GLUCOCORTICOSTEROID hormones of the adrenal cortex have striking pharmacologic effects on lymphoid tissues and cells. These effects form part of the basis for the widespread use of these hormones in the treatment of a variety of diseases involving immunologic, inflammatory or neoplastic processes. The subject is large and has been reviewed in the past,1 2 3 4 5 6 7 but many questions remain to be answered. The purpose of this article is to take a new look at the subject, concentrating on three aspects. The first is species differences in susceptibility to corticosteroids. (Although these differences have been noted before, they are often overlooked; they . . .

Corticosteroids and lymphoid cells.

Alanine is quantitatively the primary amino acid released by muscle and extracted by the splanchnic bed in postabsorptive as well as prolonged fasted man. The hepatic capacity for conversion of alanine to glucose exceeds that of all other amino acids. Insulin inhibits gluconeogenesis by reducing hepatic alanine uptake. In contrast, in diabetes, an increase in hepatic alanine extraction is observed in the face of diminished circulating substrate. In prolonged fasting, diminished alanine release is the mechanism whereby gluconeogenesis is reduced. In circumstances in which alanine is deficient, such as pregnancy and ketotic hypoglycemia of infancy, fasting hypoglycemia is accentuated. Augmented glucose utilization in exercise and hyperpyruvicemia consequent to inborn enzymatic defects are accompanied by increased circulating levels of alanine. These data thus suggest the existence of a glucose-alanine cycle in which alanine is formed peripherally by transamination of glucose-derived pyruvate and transported to the liver where its carbon skeleton is reconverted to glucose. The rate of recycling of glucose carbon skeletons in this pathway appears to occur at approximately 50% of that observed for the Cori (lactate) cycle.

The glucose-alanine cycle.

Tissue effects of glucocorticoids.

Effects of glucocorticoids on carbohydrate metabolism

The mechanism of action of glucocorticoids is reviewed from the standpoint of seeing how far current concepts of the molecular action of steroids go towards explaining the varied physiologic and metabolic effects induced. The role of plasma binding to transport proteins in modifying steroid action is considered. The interactions between glucocorticoids and other hormones, particularly those mediated by cAMP are considered along with a discussion of the mechanism of “permissive” effects. Various proposals concerning the way in which glucocorticoids induce their effects including direct interactions with enzymes, nucleic acids, lysosomes, and receptor proteins are considered in detail, and an attempt is made to consider how far each of these mechanisms can go in explaining steroid action. Those biologic effects that cannot be accounted for by currently available mechansims are mentioned. Effects of glucocorticoids on growth, differentiation, and the inflammatory response are discussed from a mechanistic point of view. Catabolic or inhibitory effects of glucocorticoids as well as enzyme induction are examined using several exemplary systems. Finally an attempt is made to summarize the current state of knowledge concerning glucocorticoid and genome interaction.

L.D. Schaeffer

Papers

Estimation of Glucose Turnover and the Cori Cycle Using Glucose-6-t-14C*

Adrenal corticosteroid involvement in the control of liver glycogen phosphorylase activity.

Adrenal corticosteroid involvement in the control of phosphorylase in muscle.

Effect of adrenalectomy on glucose turnover, the Cori cycle, and gluconeogenesis from alanine

Incorporation of 3H and 14C into plasma lactate following administration of [6-3H-14C]glucose.