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Sleep disruption and activation of cellular inflammation mediate heightened pain sensitivity: a randomized clinical trial.
Irwin, MR, Olmstead, R, Bjurstrom, MF, Finan, PH, Smith, MT
Pain. 2023;164(5):1128-1137
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Sleep disturbance is associated with elevated levels of inflammation. Experimental studies have found that even a modest amount of sleep loss activates inflammatory processes. Experimental sleep disruption also induces alterations in sleep architecture including loss of slow wave or N3 sleep and loss of rapid eye movement sleep. The aim of this study was to clarify whether changes in the amount of N3 sleep and cellular inflammation mediate thermal pain sensitivity (i.e., heat pain threshold) in response to experimental sleep disruption. This study was a secondary analysis (assessor-blind) of a randomised controlled trial. The enrolled participants were randomised to 1 of 2 groups: 2 nights of undisturbed sleep (US) and 2 nights of sleep disruption or forced awakening (FA). Participants underwent 2 consecutive nights of US (or FA), followed by a 2-week washout interval in their home environment, and then completed 2 consecutive nights of the opposing sleep condition FA (or US). Results showed that in healthy adults, experimental disruption of sleep due to the administration of FA induced a significant decrease in heat pain threshold, as compared with responses after US. Experimental manipulation of sleep with FA also led to disturbance in sleep continuity and changes in sleep architecture, including loss of N3 sleep. Moreover, in the morning after FA, there was a robust activation of cellular inflammation Authors conclude that the differential loss of N3 sleep and increases in cellular inflammation may be important drivers of pain sensitivity in response to sleep disruption.
Abstract
Sleep loss heightens pain sensitivity, but the pathways underlying this association are not known. Given that experimental sleep disruption induces increases in cellular inflammation as well as selective loss of slow wave, N3 sleep, this study examined whether these mechanisms contribute to pain sensitivity following sleep loss in healthy adults. This assessor-blinded, cross-over sleep condition, single-site, randomized clinical trial enrolled 95 healthy adults (mean [SD] age, 27.8 [6.4]; female, 44 [53.7%]). The 2 sleep conditions were 2 nights of undisturbed sleep (US) and 2 nights of sleep disruption or forced awakening (FA, 8 pseudorandomly distributed awakenings and 200 minutes wake time during the 8-hour sleep opportunity), administered in a cross-over design after 2 weeks of washout and in a random order (FA-US; US-FA). Primary outcome was heat pain threshold (hPTH). Sleep architecture was assessed by polysomnography, and morning levels of cellular inflammation were evaluated by Toll-like receptor-4 stimulated monocyte intracellular proinflammatory cytokine production. As compared with US, FA was associated with decreases in the amount of slow wave or N3 sleep ( P < 0.001), increases in Toll-like receptor-4 stimulated production of interleukin-6 and tumor necrosis factor-α ( P = 0.03), and decreases in hPTH ( P = 0.02). A comprehensive causal mediation analysis found that FA had an indirect effect on hPTH by decreases in N3 sleep and subsequent increases in inflammation (estimate=-0.15; 95% confidence interval, -0.30 to -0.03; P < 0.05) with the proportion mediated 34.9%. Differential loss of slow wave, N3 sleep, and increases in cellular inflammation are important drivers of pain sensitivity after sleep disruption.Clinical Trials Registration: NCT01794689.
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Sleep restriction for 1 week reduces insulin sensitivity in healthy men.
Buxton, OM, Pavlova, M, Reid, EW, Wang, W, Simonson, DC, Adler, GK
Diabetes. 2010;59(9):2126-33
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Short sleep duration is associated with an increased risk of many chronic diseases including diabetes, however the effects of sleep restriction on insulin sensitivity have not yet been established. The aim of study was to assess the effects of decreased sleep duration on insulin sensitivity in a controlled environment. This 12-day inpatient study included 20 healthy men who were randmoised to receive a wakefulness-promoting drug, modafinil, or placebo during the sleep restriction phase. This study showed that sleep restriction for one week significantly reduces insulin sensitivity. These findings raise concerns about chronic insufficient sleep on the development of metabolic diseases and promote further research into these effects.
