LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic ß cells.

Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning ß cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and ß cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human ß cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in ß cells to maintain appropriate insulin release.

Shift work and evening chronotype are associated with hepatic fat fraction and non-alcoholic fatty liver disease in 282,303 UK biobank participants.

Background and aims: Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease worldwide. Modern lifestyles have been linked to this rise in prevalence with changes in rhythmic human behaviour emerging as a possible mechanism. We investigated how shift working patterns and chronotype were associated with hepatic fat fraction and NAFLD in 282,303 UK Biobank participants. Methods: We stratified participants into day, irregular-shift, and permanent night-shift workers. We then utilised multiple methods of disease identification including (i) Dallas steatosis index (DSI), (ii) ICD10 codes, and (iii) hepatic proton density fat fraction (PDFF) and examined how shift work exposure impacted these variables. We further assessed the relationship of baseline chronotype with liver phenotypes using these same outcome measures. Results: Compared to day workers, irregular-shift workers were more likely to have a high DSI (OR 1.29 (1.2-1.4)) after adjusting for major covariates with some attenuation after additional adjustment for BMI (OR 1.12 (1.03-1.22)). Likelihood of high DSI was also increased in permanent night-shift workers (OR 1.08 (0.9-1.29)) in the fully adjusted model. Mediator analysis revealed that BMI was a significant mediator of the shift work effect. Compared to participants with intermediate chronotype, those with extreme late chronotype had a higher likelihood of high DSI defined NAFLD (OR 1.45 (1.34-1.56)) and a higher likelihood of NAFLD/NASH by ICD10 code (OR 1.23 (1.09-1.39)). Hepatic PDFF was elevated in irregular shift workers, but not permanent night-shift workers. Conclusions: Irregular-shift work and extreme late chronotype are associated with pathological liver fat accumulation, suggesting circadian misalignment may have an underlying pathogenic role. These findings have implications for health interventions to mitigate the detrimental effect of shift work.

Circadian regulation of liver metabolism: experimental approaches in human, rodent, and cellular models.

Circadian rhythms are endogenous oscillations with approximately a 24-h period that allow organisms to anticipate the change between day and night. Disruptions that desynchronize or misalign circadian rhythms are associated with an increased risk of cardiometabolic disease. This review focuses on the liver circadian clock as relevant to the risk of developing metabolic diseases including nonalcoholic fatty liver disease (NAFLD), insulin resistance, and type 2 diabetes (T2D). Many liver functions exhibit rhythmicity. Approximately 40% of the hepatic transcriptome exhibits 24-h rhythms, along with rhythms in protein levels, posttranslational modification, and various metabolites. The liver circadian clock is critical for maintaining glucose and lipid homeostasis. Most of the attention in the metabolic field has been directed toward diet, exercise, and rather little to modifiable risks due to circadian misalignment or disruption. Therefore, the aim of this review is to systematically analyze the various approaches that study liver circadian pathways, targeting metabolic liver diseases, such as diabetes, nonalcoholic fatty liver disease, using human, rodent, and cell biology models.NEW & NOTEWORTHY Over the past decade, there has been an increased interest in understanding the intricate relationship between circadian rhythm and liver metabolism. In this review, we have systematically searched the literature to analyze the various experimental approaches utilizing human, rodent, and in vitro cellular approaches to dissect the link between liver circadian rhythms and metabolic disease.

Identification of diurnal rhythmic blood markers in bronchial asthma.

