Elsevier

Sleep Medicine Reviews

Volume 37, February 2018, Pages 60-68
Sleep Medicine Reviews

Theoretical Review
Is exercise a viable therapeutic intervention to mitigate mitochondrial dysfunction and insulin resistance induced by sleep loss?

https://doi.org/10.1016/j.smrv.2017.01.001Get rights and content

Summary

Sleep loss has emerged as a risk factor comparable to that of physical inactivity for the development of insulin resistance, impaired glucose tolerance and type 2 diabetes mellitus. This is a concern as it was estimated in 2012 that approximately 70 million adults in the United States are sleeping less than 6 h each night, and the average nightly sleep duration of a representative sample of the U.S. adult population is reported to be significantly less than in previous decades. The underlying mechanisms responsible for chronic sleep loss induced insulin resistance include modifications in the regulation of hormone secretion, peripheral clock gene regulation, and the cellular signaling processes associated with regulating mitochondrial respiratory function. Emerging evidence shows these mechanisms share similar biochemical signaling pathways to those underpinning exercise-induced adaptations, which together suggest exercise might be a viable, suitable, and potent treatment alternative to alleviate sleep loss induced insulin resistance and glucose intolerance. In this theoretical review, we provide a summary of the impact of reduced sleep duration and quality on mitochondrial function and insulin resistance, before detailing the possible underlying mechanisms. Finally, we propose how and why regular exercise may be a therapeutic intervention to mitigate sleep loss induced mitochondrial dysfunction and insulin resistance.

Introduction

The prevalence of type 2 diabetes mellitus (T2DM) continues to rise in modern society. The World Health Organization (WHO) estimates that by the year 2025, 300 million people across the world will be diagnosed with diabetes [1]. To give this additional context, T2DM was the 7th leading cause of death in the United States in 2012 and costs their economy an estimated $245 billion each year [2]. Typically, the onset of T2DM coincides with impaired glucose tolerance (characterized by a fasting blood glucose level >7 mmol/L) and increased insulin resistance (reduced efficiency of insulin-stimulated glucose uptake) [3]. Furthermore, the health consequences arising from diabetic complications (such as heart disease, stroke and kidney damage) add to the already extraordinary burden of this metabolic disease on health services [2].

The most common risk factors associated with the onset of insulin resistance and glucose intolerance include genetic predisposition and lifestyle factors such as diet and physical inactivity [4]. However, in the last 15 y sleep has emerged as a prominent factor influencing the development of T2DM. In fact, sleep loss and reduced sleep quality are now reported to be comparable to physical inactivity [4] in terms of their relative contribution to the risk of developing T2DM. The percentage of sleep deficient people who develop insulin resistance and T2DM is difficult to determine with the available data. Nonetheless, studies investigating shift workers (a cohort often associated with insufficient sleep and reduced sleep quality [5]) indicate a significantly increased risk (40%) of developing diabetes compared to those performing day work [4]. Considering the significant reduction in average nightly sleep duration compared to previous decades [6], and that it was recently estimated via self-reported measures that ∼40% of the population are sleeping less than the recommended 7 h per night [7], the role of sleep loss in contributing to the already high prevalence of T2DM is an important area for further investigation.

Potential mechanisms by which sleep loss may contribute to insulin resistance and glucose intolerance have been identified, and include modifications to the regulation of hormone secretion [8], misalignment of the molecular clock (i.e., circadian misalignment) [9], and disruptions to cellular signaling processes (such as those involved in the insulin signaling pathway and the pathways associated with mitochondrial respiratory function) [10], [11]. If sleep loss affects signaling pathways related to mitochondrial respiratory function, then this has important implications as mitochondrial dysfunction has been associated with increased insulin resistance and T2DM [12], ∗[13]. The gold standard for the assessment of mitochondrial respiratory function is the measurement of oxygen utilization in isolated mitochondria or permeabilized tissue, and indicates the ability of mitochondria to generate adenosine triphosphate (ATP) via oxidative phosphorylation [14]. Using this method, it has been reported that mitochondrial respiratory function is significantly reduced in the skeletal muscle of T2DM patients compared with obese non-diabetic subjects [13]. Furthermore, this decrease in mitochondrial respiratory function was negatively associated with HbA1c results (glycated hemoglobin – a test that reflects blood glucose levels of the previous 3 mo) [13]. However, the effects of sleep loss on mitochondrial function are not well characterized.

