Influence of circadian phase and extended wakefulness on glucose levels during forced desynchrony.

OBJECTIVES: Circadian misalignment and sleep deprivation often occur in tandem, and both negatively impact glucose homeostasis and metabolic health. The present study employed a forced desynchrony protocol to examine the influence of extended wakefulness and circadian misalignment on hourly glucose levels. METHODS: Nine healthy adults (4F/5M; 26 ± 4years) completed a 31-day in-laboratory protocol. After three 24 hour baseline days with 8 hours scheduled sleep opportunities, participants were scheduled to 14 consecutive 42.85 hour sleep-wake cycles, with 28.57 hours extended wakefulness and 14.28 hours sleep opportunities each cycle. Blood was sampled hourly across the forced desynchrony and over 600 plasma samples per participant were analyzed for glucose levels. RESULTS: Both hours into the 42.85 hours forced desynchrony day and circadian phase modulated glucose levels (p < .0001). Glucose peaked after each meal during scheduled wakefulness and decreased during scheduled sleep/fasting. Glucose levels were, on average, lowest during the biological daytime and rose throughout the biological night, peaking in the biological morning. When analyzed separately for scheduled sleep vs. wakefulness, the peak timing of the circadian rhythm in glucose was later during sleep (p < .05). Glucose area under the curve levels increased rapidly from the beginning of the forced desynchrony protocol and were highest on the second forced desynchrony day (p < .01), returning towards forced desynchrony day 1 levels thereafter. CONCLUSIONS: These findings have important implications for understanding factors contributing to altered glucose metabolism during sleep loss and circadian misalignment, and for potential physiological adaptation of metabolism in healthy adults, who are increasingly exposed to such conditions in our society.

Effect of sleep restriction on insulin sensitivity and energy metabolism in postmenopausal women: A randomized crossover trial.

OBJECTIVE: The aim of this study was to investigate the effect of sleep restriction (SR) on insulin sensitivity and energy metabolism in postmenopausal women. METHODS: In a randomized crossover trial, 14 women underwent four nights of habitual sleep (HS, 100% normal sleep) and SR (60% of HS) while following a eucaloric diet. Outcomes included the following: (1) insulin sensitivity by hyperinsulinemic-euglycemic clamp, defined as the glucose infusion rate (GIR); (2) resting metabolism and substrate oxidation by indirect calorimetry; and (3) glucose, insulin, and C-peptide concentrations following a standard meal test. RESULTS: Nine postmenopausal women (mean [SD], age 59 [4] years, BMI 28.0 [2.6] kg/m2 ) were analyzed. Accelerometer-determined total time in bed was 8.4 ± 0.6 hours during HS versus 5.0 ± 0.4 hours during SR (38% reduction, p < 0.0001). SR reduced low-dose insulin GIR by 20% (HS: 2.55 ± 0.22 vs. SR: 2.03 ± 0.20 mg/kg/min; p = 0.01) and high-dose insulin GIR by 12% (HS: 10.48 ± 0.72 vs. SR: 9.19 ± 0.72 mg/kg/min; p < 0.001). SR reduced fat oxidation during high-dose insulin infusion (p < 0.01), and it did not alter resting energy metabolism. CONCLUSIONS: Four nights of SR reduced insulin sensitivity and fat oxidation in postmenopausal women. These findings underscore the role of insufficient sleep in metabolic dysfunction following menopause. Larger trials investigating how sleep disturbances cause metabolic dysfunction during menopause are needed across all stages of menopause.

The role of insufficient sleep and circadian misalignment in obesity.

Traditional risk factors for obesity and the metabolic syndrome, such as excess energy intake and lack of physical activity, cannot fully explain the high prevalence of these conditions. Insufficient sleep and circadian misalignment predispose individuals to poor metabolic health and promote weight gain and have received increased research attention in the past 10 years. Insufficient sleep is defined as sleeping less than recommended for health benefits, whereas circadian misalignment is defined as wakefulness and food intake occurring when the internal circadian system is promoting sleep. This Review discusses the impact of insufficient sleep and circadian misalignment in humans on appetite hormones (focusing on ghrelin, leptin and peptide-YY), energy expenditure, food intake and choice, and risk of obesity. Some potential strategies to reduce the adverse effects of sleep disruption on metabolic health are provided and future research priorities are highlighted. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic functions. Furthermore, modern working patterns, lifestyles and technologies are often not conducive to adequate sleep at times when the internal physiological clock is promoting it (for example, late-night screen time, shift work and nocturnal social activities). Efforts are needed to highlight the importance of optimal sleep and circadian health in the maintenance of metabolic health and body weight regulation.

