Can chronic stress and unrefreshed sleep raise glucose output and impair insulin signaling?

Chronic physiological stress and unrefreshed sleep act as potent systemic stressors that disrupt metabolic homeostasis through hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) dysregulation.

Mechanistic pathways of glucose and insulin dysregulation

• Elevated glucose output: HPA-axis and SNS hyperactivation due to chronic stress and sleep fragmentation elevate cortisol and sympathetic tone, directly driving hepatic gluconeogenesis and increasing glucose output.
• Impaired insulin signaling: Elevated cortisol, free fatty acids, and inflammatory cytokines activate serine/threonine kinases, notably c-Jun N-terminal kinase (JNK). This induces inhibitory serine phosphorylation of insulin receptor substrate-1 (IRS-1, such as Ser307), disrupting downstream PI3K/AKT signaling and preventing GLUT4 translocation for glucose uptake.

HPA-axis strain and metabolic flexibility

• Biomarkers of strain: Low dehydroepiandrosterone sulfate (DHEA-S) levels, especially when presenting with an elevated cortisol-to-DHEA-S ratio, serve as robust biomarkers of chronic HPA-axis strain and allostatic load.
• Loss of metabolic flexibility: Physiologically, DHEA-S counters glucocorticoid action by suppressing 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which limits local cortisol generation in adipose tissue. Depleted DHEA-S impairs this protective mechanism, promoting visceral adiposity and insulin resistance, which directly compromises metabolic flexibility—the cellular capacity to switch between glucose and lipid oxidation.

Bottom line

• Chronic stress and sleep fragmentation elevate glucose output and impair insulin signaling via inhibitory IRS-1 serine phosphorylation, while low DHEA-S signals HPA-axis strain that directly compromises metabolic flexibility.