Many of the aforementioned mechanisms that are potentially disrupted with sleep loss, particularly insulin signaling and mitochondrial function, share similar biochemical signaling pathways to those connected with exercise (an area of research that is comparably well studied). This suggests exercise as a potential intervention to counteract some of the negative effects associated with sleep loss. For example, single [15] and multiple [16] bouts of exercise induce a cascade of cellular signaling events that lead to improvements in mitochondrial function and insulin sensitivity [17]. Exercise has long been considered the cornerstone for the treatment and prevention of T2DM, with reports that those who regularly engage in moderate physical activity (even brisk walking) have approximately a 30% lower risk of developing T2DM compared to sedentary individuals [18]. However, limited research has investigated the ability of exercise to counteract the negative effects of sleep loss on glucose tolerance and insulin resistance [19]. Nevertheless, it is plausible that by increasing basal levels of exercise some of the detrimental effects associated with sleep loss might be mitigated.

The aim of this theoretical review is to draw on the available literature and propose exercise as a viable strategy to alleviate the negative effects of sleep loss. In doing so we contextualize the effect of reduced sleep duration and quality on insulin resistance, glucose tolerance, and T2DM, along with the potential underlying mechanisms, while demonstrating how and why engaging in regular exercise may act as a therapeutic intervention to mitigate sleep loss induced insulin resistance and T2DM.

The U.S.-based National Sleep Foundation recommends adults between the age of 18 and 64 y sleep 7–9 h each night [7]. Despite this approximately 70 million Americans (30% of the population) sleep less than 6 h per night – significantly less per night than that reported in 1985 (22%), based on a large representative sample of the U.S. adult population. This reduction in sleep has been attributed to a range of lifestyle factors and work pressures, including shift work, increased work demands, changing social pressures and roles, increased travel and the consequent jet lag, sleep disorders, and stress [20]. Changes in sleep habits have important consequences and have been linked to increased absenteeism, disability, industrial and motor vehicle accidents, increased alcohol consumption, risk of cardiovascular disease, and possibly increased mental health issues [21], [22].

Recent epidemiological and laboratory-based studies have also associated sleep loss with a range of chronic health concerns, particularly in relation to insulin resistance and T2DM ∗[4], [21], [23]. In humans, a 40% reduction in glucose tolerance and a 30% reduction in the acute insulin response following a glucose tolerance test (measurement of glucose and insulin levels following oral glucose administration) has been reported after six nights of 4 h of time in bed (TIB) per night [8]. More recently, it was reported that just one night of 4 h of sleep time reduces insulin sensitivity [24], [25], [26], with many other studies consistently reporting sleep loss induced insulin resistance [10], [24], [25], [26], [27], [28]. Thus, evidence from both epidemiological studies and intervention studies support a key role for sleep in the regulation of glucose tolerance and insulin resistance.

One proposed mechanism contributing to sleep loss induced changes in glucose tolerance and insulin resistance is circadian misalignment, a condition in which the exogenous behavioral sleep/wake schedule and feeding schedule are not aligned with endogenously generated circadian rhythms [29]. These circadian rhythms include changes in hormone secretion, body temperature, heart rate, muscle tone, and substrate utilization/metabolism, which persist throughout a 24-h period under constant conditions (i.e., without environmental/exogenous time cues) [30], [31]. Circadian rhythms are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, and the molecular clocks of peripheral tissues (such as skeletal muscle) acting synchronously as biological timekeepers. Altering the sleep/wake cycle (i.e., reduced sleep duration) may also independently alter the central and peripheral molecular clocks of human skeletal muscle [9] such that they become desynchronized with exogenous stimuli – a notion supported by rodent studies [32], [33]. As over 800 genes are regulated in a circadian manner within skeletal muscle of mice [34], sleep loss induced disruption of the molecular clocks that regulate the expression of these genes may have far-reaching effects, particularly in regard to normal cellular function and health. As such, the misalignment of both the central and peripheral clocks by exogenous stimuli has been proposed as another potential mechanism contributing to sleep loss induced insulin resistance and impaired glucose tolerance ∗[9], [29], ∗[35], ∗[36].