In Vitro Circadian Clock Gene Expression Assessments in Mesenchymal Stem Cells from Human Infants: A Pilot Study.

BACKGROUND: Exposure to intrauterine obesity can disrupt clock gene rhythmicity in animal models. The aim of this pilot study was to determine if maternal obesity alters rhythmic expression of core clock in mesenchymal stem cells (MSCs) from umbilical cords of human infants born to mothers with obesity (Ob-MSC) vs. normal weight (NW-MSC). METHODS: We compared in vitro rhythmic expression patterns of core clock (BMAL1, CLOCK, PER2) and clock-output (NR1D1), components in undifferentiated Ob-MSCs (n = 3) vs. NW-MSCs (n = 3). MSCs were harvested every 2 h, following a dexamethasone shock, for 30 h. Adipogenesis or myogenesis was induced in vitro and markers of adipogenesis and fat storage were assessed, respectively. RESULTS: We detected significant rhythmicity in expression patterns of BMAL1, PER2, and NR1D1 at the group level in Ob- and NW-MSCs (p < 0.05). PER2 oscillatory amplitude was 3-fold higher in Ob-MSCs vs. NW-MSCs (p < 0.006). During adipogenesis, Ob-MSCs had higher PPARγ protein content (p = 0.04) vs. NW-MSC. During myogenesis, Ob-MSCs had higher saturated triacylglycerols (p = 0.04) vs. NW-MSC. CONCLUSION: Rhythmic expressions of BMAL1, PER2, and NR1D1 are detectable in undifferentiated MSCs. Higher PER2 oscillatory amplitude was paralleled by higher markers of fat storage during differentiation in Ob-MSCs vs. NW-MSCs, and supports that the core clock and cellular metabolism may be linked in infant MSCs.

Insufficient sleep and obesity: cause or consequence.

Sleep is an ancient and evolutionarily conserved biological process that, when disturbed, increases the risk for a variety of diseases in people, including diabetes, cardiovascular disease, kidney disease, and cancer. Although results from epidemiological studies support the link between insufficient sleep and an increased risk of obesity, the directionality of this link is unknown. Results from short-term controlled clinical studies, conducted almost exclusively in people who are normal weight, demonstrate that sleep restriction increases hunger, appetite, energy intake, and body weight. However, the authors are not aware of any studies that have evaluated the effect of more than 3 weeks of experimental sleep restriction on obesity risk factors, and few studies have been conducted in people with preexisting obesity. This Perspective reviews the link between insufficient sleep and obesity risk and the potential therapeutic effects of sleep extension in people with chronic sleep insufficiency.

Complex physiology and clinical implications of time-restricted eating.

Time-restricted eating (TRE) is a dietary intervention that limits food consumption to a specific time window each day. The effect of TRE on body weight and physiological functions has been extensively studied in rodent models, which have shown considerable therapeutic effects of TRE and important interactions among time of eating, circadian biology, and metabolic homeostasis. In contrast, it is difficult to make firm conclusions regarding the effect of TRE in people because of the heterogeneity in results, TRE regimens, and study populations. In this review, we 1) provide a background of the history of meal consumption in people and the normal physiology of eating and fasting; 2) discuss the interaction between circadian molecular metabolism and TRE; 3) integrate the results of preclinical and clinical studies that evaluated the effects of TRE on body weight and physiological functions; 4) summarize other time-related dietary interventions that have been studied in people; and 4) identify current gaps in knowledge and provide a framework for future research directions.

Impairments in glycemic control during Eastbound transatlantic travel in healthy adults.

Study Objectives: Repeated bouts of circadian misalignment impair glucose tolerance. However, whether circadian misalignment associated with travel and jet lag impair glucose homeostasis in a free-living population is not known. The goal of the present study was to examine glycemic control during one week of Eastbound transatlantic travel in healthy men and women. Methods: Seven healthy participants (5 women; age: 35.6 ± 2.5 years, BMI: 23.9 ± 2.4 m/kg2) traveled from Colorado, USA (GMT-7) to Europe (GMT and GMT+1) and wore a continuous glucose monitor (Freestyle Libre Pro) for 8-14 days before, during, and after travel. Indices of glycemic control were summarized over 24-hour periods and by day and night. Results: Mean glucose, peak glucose, and time spent in hyperglycemia increased linearly throughout the travel period relative to baseline levels. Mean glucose concentrations rose 1.03 mg/dL (95% CI: 0.34, 1.74) and duration of hyperglycemia increased by 17 min (95% CI: 5.5, 28.6) each 24-hour period. Increases in 24-hour glucose were primarily driven by increases in daytime parameters with rising mean glucose (0.72 mg/dL per day, [95% CI: -0.1, 1.5]) and duration of hyperglycemia (13.2 min per day [95% CI: 4.3, 22.1]). Mean glucose, but not peak glucose or time spent in hyperglycemia, increased each night (0.7 mg/dL per night [95% CI: 0.2, 1.2]). Conclusions: Eastbound transatlantic travel induced a progressive worsening of glucose metrics during 24-hour, day, and night periods. Future research on managing glycemic control during jet lag in people with metabolic disorders is warranted. Clinical Trial Registration: None.

