The roles, mechanisms, and therapeutic implications of glucocorticoids in glucose and lipid metabolism.

Glucocorticoids (GCs), steroid hormones synthesized and secreted by the adrenal cortex, have been the subject of intensive scientific investigation for over eight decades due to their critical roles in physiological and pathological processes. The systemic secretion, bioavailability, and tissue-specific concentrations of GCs are strictly orchestrated by the hypothalamic-pituitary-adrenal axis, serum corticosteroid-binding globulin levels, and the enzymatic activation of 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1 and 11β-HSD2). As pivotal metabolic messengers, GCs signal through binding to glucocorticoid receptors (GR) to maintain metabolic homeostasis by modulating the transcriptional landscape of genes central to glucose and lipid metabolism. Any imbalance in GC levels, whether excess or deficiency, leads to the development of diverse metabolic disorders. Elucidating the underlying mechanisms of this metabolic regulation remains a primary objective of contemporary research. This review summarizes landmark discoveries and focuses on the metabolic impact and dysfunction of glucocorticoids, aiming to establish a robust foundation for the development of optimized therapeutic interventions for patients with metabolic diseases.