Insufficient sleep induces insulin resistance and is associated with an increased risk for developing obesity and cardiometabolic diseases, implicating sleep loss as a metabolic stressor. Fibroblast growth factor 21 (FGF21) is a hepatokine secreted in response to stress and is elevated in human obesity and diabetes. FGF21 expression can be induced by free fatty acid (FFA) activation of peroxisome proliferator‐activator receptor alpha. We previously reported that insufficient sleep results in elevated FFA; however, the impact of insufficient sleep on FGF21 has not been explored. In an ongoing study, we are comparing the effects of insufficient sleep on insulin sensitivity in physically active and inactive individuals to determine whether regular exercise attenuates the adverse effects of insufficient sleep. To explore the effects of physical activity and insufficient sleep on FGF21, we compared changes in FGF21 during an oral glucose tolerance test (OGTT). Eleven sedentary (SED: 6F, 24.9±4.2y, 22.3±1.7kg/m 2 ; mean±SD) and 11 physically active adults (PA: 6F, 23.5±3.3y, 22.0±2.3kg/m 2 ) participated in a 6‐day controlled inpatient protocol. Participants were provided isocaloric diets designed to meet energy requirements. Active participants continued to exercise during insufficient sleep by conducting 60 minutes of moderate physical activity (treadmill running) at 65–75% of maximum heart rate. An OGTT was conducted at baseline (9h sleep opportunity/night) and after 3 nights of insufficient sleep (5h sleep opportunity/night). Blood was sampled at T=0, +30, +60, +90, and +120 minutes following glucose ingestion and assayed for FGF21, glucose, insulin and FFA. FGF21 was elevated in response to insufficient sleep in PA participants (Fig 1a; baseline: 40.5±13.3 v. insufficient sleep: 95.3±18.2 pg/ml, p<0.05), but not SED (baseline: 68.9±19.4 v. insufficient sleep: 95.6±24.1 pg/ml, p=ns). Both SED and PA participants displayed elevated glucose in response to the OGTT during insufficient sleep (Fig 1b), whereas insulin was elevated only in SED participants (Fig 1c). PA participants had higher levels of FFA as compared to SED, though FFA were not altered by insufficient sleep in either group (Fig 1d). Changes in FGF21 were not related to glucose, insulin or FFA. FGF21 is elevated during insufficient sleep in physically active individuals. Furthermore, insulin response to an OGTT during insufficient sleep was attenuated only in the physically active participants. Though the physiological implications of elevated FGF21 in humans are unclear, we speculate that elevated FGF21 during insufficient sleep in active individuals may act as a compensatory response to mitigate metabolic impairments. Support or Funding Information This work was supported by the Sleep Research Society Early Career Development Award, the National Institutes of Health GCRC grant RR‐00036, R01HL109706 and K01DK110138, Society in Science, and The Branco Weiss Fellowship, administered by the ETH Zürich. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Plasma levels of alpha 2 plasmin inhibitor (alpha 2 PI) were measured by both an immunological and a functional assay, and a good correlation (r = 0.793; p less than 0.001) was found between the two methods. When compared to values recorded in 17 control subjects (69.55 micrograms/ml +/- 2.04) alpha 2 PI antigen levels were found to be obviously decreased in the 10 patients with decompensated cirrhosis of the liver (41.06 micrograms/ml +/- 4.66) and slightly increased in the 13 nephrotic patients (79.73 micrograms/ml +/- 2.35) and in the 23 hypertriglyceridemic and obese patients (78.59 micrograms/ml +/- 2.23). In spite of similar plasma levels of alpha 2 PI, dilute blood clot lysis was rather accelerated in patients with the nephrotic syndrome (240 min +/- 12) and obviously delayed in patients with endogenous hypertriglyceridemia (739 min +/- 131). Apparently the rate of clot lysis is mainly determined at an earlier stage of the fibrinolytic process, represented by the balance between tissue plasminogen activator and its inhibitor. Severe decrease of alpha 2 PI may nevertheless contribute to accelerated clot lysis as noted in a patient with familial heterozygous alpha 2 PI deficiency. On the other hand increased level of factor XIII and alpha 2 PI associated to an impaired plasminogen activation would render the fibrin network more resistant to fibrinolysis.