Shift workers who undertake variable rotating day and night shifts have an increased risk of circadian misalignment [37]. These workers experience reduced sleep durations, a constantly changing light/dark cycle, altered sleep/wake patterns, and mixed feeding patterns, which together can contribute to circadian misalignment [37], ∗[38]. Of significance, these changes in daily behaviors are also associated with a 40% increase in the risk of developing diabetes [4]. Indeed, a longitudinal study (conducted between 1991 and 2001) of Japanese alternating shift workers concluded that, compared to day shift workers, alternating shift work was an independent risk factor for the onset of T2DM [39]. Importantly, in both human and mouse models, exercise has been shown to be capable of causing a phase shift (i.e., advance or delay the circadian phase depending on the time of day that the exercise occurs) ∗[38], [40], and has thus been suggested as a potential intervention to help realign circadian and diurnal rhythms in those with sleep issues [40]. Linked to phase shifts of endogenously-regulated circadian rhythms, exercise has also been shown to cause shifts of the peripheral molecular clock in skeletal muscle (both rodent and human), thus highlighting the potential role for exercise to realign disrupted metabolic rhythms to their optimal state ∗[38], ∗[41].

Emerging evidence demonstrates that skeletal muscle function, and specifically that of mitochondrial respiration, also fluctuates rhythmically throughout the day. When mitochondrial respiratory function was measured in human skeletal muscle across a 24-h period, ADP-stimulated mitochondrial respiration oscillated in a “robust day/night rhythm”, with a difference of approximately 20% between the highest (11 PM) and lowest (1 PM) values [42]. In mice, the expression of key rate-limiting mitochondrial enzymes (i.e., pyruvate dehydrogenase and carnitine palmitoyl transferase) and ∼38% of the mitochondrial proteome, which are linked to the regulation of glucose tolerance and insulin resistance, also display a diurnal rhythm [43]. Similar to circadian rhythms, a diurnal rhythm follows a distinct 24-h cycle, but is synchronized to exogenous stimuli such as day and night and other factors such as the timing of meals [44]. Therefore, it is possible that misalignment of these diurnal rhythms is detrimental to mitochondrial function, which would have further implications for glucose tolerance and insulin resistance.

As mitochondrial function is regulated in a diurnal manner, and sleep loss can lead to circadian misalignment, it is plausible that sleep loss may alter mitochondrial function – even if this remains to be fully elucidated in well-controlled laboratory studies. It has been reported that 120 h of sustained wakefulness (sleep loss) reduces the activity of citrate synthase (CS) (24%), malate dehydrogenase (35%), and glycerol-3-phosphate dehydrogenase (17%) in human skeletal muscle [11], collectively suggesting a decreased functional capacity of the mitochondria. More recently, 72-h of sleep deprivation was associated with reduced mitochondrial respiratory function in the hypothalamus of rats [45]. Whilst these studies indicate that mitochondrial function may be directly reduced as a consequence of severe sleep loss, these initial findings have not been characterized in models that replicate the sleep loss encountered by humans. Nonetheless, the implications are significant considering the proposed contribution of mitochondrial dysfunction to the development of insulin resistance and T2DM [12], ∗[13]. It may therefore be hypothesized that chronic sleep loss, such as that experienced by at least 30% of the American population, leads to defects in mitochondrial function and a consequent increase in the risk of developing insulin resistance and T2DM [46]. Strategies to improve mitochondrial function, such as exercise [14], might be useful to combat some of the negative consequences of sleep loss.