The human gut microbiome and health inequities.

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

Sex Differences in Insulin Sensitivity are Related to Muscle Tissue Acylcarnitine But Not Subcellular Lipid Distribution.

OBJECTIVE: Sex differences in insulin sensitivity are present throughout the life-span, with men having a higher prevalence of insulin resistance and diabetes compared with women. Differences in lean mass, fat mass, and fat distribution-particularly ectopic fat-have all been postulated to contribute to the sexual dimorphism in diabetes risk. Emerging data suggest ectopic lipid composition and subcellular localization are most relevant; however, it is not known whether they explain sex differences in obesity-induced insulin resistance. METHODS: To address this gap, this study evaluated insulin sensitivity and subcellular localization of intramuscular triacylglycerol, diacylglycerol, and sphingolipids as well as muscle acylcarnitines and serum lipidomics in people with obesity. RESULTS: Insulin sensitivity was significantly lower in men (P < 0.05); however, no sex differences were found in localization of intramuscular triacylglycerol, diacylglycerol, or sphingolipids in skeletal muscle. In contrast, men had higher total muscle acylcarnitine (P < 0.05) and long-chain muscle acylcarnitine (P < 0.05), which were related to lower insulin sensitivity (r = -0.42, P < 0.05). Men also displayed higher serum ceramide (P = 0.05) and lysophosphatidylcholine (P < 0.01). CONCLUSIONS: These data reveal novel sex-specific associations between lipid species involved in the coupling of mitochondrial fatty acid transport, ß-oxidation, and tricarboxylic acid cycle flux that may provide therapeutic targets to improve insulin sensitivity.

Circadian Rhythm of Substrate Oxidation and Hormonal Regulators of Energy Balance.

OBJECTIVE: The circadian system provides an organism with the ability to anticipate daily food availability and appropriately coordinate metabolic responses. Few studies have simultaneously assessed factors involved in both the anticipation of energy availability (i.e., hormones involved in appetite regulation) and subsequent metabolic responses (such as energy expenditure and substrate oxidation) under conditions designed to reveal circadian rhythmicity. METHODS: Eight healthy adults (four females; age: 28.0 ± 2.3 years; BMI: 24.3 ± 2.9 kg/m2 ) participated in a 26-hour constant routine protocol involving continuous wakefulness with constant posture, temperature, dim light, and hourly isocaloric snacks. Indirect calorimetry was performed every 3 hours for measurement of energy expenditure and substrate oxidation. Subjective hunger was obtained hourly using questionnaires. Saliva and plasma were obtained hourly to assess melatonin (circadian phase marker) and hormones (leptin, ghrelin, and peptide YY). RESULTS: Fat and carbohydrate oxidation was highest in the biological evening and morning, respectively. Subjective hunger ratings peaked during the middle of the biological day. Significant circadian rhythms were identified for ghrelin and peptide YY with peaks in the biological evening and morning, respectively. CONCLUSIONS: These findings support a role for the circadian system in the modulation of nutrient oxidation, subjective measures of appetite, and appetitive hormones.

Impact of sleep deprivation and high-fat feeding on insulin sensitivity and beta cell function in dogs.

