A State-of-Art Review of the Vicious Circle of Sleep Disorders, Diabetes and Neurodegeneration Involving Metabolism and Microbiota Alterations

Abstract

In the context of neurodegenerative disorders, cognitive decline is frequently reported in older population. Recently, numerous metabolic pathways have been implicated in neurodegeneration, including signaling disruption of insulin and other glucose-regulating hormones. In fact, Alzheimer's disease has now been considered as "type-3 diabetes". In this review, we tried to clarify the role of sleep impairment as the third major player in the complex relationship between metabolic and neurodegenerative diseases. Altered sleep may trigger or perpetuate these vicious mechanisms, leading to the development of both dementia and type 2 diabetes mellitus. Finally, we analyzed these reciprocal interactions considering the emerging role of the gut microbiota in modulating the same processes. Conditions of dysbiosis have been linked to circadian rhythm disruption, metabolic alterations, and release of neurotoxic products, all contributing to neurodegeneration. In a future prospective, gut microbiota could provide a major contribution in explaining the tangled relationship between sleep disorders, dementia and diabetes.

Keywords: Alzheimer’s disease; brain–gut axis; cognition; diabetes; gut microbiota; inflammation; insulin resistance; neurodegeneration; sleep disorders.

Figure 1

A summary of possible interactions between sleep disorders, diabetes, and neurodegeneration. Sleep impairment can lead to neurodegeneration and cognitive decline; part of this process is mediated by metabolic alterations [90]. Sleep alterations contributes to amyloid accumulation by impairing glymphatic system function and favoring the activation of systemic inflammatory response. Moreover, disturbed sleep dysregulates crucial hormones involved in glucose homeostasis (i.e., insulin, GH/IGF-1 axis and GLP-1), predisposing to both T2DM and AD. These mechanisms can enter a vicious cycle and build on each other. Neuroinflammation propagates via the activation of astrocytes and microglia; Aβ plaques themselves can activate astrocytes to release pro-inflammatory cytokines. Neurodegeneration also involves crucial structures for sleep physiology (e.g., hypothalamic SCN) [11] perpetuating and worsening sleep alterations, with further amyloid deposition.

Figure 2

A summary of how central and peripheral clocks alterations can lead to a consequential behavioral and metabolic dysregulation, thus contributing to the development of diabetes and dementia [75,77,86]. The hypothalamic SCN acts as the central clock, modulating the intrinsic oscillating activity of peripheral clocks. SCN: suprachiasmatic nucleus; LPS: lipopolysaccharides; SCFAs: short-chain fatty acids: HDAC3: histone deacetylase 3 gene; NFIL3: nuclear factor interleukin 3 gene. Figure 2 was created with BioRender.com, accessed on 15 June 2023.