At a molecular level, circadian rhythms are controlled by a number of genes – collectively known as Clock genes. A transcriptional:translational feedback loop, which includes the core Clock genes brain and muscle Arnt-like protein-1 (Bmal1), Clock and RAR-related orphan receptor α (Ror-α) (often referred to as the activators of the feedback loop), and period 1,2 and 3 (Per 1–3), cryptochrome 1/2 (Cry 1/2) and NR1D1; Nuclear receptor subfamily 1, group D, member 1 (Rev-erb-α) (considered the repressors of the feedback loop), together coordinate circadian rhythmicity and metabolism at a cellular level via their ability to regulate the transcriptional activity of a host of other genes (clock controlled genes – CCGs) (see [47] for review). Of significant note, the messenger ribonucleic acid (mRNA) expression in human skeletal muscle of two of these clock genes (Bmal1 and Cry1) is decreased following a night of sleep loss [9].

Central to metabolic health and circadian regulation is the energy sensor, AMP-activated protein kinase (AMPK). AMPK is activated upon changes in the AMP:ATP ratio, is important in the regulation of mitochondrial biogenesis, and interacts closely with clock genes. Activation of AMPK causes the phosphorylation and destabilization of Cry1, leading to de-repression of the BMAL1:CLOCK complex [48]. Moreover, Rev-erb-α (a regulator of the clock gene transcriptional feedback loop and mitochondrial biogenesis) [49] regulates AMPK [50] via liver kinase B1 (LKB1) – a protein responsible for upstream regulation of AMPK. It has also been suggested that clock genes within skeletal muscle (i.e., Per1, Cry2) are regulated by AMPKγ3 [51] – an AMPK isoform specific to skeletal muscle and essential for the regulation of glucose tolerance and insulin sensitivity [52]. Exercise also activates and phosphorylates AMPK [15], which subsequently plays a role in GLUT4 (glucose transporter 4) mediated skeletal muscle glucose uptake [53]. Furthermore, muscle-specific Bmal1 knockout mice have decreased skeletal muscle glucose uptake through decreased GLUT4 translocation [36], which may be due to reduced expression of Tbc1d1 – a Rab-GTPase member involved in the GLUT4 translocation process and a potential target of the CLOCK:BMAL1 complex [54]. Together, this suggests exercise-induced AMPK activation might help counteract impairments in insulin resistance and glucose tolerance that may be associated with abnormalities in clock gene expression.

Downstream of AMPK is the transcriptional co-activator peroxisome proliferator-activated receptor γ (PGC-1α) [55], which is also upregulated in response to exercise [15]. PGC-1α is often referred to as the ‘master regulator’ of mitochondrial biogenesis, due to its role in the transcriptional co-activation of a number of transcription factors (nuclear respiratory factor 1/2 (NRF 1/2), mitochondrial transcription factor A (Tfam) and peroxisome proliferator-activated receptor (PPARs)) involved in the regulation of mitochondrial respiratory function and content [16]. Importantly, PGC-1α also regulates the expression of, and is in itself regulated by interactions with, members of the clock gene family (as demonstrated in a number of rodent studies) ∗[35], [56], ∗[57]. For example, PGC-1α knockout mice models demonstrate reduced clock gene expression, while Bmal1 knockout mice models and mice with a mutated CLOCK protein (truncated CLOCKΔ19 protein) display reduced PGC-1α protein content ∗[35], [56], ∗[57]. Decreases in PGC-1α protein content may contribute to the reductions in mitochondrial content and respiration that are observed in Bmal1 knockout mice and CLOCKΔ19 mutant mice ∗[35], ∗[57]. These same clock gene mutant mice have also been shown to have reduced insulin sensitivity, and the early development of T2DM ∗[47], [58], [59], [60], which may be explained in part by the close association between mitochondrial dysfunction and the development of insulin resistance and T2DM [12], ∗[13], [46], [61]. These findings suggest that reductions in the protein content and expression of clock genes and PGC-1α may help to explain the reported effects of sleep loss on insulin sensitivity and T2DM. Importantly, both single and multiple bouts of exercise increase PGC-1α expression [15], [62] and mitochondrial function [63], [64], with subsequent improvements in insulin sensitivity [17]. Thus, there is emerging evidence suggesting exercise might be a viable strategy to counteract the effects of sleep loss on clock gene expression, PGC-1α expression, reduced mitochondrial function, and subsequently increased insulin resistance.