AIMS/HYPOTHESIS: Insufficient sleep is increasingly recognised as a major risk factor for the development of obesity and diabetes, and short-term sleep loss in clinical studies leads to a reduction in insulin sensitivity. Sleep loss-induced metabolic impairments are clinically relevant, since reductions in insulin sensitivity after sleep loss are comparable to insulin sensitivity differences between healthy individuals and those with impaired glucose tolerance. However, the relative effects of sleep loss vs high-fat feeding in the same individual have not been assessed. In addition, to our knowledge no diurnal (active during the daytime) non-human mammalian model of sleep loss-induced metabolic impairment exists, which limits our ability to study links between sleep and metabolism. METHODS: This study examined the effects of one night of total sleep deprivation on insulin sensitivity and beta cell function, as assessed by an IVGTT, before and after 9 months of high-fat feeding in a canine model. RESULTS: One night of total sleep deprivation in lean dogs impaired insulin sensitivity to a similar degree as a chronic high-fat diet (HFD)(normal sleep: 4.95 ± 0.45 mU-1 l-1 min-1; sleep deprivation: 3.14 ± 0.21 mU-1 l-1 min-1; HFD: 3.74 ± 0.48 mU-1 l-1 min-1; mean ± SEM). Hyperinsulinaemic compensation was induced by the chronic HFD, suggesting adequate beta cell response to high-fat feeding. In contrast, there was no beta cell compensation after one night of sleep deprivation, suggesting that there was metabolic dysregulation with acute sleep loss that, if sustained during chronic sleep loss, could contribute to the risk of type 2 diabetes. After chronic high-fat feeding, acute total sleep deprivation did not cause further impairments in insulin sensitivity (sleep deprivation + chronic HFD: 3.28 mU-1 l-1 min-1). CONCLUSIONS/INTERPRETATION: Our findings provide further evidence that sleep is important for metabolic health and establish a diurnal animal model of metabolic disruption during insufficient sleep.

Later Meal and Sleep Timing Predicts Higher Percent Body Fat.

Accumulating evidence suggests that later timing of energy intake (EI) is associated with increased risk of obesity. In this study, 83 individuals with overweight and obesity underwent assessment of a 7-day period of data collection, including measures of body weight and body composition (DXA) and 24-h measures of EI (photographic food records), sleep (actigraphy), and physical activity (PA, activity monitors) for 7 days. Relationships between body mass index (BMI) and percent body fat (DXA) with meal timing, sleep, and PA were examined. For every 1 h later start of eating, there was a 1.25 (95% CI: 0.60, 1.91) unit increase in percent body fat (False Discovery Rate (FDR) adjusted p value = 0.010). For every 1 h later midpoint of the eating window, there was a 1.35 (95% CI: 0.51, 2.19) unit increase in percent body fat (FDR p value = 0.029). For every 1 h increase in the end of the sleep period, there was a 1.64 (95% CI: 0.56, 2.72) unit increase in percent body fat (FDR p value = 0.044). Later meal and sleep timing were also associated with lower PA levels. In summary, later timing of EI and sleep are associated with higher body fat and lower levels of PA in people with overweight and obesity.

Insulin Access to Skeletal Muscle is Preserved in Obesity Induced by Polyunsaturated Diet.

OBJECTIVE: Diets high in saturated fat induce obesity and insulin resistance and impair insulin access to skeletal muscle, leading to reduced insulin levels at the muscle cell surface available to bind insulin receptors and induce glucose uptake. In contrast, diets supplemented with polyunsaturated fat improve insulin sensitivity (SI) and reduce the risk for type 2 diabetes. It was hypothesized that a diet high in polyunsaturated fat would preserve SI and insulin access to muscle, as compared with a diet high in saturated fat. METHODS: After 12 weeks of control, saturated (LARD), or polyunsaturated (salmon oil [SO]) high-fat diet feeding, muscle SI and insulin access to skeletal muscle were measured by using lymph, a surrogate of skeletal muscle interstitial fluid. RESULTS: Both high-fat diets induced similar weight gain, yet only LARD impaired SI. Hyperinsulinemia in the LARD group did not induce an increase in basal interstitial insulin, suggesting reduced insulin access to muscle after LARD, but not after SO. CONCLUSIONS: A diet high in polyunsaturated fat does not impair insulin access to muscle interstitium or induce insulin resistance as observed with a saturated fat diet, despite similar weight gain. Future studies should determine whether dietary SO supplementation improves impairments in insulin access to skeletal muscle.

Isoflurane and Sevoflurane Induce Severe Hepatic Insulin Resistance in a Canine Model.

