Can fasting stress and slow catecholamine clearance drive sleep-maintenance insomnia and daytime fatigue?

Persistent sleep-maintenance insomnia and daytime fatigue in individuals with otherwise excellent lifestyle habits often stem from a complex convergence of metabolic, endocrine, and genetic stressors that drive nocturnal hyperarousal.

Mechanistic pathways of nocturnal arousal

• Fasting and recovery-induced fuel stress: Prolonged fasting and high physical recovery demands deplete glycogen stores, triggering nocturnal hypoglycemia or rapid glucose declines. This stimulates a counterregulatory response, prompting a sudden surge of epinephrine, norepinephrine, and cortisol to restore euglycemia. These hormones activate central arousal networks, directly causing abrupt 2 AM to 3 AM awakenings.
• Steroid precursor depletion: Sustained physical and metabolic recovery demands can deplete upstream adrenal substrates like the precursor pregnenolone. Depleting these vital steroidogenesis resources compromises overall HPA-axis resilience, leaving the autonomic nervous system vulnerable to volatile, unbuffered stress responses.
• Delayed catecholamine clearance: Genetic variations, specifically the COMT Val158Met polymorphism, dictate the clearance rate of excitatory neurotransmitters. Individuals carrying the Met allele ("slow COMT") exhibit a 40% reduction in enzymatic activity. This allows dopamine, epinephrine, and norepinephrine to linger in the prefrontal cortex and peripheral circulation, sustaining autonomic activation into the night and causing fragmented, light sleep.

Bottom line

• Fasting fuel stress, high physical recovery demands, steroid precursor limitations, and genetic catecholamine-clearance vulnerabilities (such as slow COMT activity) converge to hyper-activate HPA-axis and sympathetic pathways, directly causing nocturnal awakenings and daytime fatigue despite optimal sleep hygiene.