While the role of PGC-1α as a key metabolic regulator is well established, it is also important to note its role may be determined by factors such as tissue specificity and its level of expression [65], [66]. Hepatic overexpression of PGC-1α in mice induces hepatic insulin resistance, potentially via increased stimulation of gluconeogenesis, leading to hyperglycemia [66]. However, increased expression of PGC-1α within physiological levels (as seen with exercise), improves mitochondrial content, GLUT4 expression, and insulin sensitivity in skeletal muscle [65].

Another key regulator of mitochondrial function, which can also be classified as a clock-controlled gene, is SIRT3 (a member of the sirtuin family) [67]. SIRT3 is a mitochondrial protein that controls the acetylation levels of key functional oxidative metabolism and fatty acid oxidation proteins (i.e., long-chain acyl dehydrogenase), and thus can influence the overall respiratory function of the mitochondria [67]. Knockout of SIRT3 in mice causes a reduction in the expression of mitochondria related genes that are induced by PGC-1α [68]. Using liver-specific Bmal1 knockout mice, it was reported that mitochondrial respiration in the liver could be influenced in a circadian manner via clock gene dependent regulation of nicotinamide adenine dinucleotide (NAD+ – a mitochondrial co-enzyme), which in turn controls the deacetylase activity of SIRT3 [67]. Another member of the sirtuin family, SIRT1 – a regulator of insulin sensitivity in mouse skeletal muscle, also appears to be activated by CLOCK and BMAL1, with mutation and knockout of these clock proteins, respectively, leading to the induction of insulin resistance [69]. This indicates the dysregulation of clock genes, suggested to occur in response to sleep loss [9], may also lead to increased insulin resistance via a reduced content of SIRT proteins.

Of note, and similar to both AMPK and PGC-1α, it has been shown that SIRT1 and SIRT3 can be upregulated by exercise in the skeletal muscle of both animals [70], [71] and humans [72]. Elevated SIRT1 activity has been shown to be important in the subsequent deacetylation and induction of PGC-1α transcriptional activity [73]. Together, this demonstrates that both clock genes and exercise influence many regulators of mitochondrial biogenesis. This might help to explain why there is a diurnal rhythm to mitochondrial function and enzyme activity, why these may be affected by sleep loss, and equally why exercise may play a role in mitigating sleep loss induced insulin resistance. The connection between clock genes, AMPK, PGC-1α, SIRT1 and SIRT3 is summarized in Fig. 1.

Exercise induced increases in the activation of AMPK, the protein content of PGC-1α, and activity of SIRT1 and SIRT3, are important signaling events that coordinate the expression of mitochondria-related genes (leading to increased mitochondrial content and function) as well as improvements in insulin sensitivity [74], [75]. Among the genes that PGC-1α increases the expression of, are the mitochondrial enzymes that have been reported to have diminished activity following sleep loss in humans. For example, CS activity (a key enzyme of the citric acid cycle and a marker of mitochondrial content) is significantly reduced in human skeletal muscle following 120 h of sustained wakefulness [11]. Importantly, skeletal muscle CS mRNA and PGC-1α mRNA is increased following a single bout of high-intensity interval exercise (HIIE), with subsequent increases in CS activity and PGC-1α content [16]. Moreover, activity of the same complexes in the electron transport system that are reduced following sleep deprivation in rats [45] can be improved via exercise training [76]. Therefore, exercise can promote increased activity and content of mitochondrial enzymes that are reduced following sleep loss and which may lead to insulin resistance and T2DM.