INTRODUCTION: Anesthesia induces insulin resistance, which may contribute to elevated blood glucose and adverse post-operative outcomes in critically ill patients, and impair glycemic control in surgical patients with diabetes. However, little is known about the mechanisms by which anesthesia impairs insulin sensitivity. Here we investigate the effects of anesthesia on insulin sensitivity in metabolic tissues. METHODS: Hyperinsulinemic-euglycemic clamps were performed in 32 lean (control diet; n = 16 conscious versus n = 16 anesthetized) and 24 fat-fed (6 weeks fat-feeding; n = 16 conscious versus n = 8 anesthetized) adult male mongrel dogs in conjunction with tracer methodology to differentiate hepatic versus peripheral insulin sensitivity. Propofol was administered as an intravenous bolus (3mg/kg) to initiate anesthesia, which was then maintained with inhaled sevoflurane or isoflurane (2-3%) for the duration of the procedure. RESULTS: Anesthesia reduced peripheral insulin sensitivity by approximately 50% in both lean and fat-fed animals as compared to conscious animals, and insulin action at the liver was almost completely suppressed during anesthesia such that hepatic insulin sensitivity was decreased by 75.5% and; 116.2% in lean and fat-fed groups, respectively. CONCLUSION: Inhaled anesthesia induces severe hepatic insulin resistance in a canine model. Countermeasures that preserve hepatic insulin sensitivity may represent a therapeutic target that could improve surgical outcomes in both diabetic and healthy patients.

Disturbances of sleep and circadian rhythms: novel risk factors for obesity.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent developments linking disturbances of sleep and circadian rhythms to an increased risk for obesity, and to review novel research on potential countermeasures. RECENT FINDINGS: Effective treatments for obesity are limited, with long-term adherence to lifestyle changes proving difficult to maintain. Identifying new preventive strategies based on modifiable risk factors is therefore imperative in the fight against obesity. Disturbances of sleep and circadian rhythms have an adverse impact on food choices, hunger and appetite, and have lifelong deleterious metabolic consequences when they occur during childhood and early adulthood. The upregulation of the endocannabinoid system and abnormalities in the temporal distribution of caloric intake were recently implicated in the link between sleep loss and obesity risk. In addition, alterations in circadian variation in the composition and functionality of the gut microbiome have been identified as potential contributors to metabolic dysfunction during jet lag and shift work. Insufficient sleep and circadian misalignment are thus new modifiable risk factors for obesity. Emerging evidence suggests that novel countermeasures, such as manipulations of the timing of food intake, may be effective strategies in the prevention of obesity. SUMMARY: Four important findings are briefly reviewed: disturbances of sleep and circadian rhythms in children and young adults are risk factors for the development of lifelong obesity; circadian misalignment, as occurs in shift work, has an adverse impact on energy balance and increases the risk of weight gain; the endocannabinoid system, an important regulator of hedonic feeding, could be a potential link between sleep, circadian rhythms, and feeding behavior; and disturbances of the circadian variation in composition of the gut microbiome may be involved in the increased risk of obesity associated with insufficient sleep and circadian misalignment.

The changing microbial landscape of Western society: Diet, dwellings and discordance.

BACKGROUND: The last 50-100 years has been marked by a sharp rise in so-called "Western-diseases" in those countries that have experienced major industrial advances and shifts towards urbanized living. These diseases include obesity, type 2 diabetes, inflammatory bowel diseases, and food allergies in which chronic dysregulation of metabolic and/or immune processes appear to be involved, and are likely a byproduct of new environmental influences on our ancient genome. What we now appreciate is that this genome consists of both human and co-evolved microbial genes of the trillions of microbes residing in our body. Together, host-microbe interactions may be determined by the changing diets and behaviors of the Western lifestyle, influencing the etiopathogenesis of "new-age" diseases. SCOPE OF REVIEW: This review takes an anthropological approach to the potential interplay of the host and its gut microbiome in the post-industrialization rise in chronic inflammatory and metabolic diseases. The discussion highlights both the changes in diet and the physical environment that have co-occurred with these diseases and the latest evidence demonstrating the role of host-microbe interactions in understanding biological responses to the changing environment. MAJOR CONCLUSIONS: Technological advances that have led to changes in agriculture and engineering have altered our eating and living behaviors in ways never before possible in human history. These changes also have altered the bacterial communities within the human body in ways that are seemingly linked with the rise of many intestinal and systemic metabolic and inflammatory diseases. Insights into the mechanisms of this reciprocal exchange between the environment and the human gut microbiome may offer potential to attenuate the chronic health conditions that derail quality of life. This article is part of a special issue on microbiota.

Diagnosis, Cause, and Treatment Approaches for Delayed Sleep-Wake Phase Disorder.

Delayed sleep-wake phase disorder (DSWPD) is commonly defined as an inability to fall asleep and wake at societal times resulting in excessive daytime sleepiness. Although the cause is multifaceted, delays in sleep time are largely driven by misalignment between the circadian pacemaker and the desired sleep-wake timing schedule. Current treatment approaches focus on correcting the circadian delay; however, there is a lack of data investigating combined therapies for treatment of DSWPD.