balance. As a stress hormone, cortisol plays an important role in maintaining immune homeostasis. Cortisol, along with epinephrine and norepinephrine, represses production of proinflammatory cytokines and stimulates production of antiinflammatory cytokines.
Stress during interdigestive period (e.g., elderly person slips on ice and dislocates hip) Liver ˜ Glycogenolysis ˜ Gluconeogenesis
Metabolic responses to stress ensure sufficient energy to meet increased demand on body, and will maintain adequate blood glucose levels necessary for conscious, deliberate action by the individual. The metabolic responses are supported by cardiovascular ones, first by those induced by the sympathoadrenal output (see Fig.
43.6) but also by cortisol, which optimizes adrenergic receptor function. Cortisol will also contribute to providing energy for the incipient inflammatory and immune response to this stress, but will also protect the individual from the potential damage of unregulated inflammation.