The daily secretion rate of cortisol varies little in the absence of stress. Cortisol interacts in a permissive fashion with many other hormones, including insulin, glucagon, catecholamines, and growth hormone, to achieve full homeostasis. For example, glucocorticoids are essential for normal epinephrine- or glucagon-stimulated lipolysis, gluconeogenesis, and glycogenolysis.21,22 Excess cortisol increases hepatic glycogen and glucose production and decreases glucose uptake and utilization in the peripheral tissues. These effects combine to cause hyperglycemia. This may lead to overt diabetes in persons who have a decreased capacity to produce insulin. By contrast, glucocorticoid deficiency decreases glucose production and hepatic glycogen content and may cause hypoglycemia. However, serum glucose levels may be normal in the chronically ill patient with Addison disease because of a compensatory decrease in insulin secretion.

The primary action of the glucocorticoids on carbohydrate metabolism is to increase glucose production by increasing hepatic gluconeogenesis. Gluconeogenesis uses substrates derived from glycolysis, proteolysis, and lipolysis. Lactate is derived from glycolysis in muscle. Alanine is the primary substrate derived from proteolysis; fatty acids and glycerol are derived from lipolysis. In addition to inducing gluconeogenic enzymes, glucocorticoids stimulate glycolysis, proteolysis, and lipolysis, thus providing more substrate for gluconeogenesis. Glucocorticoids also increase cellular resistance to insulin, thereby decreasing entry of glucose into the cell. This inhibition of glucose uptake occurs in adipocytes, muscle cells, and fibroblasts. (Also see Chap. 75 and Chap. 139.)

In addition to opposing insulin action, glucocorticoids may work in parallel with insulin to protect against long-term starvation by stimulating glycogen deposition and production in liver. Both hormones stimulate glycogen synthetase activity and decrease glycogen breakdown.

Glucocorticoids increase free fatty acid levels by enhancing lipolysis, decreasing cellular glucose uptake, and decreasing glycerol production, which is necessary for reesterification of fatty acids. This increase in lipolysis is also stimulated through the permissive enhancement of the lipolytic action of other factors such as epinephrine. This action affects adipocytes differently according to their anatomic locations. In the patient with glucocorticoid excess, fat is lost in the extremities, but it is increased in the trunk (centripetal obesity), neck, and face (moon facies).23 This may involve effects on adipocyte differentiation.24

The glucocorticoids generally exert a catabolic/antianabolic effect on protein metabolism. This proteolysis in fat, skeletal muscle, bone, and lymphoid and connective tissue increases amino-acid substrates that can be used in gluconeogenesis. In muscle, the type II white glycolytic fibers are more affected than the type I fibers. Cardiac muscle and the diaphragm are almost entirely spared from this catabolic effect.

Glucocorticoids play a profound role in immune regulation.16,18 At high concentrations, they inhibit most immunologic and inflammatory responses. Although these effects may have beneficial aspects, they may also be detrimental to the host by inducing a state of immunosuppression that predisposes to infection. Glucocorticoids inhibit eicosanoid and glycolipid synthesis and the actions of bradykinin. They also block histamine and proinflammatory cytokine (tumor necrosis factor α, interleukin-1, and interleukin-6) secretion and effects.25 These actions inhibit vasoactive agents and diminish the inflammatory process. Glucocorticoids may cause lymphocytopenia with a relative T-cell depletion, monocytopenia, and eosinopenia. They do so at least in part by inducing cell cycle arrest in the G₁ phase and by activating the apoptosis pathway through glucocorticoid receptor–mediated effects.26