Disrupted Cortico – Metabolic Adaptation in Sepsis: Pathophysiologic Basis of Critical Illness Hypoglycemia and Mortality
DOI:
https://doi.org/10.52340/GBMN.2025.01.01.139Keywords:
Corticosteroid insufficiency, glucocorticoid resistance, hypoglycemia, mitochondrial dysfunction, sepsisAbstract
Sepsis is a significant disruptor of endocrine and metabolic homeostasis. During the early adaptive response, the hypothalamic–pituitary–adrenal (HPA) axis is activated to increase glucocorticoid production, promote stress hyperglycemia, and maintain cardiovascular homeostasis. When sepsis persists or is severe, this cortico–metabolic adaptation can fail. Experimental murine models show a transition from an early state of hypermetabolism and hyperglycemia to a hypometabolic state that includes hypoglycemia, lactic acidosis, and organ dysfunction. In critically ill patients, hypoglycemia often indicates failure of hepatic gluconeogenesis, depletion of energy reserves, and low glucocorticoid activity from critical illness–related corticosteroid insufficiency and tissue glucocorticoid resistance. Along with these changes, sepsis also causes metabolic disturbances, including mitochondrial dysfunction characterized by impaired oxidative phosphorylation, increased reliance on anaerobic glycolysis, and tissue accumulation of lactate. These metabolic disturbances create a bioenergetic crisis that can contribute to shock and death. This narrative review compiles findings from sepsis research published between 2020 and 2025 on adrenal axis failure, changes in glucocorticoid receptors, mitochondrial failure, and glucose dysregulation. We present an integrative pathophysiology that explicitly links endocrine and metabolic derangements and hypoglycemia in critical illness, and discuss how the experimental data presented may inform potential adjunctive therapies to restore cortico– metabolic homeostasis in patients with septic shock.References
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