Despite our increased understanding of mitochondrial signaling, and models of sleep disruption and circadian misalignment, there are a number of additional exercise-induced signaling pathways associated with improved mitochondrial function that have yet to be investigated in response to sleep loss. In humans muscle contraction leads to the activation of kinases such as calmodulin-dependent protein kinase (CAMK) and p38 mitogen activated protein kinase (p38MAPK) (in addition to AMPK), via changes in calcium and reactive oxygen species, respectively, which converge on myocyte enhancer factor 2 (MEF-2), activating transcription factor 2 (ATF2) and cyclic-AMP response element binding protein (CREB), and exert their influence on enhancing PGC-1α promoter activity [77]. In addition, Perry et al. [16] demonstrated that exercise training modulates mitochondrial fission and fusion proteins important for regulating mitochondrial integrity and turnover. Moreover, we have recently reported in human skeletal muscle that single [15] and multiple [62] bouts of exercise increase phosphorylation and protein levels of the tumor suppressor protein, p53. Ablation of p53 content in mice results in reduced mitochondrial respiration, lowered PGC-1α content and decreased exercise capacity [78], whilst p53 has also been shown to regulate insulin resistance [79]. Collectively, these pathways represent varying avenues for future research in the context of sleep loss, exercise, mitochondrial function and insulin resistance.

The detrimental mitochondrial characteristics previously demonstrated in clock gene knockout mice can also be somewhat ameliorated by exercise [57]. Following an 8-wk exercise training program, mice with mutated CLOCKΔ19 proteins were able to restore PGC-1α protein content to that of trained wild-type mice [57]. This was accompanied by similar increases in cytochrome c oxidase subunit 1 (COX-I) activity (another marker of mitochondrial content [80]). Moreover, a single bout of resistance exercise is associated with increased expression of Per2, Cry1 and Bmal1 in human skeletal muscle, compared with resting muscle [41]. Together, these associations between clock controlled genes, PGC-1α, and mitochondrial dysfunction ∗[35], [56] provide a theoretical mechanism by which exercise-induced contractile activity may play a role in ameliorating sleep loss induced disruptions of clock genes following a night of sleep loss [9] and hence mitigate consequent impairments in mitochondrial function and insulin sensitivity. That said, future research should focus on uncovering the specific relationships and underpinning mechanisms between sleep loss, changes in skeletal muscle mitochondrial function, and exercise. A schematic overview summarizing the hypothesized connection between sleep, exercise and insulin resistance is shown in Fig. 2.

As skeletal muscle is the major site for glucose disposal, it is conceivable that maintenance of muscle mass and function is also important for maintaining glucose tolerance and insulin sensitivity. In this context, it has been reported that sleep loss can lead to a decrease in muscle mass – likely due to an increased catabolic and reduced anabolic hormone profile [81], [82], [83]. Moreover, while on a calorie restricted diet, curtailing sleep opportunities to 5.5 h a night for 14 consecutive nights increased the fraction of muscle mass lost compared to participants who had an 8.5 h sleep opportunity each night [84]. Together, this marks another possible convergence point at which sleep and exercise may interact.

While inconclusive thus far, evidence from animal models used to investigate muscle atrophy and sarcopenia (a progressive loss of muscle mass, quality and function, associated with aging [85]) point towards the disruption of clock genes as a contributing mechanism. For example, Bmal1 knockout mice display features associated with advanced aging and sarcopenia, including significantly reduced strength and altered myofilament structure ∗[35], [86]. This suggests that the molecular clock is necessary for the maintenance of skeletal muscle function and phenotype. Another mechanism thought important in the regulation of muscle mass is inflammation. Indeed, lifestyle factors such as sedentary behaviors and sleep loss, as well as obesity and T2DM, induce dramatic increases in pro-inflammatory signaling [87], which may also be implicated in muscle atrophy [88].

Strategies that can regulate the molecular clock, such as resistance-based exercise interventions, have also been shown to increase muscle mass and to protect against sarcopenia [89]. Furthermore, exercise has been shown to have anti-inflammatory properties [90], providing a potential additional mechanism to counteract sleep loss induced muscle loss. Importantly, it has been shown in rats that resistance exercise training performed prior to sleep loss attenuates muscle atrophy [82], providing preliminary evidence of the role contractile activity can play in protecting against sleep loss induced muscle mass loss. Whether it also helps reduce the development of insulin resistance, by maintaining skeletal muscle functionality, remains to be determined. Nonetheless, considering the increased prevalence of sarcopenia in T2DM patients [91], [92], this appears an important area of emerging research.

In addition to sleep loss, sleep quality may also be a critical factor influencing the regulation of insulin sensitivity [93]. It was recently reported that, like sleep loss, reduced sleep quality is associated with a similar increase in the risk of T2DM as physical inactivity (∼40%) [4]. Additionally, patients with sleep disorders, such as obstructive sleep apnea (OSA), in which sleep quality is significantly reduced, have an increased risk of insulin resistance [4]. Sleep quality can be determined via polysomnography, which analyzes multiple physiological parameters relevant to sleep. Specifically, the time spent in different stages of sleep can be quantified (i.e., non-rapid eye movement (nREM, stages 1–3) and rapid eye movement (REM)) [94]. A reduction in the time spent in slow wave sleep (SWS, nREM stage 3) (i.e., restorative sleep) is also associated with increased insulin resistance [93], ∗[95]. Indeed, when SWS is disturbed, but the overall time spent asleep is not reduced, there are increases in insulin resistance of between 20 and 25%. However, a night of REM sleep disturbance did not produce similar reductions in insulin sensitivity, suggesting that SWS rather than REM sleep may play a role in the regulation of insulin sensitivity [95]. Taken together with the fact that there is no association between sleep stages and fasting insulin resistance following one night of sleep restricted sleep [25], more research is warranted to determine the role of REM and SWS on the regulation of glucose tolerance and insulin resistance.

Given that sleep quality is an important determinant of glucose tolerance and insulin sensitivity [23], [93], improving sleep quality by means of regular engagement in exercise could also prove beneficial in the treatment and prevention of insulin resistance and T2DM. There are a number of strategies for improving sleep quality (e.g., sleep hygiene practices such as caffeine restriction and reducing the use of electronic devices prior to bed). However, engaging in physical activity and exercise (both acutely and chronically), as alternative or complementary approaches, may be beneficial [96], [97]. In a comparison of older adults who were assigned to either a moderate-intensity exercise program or a health education control program over a 12-month period, an exercise program was shown to improve aspects of sleep quality [98]. Indeed, decreases in nREM stage 1 sleep (considered a transitional state from wake to sleep), increases in nREM stage 2 sleep (considered more stable sleep than stage 1) and reduced sleep disturbances (as assessed via polysomnography) were reported, which coincided with improved self-reported parameters of sleep quality following the exercise program. Moreover, exercise is currently prescribed, and has been shown to be effective in improving sleep quality, for a variety of clinical sleep disorders, including insomnia and obstructive sleep apnea, in which sleep quality is typically reduced [99], [100]. However, further research is required to determine whether, in addition to metabolic function, exercise-induced improvements in sleep quality (regardless of duration) can help to maintain glucose tolerance and insulin resistance.

Section snippets

Conclusion

To date, sleep and exercise in the context of human health have remained relatively independent lines of research. However, with the emergence of sleep loss as a significant risk factor for the development of insulin resistance and T2DM, engagement in exercise to mitigate these risks may offer an alternative solution. Indeed, this review presents and uncovers a framework and mechanistic underpinning of how exercise can be of significant benefit to counteract the mechanisms by which sleep loss

Conflict of interest

The authors do not have any conflicts of interest to disclose.

Acknowledgements

No financial support was provided in the development of this manuscript.

References (100)

  • M. Lefta et al.

    Circadian rhythms, the molecular clock, and skeletal muscle

    Curr Top Dev Biol

    (2011)
  • M. Suwa et al.

    Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1alpha protein expressions in rat skeletal muscle

    Metabolism

    (2008)
  • P. Puigserver et al.

    A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis

    Cell

    (1998)
  • L.N. Bell et al.

    Effects of sleep restriction on the human plasma metabolome

    Physiol Behav

    (2013)
  • J.M. Mullington et al.

    Sleep loss and inflammation

    Best Pract Res Clin Endocrinol Metab

    (2010)
  • N. Herzog et al.

    Selective slow wave sleep but not rapid eye movement sleep suppression impairs morning glucose tolerance in healthy men

    Psychoneuroendocrinology

    (2013)
  • P.Y. Yang et al.