Rationale: Asthma is a rhythmic inflammatory disease of the airway, regulated by the circadian clock. "Spill-over" of airway inflammation into the systemic circulation occurs in asthma and is reflected in circulating immune cell repertoire. The objective of the present study was to determine how asthma impacts peripheral blood diurnal rhythmicity. Methods: 10 healthy and 10 mild/moderate asthma participants were recruited to an overnight study. Blood was drawn every 6 h for 24 h. Main results: The molecular clock in blood cells in asthma is altered; PER3 is significantly more rhythmic in asthma compared to healthy controls. Blood immune cell numbers oscillate throughout the day, in health and asthma. Peripheral blood mononucleocytes from asthma patients show significantly enhanced responses to immune stimulation and steroid suppression at 16:00 h, compared to at 04:00 h. Serum ceramides show complex changes in asthma: some losing and others gaining rhythmicity. Conclusions: This is the first report showing that asthma is associated with a gain in peripheral blood molecular clock rhythmicity. Whether the blood clock is responding to rhythmic signals received from the lung or driving rhythmic pathology within the lung itself is not clear. Dynamic changes occur in serum ceramides in asthma, probably reflecting systemic inflammatory action. The enhanced responses of asthma blood immune cells to glucocorticoid at 16:00 h may explain why steroid administration is more effective at this time.

Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356).

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.

Self-supervised learning of accelerometer data provides new insights for sleep and its association with mortality.

Background: Sleep is essential to life. Accurate measurement and classification of sleep/wake and sleep stages is important in clinical studies for sleep disorder diagnoses and in the interpretation of data from consumer devices for monitoring physical and mental well-being. Existing non-polysomnography sleep classification techniques mainly rely on heuristic methods developed in relatively small cohorts. Thus, we aimed to establish the accuracy of wrist-worn accelerometers for sleep stage classification and subsequently describe the association between sleep duration and efficiency (proportion of total time asleep when in bed) with mortality outcomes. Methods: We developed and validated a self-supervised deep neural network for sleep stage classification using concurrent laboratory-based polysomnography and accelerometry data from three countries (Australia, the UK, and the USA). The model was validated within-cohort using subject-wise five-fold cross-validation for sleep-wake classification and in a three-class setting for sleep stage classification wake, rapid-eye-movement sleep (REM), non-rapid-eye-movement sleep (NREM) and by external validation. We assessed the face validity of our model for population inference by applying the model to the UK Biobank with 100,000 participants, each of whom wore a wristband for up to seven days. The derived sleep parameters were used in a Cox regression model to study the association of sleep duration and sleep efficiency with all-cause mortality. Findings: After exclusion, 1,448 participant nights of data were used to train the sleep classifier. The difference between polysomnography and the model classifications on the external validation was 34.7 minutes (95% limits of agreement (LoA): -37.8 to 107.2 minutes) for total sleep duration, 2.6 minutes for REM duration (95% LoA: -68.4 to 73.4 minutes) and 32.1 minutes (95% LoA: -54.4 to 118.5 minutes) for NREM duration. The derived sleep architecture estimate in the UK Biobank sample showed good face validity. Among 66,214 UK Biobank participants, 1,642 mortality events were observed. Short sleepers (<6 hours) had a higher risk of mortality compared to participants with normal sleep duration (6 to 7.9 hours), regardless of whether they had low sleep efficiency (Hazard ratios (HRs): 1.69; 95% confidence intervals (CIs): 1.28 to 2.24 ) or high sleep efficiency (HRs: 1.42; 95% CIs: 1.14 to 1.77). Interpretation: Deep-learning-based sleep classification using accelerometers has a fair to moderate agreement with polysomnography. Our findings suggest that having short overnight sleep confers mortality risk irrespective of sleep continuity.

Timing of energy intake and the therapeutic potential of intermittent fasting and time-restricted eating in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) represents a major public health concern and is associated with a substantial global burden of liver-related and cardiovascular-related morbidity and mortality. High total energy intake coupled with unhealthy consumption of ultra-processed foods and saturated fats have long been regarded as major dietary drivers of NAFLD. However, there is an accumulating body of evidence demonstrating that the timing of energy intake across a the day is also an important determinant of individual risk for NAFLD and associated metabolic conditions. This review summarises the available observational and epidemiological data describing associations between eating patterns and metabolic disease, including the negative effects of irregular meal patterns, skipping breakfast and night-time eating on liver health. We suggest that that these harmful behaviours deserve greater consideration in the risk stratification and management of patients with NAFLD particularly in a 24-hour society with continuous availability of food and with up to 20% of the population now engaged in shiftwork with mistimed eating patterns. We also draw on studies reporting the liver-specific impact of Ramadan, which represents a unique real-world opportunity to explore the physiological impact of fasting. By highlighting data from preclinical and pilot human studies, we present a further biological rationale for manipulating timing of energy intake to improve metabolic health and discuss how this may be mediated through restoration of natural circadian rhythms. Lastly, we comprehensively review the landscape of human trials of intermittent fasting and time-restricted eating in metabolic disease and offer a look to the future about how these dietary strategies may benefit patients with NAFLD and non-alcoholic steatohepatitis.

Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad?

It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome, are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11ß-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy.

Consequences of collagen induced inflammatory arthritis on circadian regulation of the gut microbiome.

The gut microbiota is important for host health and immune system function. Moreover autoimmune diseases, such as rheumatoid arthritis, are associated with significant gut microbiota dysbiosis, although the causes and consequences of this are not fully understood. It has become clear that the composition and metabolic outputs of the microbiome exhibit robust 24 h oscillations, a result of daily variation in timing of food intake as well as rhythmic circadian clock function in the gut. Here, we report that experimental inflammatory arthritis leads to a re-organization of circadian rhythmicity in both the gut and associated microbiome. Mice with collagen induced arthritis exhibited extensive changes in rhythmic gene expression in the colon, and reduced barrier integrity. Re-modeling of the host gut circadian transcriptome was accompanied by significant alteration of the microbiota, including widespread loss of rhythmicity in symbiont species of Lactobacillus, and alteration in circulating microbial derived factors, such as tryptophan metabolites, which are associated with maintenance of barrier function and immune cell populations within the gut. These findings highlight that altered circadian rhythmicity during inflammatory disease contributes to dysregulation of gut integrity and microbiome function.

Determining the temporal, dose, and composition effects of nutritional substrates in an in vitro model of intrahepatocellular triglyceride accumulation.

Pathological accumulation of intrahepatic triglyceride underpins the early stages of nonalcoholic fatty liver disease (NAFLD) and can progress to fibrosis, cirrhosis, and cancer of the liver. Studies in humans suggest that consumption of a diet enriched in saturated compared to unsaturated fatty acids (FAs), is more detrimental to liver fat accumulation and metabolism. However, the reasons for the divergence remain unclear and physiologically-relevant cellular models are required. Therefore, the aims of this study were to investigate the effect of modifying media composition, concentration, and treatment frequency of sugars, FAs and insulin on intrahepatocellular triglyceride content and intracellular glucose, FA and circadian function. Huh7 cells were treated with 2% human serum and a combination of sugars and FAs (low fat low sugar [LFLS], high fat low sugar [HFLS], or high fat high sugar [HFHS]) enriched in either unsaturated (OPLA) or saturated (POLA) FAs for 2, 4, or 7 days with a daily or alternating treatment regime. Stable isotope tracers were utilized to investigate basal and/or insulin-responsive changes in hepatocyte metabolism in response to different treatment regimes. Cell viability, media biochemistry, intracellular metabolism, and circadian biology were quantified. The FA composition of the media (OPLA vs. POLA) did not influence cell viability or intracellular triglyceride content in hepatocytes. In contrast, POLA-treated cells had lower FA oxidation and media acetate, and with higher FA concentrations, displayed lower intracellular glycogen content and diminished insulin stimulation of glycogenesis, compared to OPLA-treated cells. The addition of HFHS also had profound effects on circadian oscillation and gene expression. Cells treated daily with HFHS for at least 4 days resulted in a cellular model displaying characteristics of early stage NAFLD seen in humans. Repeated treatment for longer durations (≥7 days) may provide opportunities to investigate lipid and glucose metabolism in more severe stages of NAFLD.

Chronovaccination: Harnessing circadian rhythms to optimize immunisation strategies.

