Altered diurnal states in insomnia reflect peripheral hyperarousal and metabolic desynchrony: a preliminary study

Abstract

Study objectives: Insomnia is a common sleep disorder that is associated with a range of adverse outcomes. Patients with insomnia exhibit hyperarousal in multiple domains, including an elevated metabolic rate, but specific metabolic molecular perturbations are unknown. Furthermore, objective clinical markers of insomnia are not available and current assessment of pathological extent relies on self-report. Here, we provide preliminary evidence that chronic insomnia is remarkably reflected in the periphery through detailed metabolic assessments.

Methods: Serum from confirmed patients with insomnia and matched good sleepers (n = 15 per group) was sampled at high temporal resolution (every 2 hr over 48 hr). Food intake was controlled by providing hourly isocaloric snacks, and sleep architecture was assessed by overnight polysomnography. Quantitative metabolic assessments were conducted using nuclear magnetic resonance spectroscopy.

Results: Global metabolic profiles differentiated patients with insomnia from healthy controls, with elevated amino acid and energy metabolites and reduced branched-chain amino acid catabolic products. Strikingly, branched-chain amino acid catabolism was found to be specifically altered during the night with ~10 per cent increased accumulation of glucose in insomnia patients. Rhythmicity analysis revealed 11 metabolites that cycled diurnally across both groups, with phase advances noted for acetone and delays for lactate and branched-chain amino acids and their products.

Conclusions: These preliminary observations suggest that insomnia is associated with quantitative metabolic dysregulation and supports the hyperarousal hypothesis. Furthermore, we posit that these changes lead to a state of metabolic desynchrony in insomnia that is involved in the pathophysiology of the disorder and/or mediates its impact on health outcomes.

Clinical trials registration: NCT01957111.

Figure 1.

STROBE diagram showing the flow of participants through the study.

Figure 2.

Correlation of insomnia-specific parameters with level of metabolites at 7 am in the morning. Only sleep efficiency and WASO showed some trend towards significance. The normalized levels of acetate, succinate, and alanine were significantly correlated with sleep efficiency and those of acetate and succinate were significantly correlated with WASO.

Figure 3.

Multivariate OPLS-DA analysis of insomnia and control samples over all collection time points. Cross-validated OPLS-DA scores plot showed significant clustering of insomnia and control samples over both triplicate (A) and singlet (B) sets. The bins were selected by overlap analysis (C) and metabolites were assigned by spectral profiling (D).

Figure 4.

Multivariate OPLS-DA analysis of insomnia and control samples over day (9 am–5 pm, A–D) and night (11 pm–7 am, E–H) samples. Cross-validated OPLS-DA scores plot showed significant clustering of insomnia and control samples over both triplicate (A/E) and singlet (B/D) sets. The bins were selected by overlap analysis (C/G) and metabolites were assigned by spectral profiling (D/H).

Figure 5.

Time series analysis of metabolites. Only the second night data are shown here. The samples were analyzed by two-group SAM for significantly different temporal trend of metabolites in insomnia (red) and control (blue) population. Metabolites with significant differences across control and insomnia population are presented.

Figure 6.

Analysis of metabolite rhythm in insomnia and control population using Metacycle 2D. Insomnia and control population was subjected to metabolite rhythm analysis separately. Control population showed 6 and insomnia population showed 7 unique cyclers, whereas 11 cyclers were common (A and B). Among the common cycling metabolites, many showed differences in fold change and amplitude (C). Representative time course plots are shown for four common metabolites (D, insomnia—blue, control—red). A proposed general metabolic state shift of insomniacs is shown over the diurnal day based on the time series analysis (E). 3-Me-2-OV = 3-methyl-2-oxovalerate; 3-HIB = 3-hydroxyisobutyrate; 3-HB = 3-hydroxybutyrate; Trp = tryptophan.