    Exercise training improves sleep quality in middle-aged and older adults with sleep problems: a systematic review

    J Physiother

    (2012)
  • World Health Organization

    Life in the 21st century – a vision for all

    (1998)
  • Centers for Disease Control and Prevention

    National diabetes statistics report: estimates of diabetes and its burden in the United States

    (2014)
  • National Collaborating Centre for Chronic Conditions

    Type 2 diabetes: national clinical guideline for management in primary and secondary care (update) London

    (2008)
  • T. Anothaisintawee et al.

    Sleep disturbances compared to traditional risk factors for diabetes development: systematic review and meta-analysis

    Sleep Med Rev

    (2015)
  • T. Akerstedt

    Shift work and disturbed sleep/wakefulness

    Occup Med Lond

    (2003)
  • E.S. Ford et al.

    Trends in self-reported sleep duration among US adults from 1985 to 2012

    Sleep

    (2015)
  • National sleep foundation. International bedroom poll

    (2013)
  • J. Cedernaes et al.

    Acute sleep loss induces tissue-specific epigenetic and transcriptional alterations to circadian clock genes in men

    J Clin Endocrinol Metab

    (2015)
  • J.L. Broussard et al.

    Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study

    Ann Intern Med

    (2012)
  • K. Vondra et al.

    Effects of sleep-deprivation on the activity of selected metabolic enzymes in skeletal-muscle

    Eur J Appl Physiol Occup Physiol

    (1981)
  • B.B. Lowell et al.

    Mitochondrial dysfunction and type 2 diabetes

    Science

    (2005)
  • M. Mogensen et al.

    Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes

    Diabetes

    (2007)
  • J.D. Bartlett et al.

    Matched work high-intensity interval and continuous running induce similar increases in PGC-1alpha mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle

    J Appl Physiol (1985)

    (2012)
  • C.G.R. Perry et al.

    Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle

    J Physiol-Lond

    (2010)
  • R.C. Meex et al.

    Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity

    Diabetes

    (2010)
  • C.Y. Jeon et al.

    Physical activity of moderate intensity and risk of type 2 diabetes: a systematic review

    Diabetes Care

    (2007)
  • T. VanHelder et al.

    Effects of sleep deprivation and exercise on glucose tolerance

    Aviat Space Environ Med

    (1993)
  • Sleep Health Foundation

    Common reasons why people don't get enough sleep

    (2011)
  • S. Banks et al.

    Behavioral and physiological consequences of sleep restriction

    J Clin Sleep Med

    (2007)
  • F.P. Cappuccio et al.

    Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis

    Diabetes Care

    (2010)
  • E. Donga et al.

    A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects

    J Clin Endocrinol Metab

    (2010)
  • J. Cedernaes et al.

    A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men

    J Sleep Res

    (2015)
  • M.N. Rao et al.

    Subchronic sleep restriction causes tissue-specific insulin resistance

    J Clin Endocrinol Metab

    (2015)
  • R. Leproult et al.

    Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss

    Diabetes

    (2014)
  • H.R. Colten et al.

    Sleep disorders and sleep deprivation: an unmet public health problem

    (2006)
  • J.C. Dunlap et al.

    Chronobiology: biological timekeeping

    (2004)
  • S. Yamazaki et al.

    Resetting central and peripheral circadian oscillators in transgenic rats

    Science

    (2000)
  • M.C. Antle et al.

    Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster

    J Neurosci

    (2000)
  • J.J. McCarthy et al.

    Identification of the circadian transcriptome in adult mouse skeletal muscle

    Physiol Genomics

    (2007)
  • J.L. Andrews et al.

    CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function

    Proc Natl Acad Sci U. S. A

    (2010)
  • M. Nagano et al.

    An abrupt shift in the day/night cycle causes desynchrony in the mammalian circadian center

    J Neurosci

    (2003)
  • G. Wolff et al.

    Scheduled exercise phase shifts the circadian clock in skeletal muscle

    Med Sci Sports Exerc

    (2012)
  • Y. Suwazono et al.

    Long-term longitudinal study on the relationship between alternating shift work and the onset of diabetes mellitus in male Japanese workers

    J Occup Environ Med

    (2006)
  • Cited by (0)

    The most important references are denoted by an asterisk.

    View full text