Abstract Introduction Late chronotypes have been shown to have decreased positive affect during the day and during sleep loss. Findings for negative affect are inconsistent. The present analysis examined the effect of chronotype on positive and negative affect during two sleep and circadian challenges. Methods In both studies, chronotype was determined by habitual mid-sleep time. In Study 1, 10 healthy adults (5 early, 5 late chronotypes) completed a 10-day protocol of sleep restriction followed by total sleep deprivation. Participants maintained habitual 8h sleep schedules at home for 1 week, then completed a 2-day in-laboratory protocol: 4h of sleep restriction, followed by a 4h sleep opportunity, followed by 28h of sleep deprivation. Affect was assessed with the Positive and Negative Affect Schedule (PANAS) every hour during scheduled wakefulness. In Study 2, 14 healthy adults (7 early, 7 late chronotypes) completed a 39-day protocol of combined sleep restriction and circadian misalignment. Participants maintained habitual 8h sleep schedules at home for 2 weeks, then completed a 4-day in-laboratory protocol with the following sleep opportunities: 8h on night 1, 3h on night 2, and 3h on mornings 3 and 4. After 3 days of at-home unscheduled recovery sleep opportunities, the protocol was repeated. Affect was assessed with the PANAS every 3h during scheduled wakefulness. Data from each study were analyzed separately with mixed-model ANOVA. Results Positive affect decreased during sleep restriction+sleep deprivation and sleep restriction+circadian misalignment (p<.05), regardless of chronotype. However, late chronotypes reported lower positive affect than early chronotypes across both sleep/circadian challenges (p<.05), and this effect was accounted for by baseline positive affect. Negative affect was not consistently impacted by sleep/circadian challenges or chronotype, with or without considering baseline negative affect. In both studies, chronotype did not interact with sleep/circadian challenges. Conclusion These findings are consistent with prior work showing later chronotypes have lower positive affect. Chronotype and sleep loss/circadian misalignment may impact affect through independent mechanisms. Future work is needed to replicate these findings in larger samples with more extreme chronotypes. Support (If Any) Office of Naval Research MURI N00014-15-1-2809; CurAegis Technologies Inc. (formerly Torvec, Inc), NIH HL109706, NIH TR001082; Undergraduate Research Opportunities Grant University of Colorado Boulder.
Prior research indicates that sleep restriction, sleep deprivation, and circadian misalignment diminish positive affect, whereas effects on negative affect are inconsistent. One potential factor that may influence an individual’s affective response to sleep restriction, sleep deprivation, and circadian misalignment is chronotype. Later chronotypes generally report higher negative affect and lower positive affect under typical sleep conditions; however, there is mixed evidence for an influence of chronotype on affective responses to sleep restriction and sleep deprivation. The present study examined the effect of chronotype on positive and negative affect during sleep restriction and subsequent total sleep deprivation. Sixteen healthy adults (M age = 28.2 years, SD age = 11.6 years) were classified as earlier or later chronotypes using multiple chronotype definitions: morningness-eveningness (MEQ), mid-sleep on free days corrected (MSFsc), habitual mid-sleep timing, dim light melatonin onset (DLMO), and phase relationship between DLMO and bedtime. Participants completed a 10-day protocol with one night of sleep restriction and subsequent 28 h total sleep deprivation. Affect was assessed hourly during scheduled wakefulness with the Positive and Negative Affect Schedule (PANAS). Data were analyzed with mixed-model analyses of variance (ANOVAs). During sleep restriction and subsequent sleep deprivation, positive affect decreased and negative affect increased. Across all chronotype measures, relatively later chronotypes demonstrated vulnerability to increased negative affect during sleep loss. The influence of chronotype on positive affect during sleep loss varied by chronotype measure. These findings suggest later chronotypes are more vulnerable to affective impairments during sleep loss and circadian misalignment, even when late chronotype is not extreme.
Summary This paper is an attempt to assess the relevance of the inhibitors of fibrinolysis for clot lysis in selected disease states and to discuss the mechanisms leading to acquired abnormal levels of such inhibitors. When compared to 20 control subjects the 30 hypertriglyceridemic patients (14 with type IIb and 16 with type IV) displayed significantly (p <0.001) increased plasma plasminogen activator inhibitor (PAI) activity (221 ± 88% and 290 ± 104% respectively; mean ± SD), moderately (p <0.01) increased α2 antiplasmin (α2AP) level (112 ± 11% and 115 ± 16%) and accordingly an obviously prolonged dilute blood clot lysis time (DBCLT). Neither PAI activity and α2AP level nor DBCLT were significantly different from controls in the 10 patients with hyperlipoproteinemia type IIa. The 18 patients with severe hepatic cirrhosis had low α2AP level (59 ± 19.7%) and accelerated clot lysis, while mean PAI activity (160 ± 87%) was slightly (p <0.05) increased. In the 17 nephrotic patients α2AP was increased (115 ±12%) while PAI activity was similar to controls and DBCLT rather shorter. Two liver secretion enzymes, namely serum Cholinesterase and plasma protein C, were found to be decreased in cirrhotic patients, similar to control values in hyperlipoproteinemia type Ha and obviously increased in nephrotic patients as well as in hypertriglyceridemic subjects. The relevance of PAI and α2AP for clot lysis was considered in relation to data in the literature concerning the behaviour of t-PA and factor XIII. Enhanced hepatic synthesis of protease inhibitors and factor XIII as a possible cause of delayed clot lysis in hypertriglyceridemia was envisaged.
Abstract Introduction Sleep, circadian rhythms, and thermoregulatory physiology are highly integrated and impact each other. The daily rhythm in the distal-proximal skin temperature gradient (DPG) is wider/more negative during wakefulness, and narrower/closer to zero during sleep. The circadian rhythm in the DPG is wider during the biological day and narrower during the biological night. Here we aimed to quantify and compare the amplitude of the daily rhythm in the DPG under wakefulness-sleep conditions versus the amplitude of the circadian rhythm in the DPG under sleep deprivation conditions to examine associations and magnitude differences. Methods Eleven [5 females] healthy adults [aged 27.6±10.2y, BMI 23.1±2.2 (mean±SD)] participated. After one week of at-home ambulatory monitoring with 8h per night sleep opportunities at habitual bedtimes, participants were studied in the laboratory for three days under controlled dim light (< 8 lux maximum) and ambient temperature conditions (22-24°C). Participants arrived in the afternoon, were kept awake 4h later than typical and scheduled to a 4h sleep opportunity. The next day, participants were sleep deprived for 28h followed by recovery sleep. Skin temperature was assessed every min with iButtons placed subclavicular (proximal skin temperature) and foot palmar (distal skin temperature). The DPG was calculated as difference between proximal and distal skin temperatures. A three-harmonic regression model was used to fit DPG data and derive daily and circadian rhythm amplitudes, and percent difference in amplitude was calculated. Pearson correlations were calculated between daily and circadian rhythm DPG amplitudes. Results DPG amplitude was significantly greater for daily versus circadian rhythm (p < 0.05). Percent difference analyses showed daily DPG rhythm was 57% larger than circadian DPG rhythm (SD 30%, range 22-134%). A significant correlation was found between daily and circadian rhythm DPG amplitudes (r = 0.71, p< 0.05). Conclusion The amplitudes of daily and circadian rhythms of the DPG are associated, but the daily rhythm amplitude is larger. Additional research is needed to compare the relative importance of daily versus circadian skin temperature amplitudes for sleep and circadian relevant outcomes. Support (if any) CurAegis Technologies Inc., Fundacio Joan Riera I Gubau, Undergraduate Research Opportunities Program University of Colorado Boulder