Vaccination, as a public health measure, offers effective protection of populations against infectious diseases. Optimising vaccination efficacy, particularly for higher-risk individuals, like the elderly whose immunocompromised state can prevent the development of robust vaccine responses, is vital. It is now clear that 24-hour circadian rhythms, which govern virtually all aspects of physiology, can generate oscillations in immunological responses. Consequently, vaccine efficacy may depend critically on the time of day of administration(s), including for Covid-19, current vaccines, and any future diseases or pandemics. Published clinical vaccine trials exploring diurnal immune variations suggest this approach could represent a powerful adjunct strategy for optimising immunisation, but important questions remain to be addressed. This review explores the latest insights into diurnal immune variation and the outcomes of circadian timing of vaccination or 'chronovaccination'.

Circadian Rhythm and Nuclear Receptors.

All life of Earth has evolved mechanisms to track time. This permits anticipation of predictable changes in light/dark, and in most cases also directs fed/fasted cycles, and sleep/wake. The nuclear receptors enjoy a close relationship with the molecular machinery of the clock. Some play a core role within the circadian machinery, other respond to ligands which oscillate in concentration, and physical cross-talk between clock transcription factors, eg cryptochromes, and multiple nuclear receptors also enable coupling of nuclear receptor function to time of day. Essential processes including inflammation, and energy metabolism are strongly regulated by both the circadian machinery, and rhythmic behaviour, and also by multiple members of the nuclear receptor family. An emerging theme is reciprocal regulation of key processes by different members of the nuclear receptor family, for example NR1D1/2, and NR1F1, in regulation of the core circadian clock transcription factor BMAL1.

HaloChIP-seq for Antibody-Independent Mapping of Mouse Transcription Factor Cistromes in vivo.

Chromatin immunoprecipitation (ChIP) maps, on a genome-wide scale, transcription factor binding sites, and the distribution of other chromatin-associated proteins and their modifications. As such, it provides valuable insights into mechanisms of gene regulation. However, successful ChIP experiments are dependent on the availability of a high-quality antibody against the target of interest. Using antibodies with poor sensitivity and specificity can yield misleading results. This can be partly circumvented by using epitope-tagged systems ( e.g. , HA, Myc, His), but these approaches are still antibody-dependent. HaloTag ® is a modified dehalogenase enzyme, which covalently binds synthetic ligands. This system can be used for imaging and purification of HaloTag ® fusion proteins, and has been used for ChIP in vitro . Here, we present a protocol for using the HaloTag ® system for ChIP in vivo , to map, with sensitivity and specificity, the cistrome of a dynamic mouse transcription factor expressed at its endogenous locus. Graphical abstract.

Circadian rhythms in psoriasis and the potential of chronotherapy in psoriasis management.

The physiology and pathology of the skin are influenced by daily oscillations driven by a master clock located in the brain, and peripheral clocks in individual cells. The pathogenesis of psoriasis is circadian-rhythmic, with flares of disease and symptoms such as itch typically being worse in the evening/night-time. Patients with psoriasis have changes in circadian oscillations of blood pressure and heart rate, supporting wider circadian disruption. In addition, shift work, a circadian misalignment challenge, is associated with psoriasis. These features may be due to underlying circadian control of key effector elements known to be relevant in psoriasis such as cell cycle, proliferation, apoptosis and inflammation. Indeed, peripheral clock pathology may lead to hyperproliferation of keratinocytes in the basal layers, insufficient apoptosis of differentiating keratinocytes in psoriatic epidermis, dysregulation of skin-resident and migratory immune cells and modulation of angiogenesis through circadian oscillation of vascular endothelial growth factor A (VEGF-A) in epidermal keratinocytes. Chronotherapeutic effects of topical steroids and topical vitamin D analogues have been reported, suggesting that knowledge of circadian phase may improve the efficacy, and therapeutic index of treatments for psoriasis. In this viewpoint essay, we review the current literature on circadian disruption in psoriasis. We explore the hypothesis that psoriasis is circadian-driven. We also suggest that investigation of the circadian components specific to psoriasis and that the in vitro investigation of circadian regulation of psoriasis will contribute to the development of a novel chronotherapeutic treatment strategy for personalised psoriasis management. We also propose that circadian oscillations of VEGF-A offer an opportunity to enhance the efficacy and tolerability of a novel anti-VEGF-A therapeutic approach, through the timed delivery of anti-VEGF-A drugs.