Abstract
OBJECTIVE Short sleep duration is associated with impaired glucose tolerance and an increased risk of diabetes. The effects of sleep restriction on insulin sensitivity have not been established. This study tests the hypothesis that decreasing nighttime sleep duration reduces insulin sensitivity and assesses the effects of a drug, modafinil, that increases alertness during wakefulness. RESEARCH DESIGN AND METHODS This 12-day inpatient General Clinical Research Center study included 20 healthy men (age 20-35 years and BMI 20-30 kg/m(2)). Subjects spent 10 h/night in bed for >or=8 nights including three inpatient nights (sleep-replete condition), followed by 5 h/night in bed for 7 nights (sleep-restricted condition). Subjects received 300 mg/day modafinil or placebo during sleep restriction. Diet and activity were controlled. On the last 2 days of each condition, we assessed glucose metabolism by intravenous glucose tolerance test (IVGTT) and euglycemic-hyperinsulinemic clamp. Salivary cortisol, 24-h urinary catecholamines, and neurobehavioral performance were measured. RESULTS IVGTT-derived insulin sensitivity was reduced by (means +/- SD) 20 +/- 24% after sleep restriction (P = 0.001), without significant alterations in the insulin secretory response. Similarly, insulin sensitivity assessed by clamp was reduced by 11 +/- 5.5% (P < 0.04) after sleep restriction. Glucose tolerance and the disposition index were reduced by sleep restriction. These outcomes were not affected by modafinil treatment. Changes in insulin sensitivity did not correlate with changes in salivary cortisol (increase of 51 +/- 8% with sleep restriction, P < 0.02), urinary catecholamines, or slow wave sleep. CONCLUSIONS Sleep restriction (5 h/night) for 1 week significantly reduces insulin sensitivity, raising concerns about effects of chronic insufficient sleep on disease processes associated with insulin resistance.
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Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance.
Nedeltcheva, AV, Kessler, L, Imperial, J, Penev, PD
The Journal of clinical endocrinology and metabolism. 2009;94(9):3242-50
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Type-2 diabetes (T2D) is a complex disease influenced by genetic, environmental, metabolic and behavioural factors and is a rising burden in Westernised societies. Whether reduced sleep duration, in the context of a Western lifestyle, is associated with an increased incidence of T2D is unclear and available evidence is limited. The aim of this crossover study was to determine whether sleep restriction may result in a decreased glucose tolerance and reduced insulin secretion in 11 healthy middle-aged adults. Participants were restricted to 5.5 hours of sleep per night and glucose challenges and circulating plasma concentrations were used to measure hormonal and metabolic parameters. This study showed that recurrent short sleep times may facilitate the development of insulin resistance and reduced glucose tolerance. These findings suggest that combining the adverse metabolic effects of a Western lifestyle with chronically reduced sleep duration may increase the long-term risk of developing T2D.
Abstract
CONTEXT Epidemiological data indicate that reduced sleep duration is associated with increased incidence of type-2 diabetes. OBJECTIVE The aim of the study was to test the hypothesis that, when part of a Western-like lifestyle, recurrent bedtime restriction may result in decreased glucose tolerance and reduced insulin secretion and action. DESIGN AND SETTING We conducted a randomized crossover study at a university clinical research center and sleep research laboratory. PARTICIPANTS Eleven healthy volunteers (five females and six males) with a mean (+/-sd) age of 39 +/- 5 yr and body mass index of 26.5 +/- 1.5 kg/m(2) participated in the study. INTERVENTION The study included two 14-d periods of controlled exposure to sedentary living with ad libitum food intake and 5.5- or 8.5-h bedtimes. MAIN OUTCOME MEASURES Oral and iv glucose challenges were used to obtain measures of glucose tolerance, glucose effectiveness, insulin secretion, and insulin sensitivity at the end of each intervention. Secondary measures included circulating concentrations of the glucose counter-regulatory hormones, cortisol, GH, epinephrine, and norepinephrine. RESULTS Bedtime restriction reduced daily sleep by 122 +/- 25 min. Both study periods were associated with comparable weight gain; however, recurrent sleep restriction resulted in reduced oral glucose tolerance (2-h glucose value, 144 +/- 25 vs. 132 +/- 36 mg/dl; P < 0.01) and insulin sensitivity [3.3 +/- 1.1 vs. 4.0 +/- 1.6 (mU/liter)(-1) x min(-1); P < 0.03], and increased glucose effectiveness (0.023 +/- 0.005 vs. 0.020 +/- 0.005 min(-1); P < 0.04). Although 24-h cortisol and GH concentrations did not change, there was a modest increase in 24-h epinephrine and nighttime norepinephrine levels during the 5.5-h bedtime condition. CONCLUSIONS Experimental bedtime restriction, designed to approximate the short sleep times experienced by many individuals in Westernized societies, may facilitate the development of insulin resistance and reduced glucose tolerance.