Circadian clock function does not require the histone methyltransferase MLL3.

The circadian clock controls the physiological function of tissues through the regulation of thousands of genes in a cell-type-specific manner. The core cellular circadian clock is a transcription-translation negative feedback loop, which can recruit epigenetic regulators to facilitate temporal control of gene expression. Histone methyltransferase, mixed lineage leukemia gene 3 (MLL3) was reported to be required for the maintenance of circadian oscillations in cultured cells. Here, we test the role of MLL3 in circadian organization in whole animals. Using mice expressing catalytically inactive MLL3, we show that MLL3 methyltransferase activity is in fact not required for circadian oscillations in vitro in a range of tissues, nor for the maintenance of circadian behavioral rhythms in vivo. In contrast to a previous report, loss of MLL3-dependent methylation did not affect the global levels of H3K4 methylation in liver, indicating substantial compensation from other methyltransferases. Furthermore, we found little evidence of genomic repositioning of H3K4me3 marks. We did, however, observe repositioning of H3K4me1 from intronic regions to intergenic regions and gene promoters; however, there were no changes in H3K4me1 mark abundance around core circadian clock genes. Output functions of the circadian clock, such as control of inflammation, were largely intact in MLL3-methyltransferase-deficient mice, although some gene-specific changes were observed, with sexually dimorphic loss of circadian regulation of specific cytokines. Taken together, these observations indicate that MLL3-directed histone methylation is not essential for core circadian clock function; however, it may influence the inflammatory response.

HNF4A modulates glucocorticoid action in the liver.

The glucocorticoid receptor (GR) is a nuclear receptor critical to the regulation of energy metabolism and inflammation. The actions of GR are dependent on cell type and context. Here, we demonstrate the role of liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver specificity of GR action. In mouse liver, the HNF4A motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodeled, with loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites associates with loss of GR binding at weak GRE motifs. GR binding and chromatin accessibility are gained at sites characterized by strong GRE motifs, which show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is indicated by an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

Chronic inflammatory arthritis drives systemic changes in circadian energy metabolism.

Chronic inflammation underpins many human diseases. Morbidity and mortality associated with chronic inflammation are often mediated through metabolic dysfunction. Inflammatory and metabolic processes vary through circadian time, suggesting an important temporal crosstalk between these systems. Using an established mouse model of rheumatoid arthritis, we show that chronic inflammatory arthritis results in rhythmic joint inflammation and drives major changes in muscle and liver energy metabolism and rhythmic gene expression. Transcriptional and phosphoproteomic analyses revealed alterations in lipid metabolism and mitochondrial function associated with increased EGFR-JAK-STAT3 signaling. Metabolomic analyses confirmed rhythmic metabolic rewiring with impaired ß-oxidation and lipid handling and revealed a pronounced shunt toward sphingolipid and ceramide accumulation. The arthritis-related production of ceramides was most pronounced during the day, which is the time of peak inflammation and increased reliance on fatty acid oxidation. Thus, our data demonstrate that localized joint inflammation drives a time-of-day­dependent build-up of bioactive lipid species driven by rhythmic inflammation and altered EGFR-STAT signaling.

Postradioiodine Graves' management: The PRAGMA study.

OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.

Assessing the Causal Role of Sleep Traits on Glycated Hemoglobin: A Mendelian Randomization Study.

OBJECTIVE: To examine the effects of sleep traits on glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS: This study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female). RESULTS: Across MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA1c (MVR 0.05 SD units [95% CI 0.04-0.06]; 1SMR 0.52 [0.42-0.63]; 2SMR 0.24 [0.11-0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect. CONCLUSIONS: Our results suggest that frequent insomnia symptoms cause higher HbA1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes.