CoChat
Sign Up
Cited by 387Circadian rhythm and melatoninSleep and Work-Related FatigueDietary Effects on Health

The Circadian Syndrome: is the Metabolic Syndrome and much more!

Open access
Zimmet, P., Alberti, K. G. M. M., Stern, N., Bilu, C., El‐Osta, A., Einat, H., Kronfeld‐Schor, N.·2019·Journal of Internal Medicine
DOI 10.1111/joim.12924PMC PMC6851668
Open this paper in CoChat — free accountOpen PDF

Abstract

The Metabolic Syndrome is a cluster of cardio‐metabolic risk factors and comorbidities conveying high risk of both cardiovascular disease and type 2 diabetes. It is responsible for huge socio‐economic costs with its resulting morbidity and mortality in most countries. The underlying aetiology of this clustering has been the subject of much debate. More recently, significant interest has focussed on the involvement of the circadian system, a major regulator of almost every aspect of human health and metabolism. The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease. There is now increasing evidence connecting disturbances in circadian rhythm with not only the key components of the Metabolic Syndrome but also its main comorbidities including sleep disturbances, depression, steatohepatitis and cognitive dysfunction. Based on this, we now propose that circadian disruption may be an important underlying aetiological factor for the Metabolic Syndrome and we suggest that it be renamed the ‘Circadian Syndrome’. With the increased recognition of the ‘Circadian Syndrome’, circadian medicine, through the timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in the maintenance of both individual and population health in the future.

AI snapshot

Written from the paper’s full text.

TL;DR

The authors propose that the Metabolic Syndrome be renamed the “Circadian Syndrome,” arguing that circadian disruption is a common underlying aetiological factor linking cardio-metabolic risk factors with comorbidities such as sleep disturbance, depression, and nonalcoholic fatty liver disease. They suggest circadian medicine—timing of light, exercise, food, medications, and sleep—should play a greater role in prevention and management.

Key findings

  • The paper proposes that the existing “harmonized” Metabolic Syndrome criteria be modified to include associated comorbidities and renamed the “Circadian Syndrome.”
  • It argues that circadian disruption is linked not only to core components such as obesity, T2DM, CVD, hypertension, dyslipidaemia, and raised fasting glucose, but also to comorbidities including sleep disturbances, depression, NAFLD/steatohepatitis, and cognitive dysfunction.
  • It cites evidence that glucose tolerance has a diurnal pattern: in 1974 the authors reported blood glucose levels were higher in the afternoon, indicating impaired glucose tolerance during evening hours, and state that oral glucose tolerance tests and fasting glucose should be performed in the morning to avoid false diabetes diagnosis.
  • It highlights sand rat data: animals held outdoors under natural environmental conditions and fed standard rodent chow had robust daily rhythms and did not develop T2DM or depressive-like behaviour, whereas animals held indoors with only light cycling and the same diet showed low amplitude rhythmicity, depressive-like behaviour, and developed T2DM.

Methods

  • Narrative review and perspective/proposal, not a primary empirical study; the authors synthesize prior human and animal evidence and present a conceptual argument for the “Circadian Syndrome.”
  • The paper includes two tables: Table 1 reproduces the “harmonized” Metabolic Syndrome diagnostic criteria, and Table 2 lists circadian system involvement in key cardio-metabolic risk factors and outcomes in humans and sand rats.
  • It discusses evidence from human studies, animal models, and the authors’ sand rat model, including comparisons of outdoor versus indoor laboratory housing.

Limitations

  • The paper states that most studies of Metabolic Syndrome, T2DM, and depression use nocturnal mice and rats while modelling diurnal humans, and suggests that diurnal model animals such as the sand rat are advantageous for studying these processes.
  • Evident from the text: as a narrative review and proposal, it does not report a systematic search strategy, formal quality appraisal, or quantitative synthesis, and the proposed “Circadian Syndrome” is not tested empirically as a diagnostic category.
  • Evident from the text: causal direction between circadian disruption and the cluster/comorbidities is asserted from associative and model evidence rather than established by intervention trials in the review.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/joim.12924

Cites

112 of 112 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 101 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The circadian system is the major regulator of almost every aspect of human health and metabolism.

    “The circadian system is the major regulator of almost every aspect of human health and metabolism.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Panda S. The arrival of circadian medicine. Nat Rev Endocrinol 2019; 1. 30602736

      Not checked in the free run.

    • cites [4] Orozco‐Solis R, Sassone‐Corsi P. Epigenetic control and the circadian clock: linking metabolism to neuronal responses. Neuroscience 2014; 264: 76– 87. 24486964 PMC6501790 source

      Not checked in the free run.

    • cites [20] Sato S, Sassone‐Corsi P. Circadian and epigenetic control of depression‐like behaviors. Curr Opin Behav Sci 2019; 25: 15– 22. source

      Not checked in the free run.

  • Premisecitation

    The master clock regulates the body's metabolism through controlling body functions and synchronizing peripheral clocks in almost all cells, including heart, liver, muscle and adipose tissue.

    “This master clock regulates the body's metabolism through controlling body functions, and synchronizing peripheral clocks in almost all cells in the body, including the body's key tissues such as the heart, liver, muscle and adipose tissue 3, 4, 5, 6.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Panda S. The arrival of circadian medicine. Nat Rev Endocrinol 2019; 1. 30602736

      Not checked in the free run.

    • cites [4] Orozco‐Solis R, Sassone‐Corsi P. Epigenetic control and the circadian clock: linking metabolism to neuronal responses. Neuroscience 2014; 264: 76– 87. 24486964 PMC6501790 source

      Not checked in the free run.

    • cites [5] Kalsbeek A, Scheer F. A.., Perreau-lenz S., et al Circadian disruption and SCN control of energy metabolism. FEBS Lett 2011; 585: 1412– 26. 21414317 PMC3095769 source

      Not checked in the free run.

  • Premisecitation

    Nondipping hypertension has been associated with insulin resistance, obesity, the Metabolic Syndrome and type 2 diabetes.

    “Nondipping hypertension has been associated with insulin resistance, obesity, the Metabolic Syndrome and type 2 diabetes 64.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Hassan MO et al Non‐dipping blood pressure in the metabolic syndrome among arabs of the oman family study. Obesity 2007; 15: 2445– 53. 17925470 source

      Not checked in the free run.

  • Interpretationreasoning

    Sleep apnoea may be an important common denominator linking obesity and the Metabolic Syndrome to nondipping hypertension.

    “Sleep apnoea may be one important common denominator linking obesity and the Metabolic Syndrome to nondipping hypertension.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In most healthy subjects, there is diurnal variation in blood pressure that parallels the circadian variation of blood pressure regulating systems such as sympathetic activity, cortisol and aldosterone.

    “In most healthy subjects, there is diurnal variation in blood pressure with systolic and diastolic blood pressures which parallels, in general, the circadian variation of blood pressure regulating systems such as sympathetic activity, cortisol and aldosterone 62.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Fabbian F et al Dipper and non‐dipper blood pressure 24‐hour patterns: circadian rhythm–dependent physiologic and pathophysiologic mechanisms. Chronobiol Int 2013; 30: 17– 30. 23002916 source

      Not checked in the free run.

  • May combine two claims. 17
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    Light is the main cue influencing the SCN master circadian clock, turning on or off genes that control the individual's internal clock function.

    “Light is the main cue influencing the SCN master circadian clock, turning on or off genes that control the individual's internal clock function.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Orozco‐Solis R, Sassone‐Corsi P. Epigenetic control and the circadian clock: linking metabolism to neuronal responses. Neuroscience 2014; 264: 76– 87. 24486964 PMC6501790 source

      Not checked in the free run.

    • cites [7] Li M‐D, Li C‐M, Wang Z. The role of circadian clocks in metabolic disease. Yale J Biol Med 2012; 85: 387. 23012586 PMC3447202

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The human brain has a master 'Body Clock' which resides in the suprachiasmatic nucleus (SCN) of the hypothalamus and it determines our daily rhythms.

    “The human brain has a master ‘Body Clock’ which resides in the suprachiasmatic nucleus (SCN) of the hypothalamus and it determines our daily rhythms, a phenomenon also widely described in nature in almost all living organisms 1, 2.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Kuhlman SJ, Craig LM, Duffy JF. Introduction to chronobiology. Cold Spring Harb Perspect Biol 2018; 10: a033613. 29038118 PMC6120700 source

      Not checked in the free run.

    • cites [2] Top D, Young MW. Coordination between differentially regulated circadian clocks generates rhythmic behavior. Cold Spring Harb Perspect Biol 2018; 10: a033589. 28893860 PMC6028074 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The concentration is controlled by the SCN both indirectly, via controlling feeding rhythms, and directly, by affecting glucose production and utilization and insulin sensitivity in tissues like liver, muscle and pancreas.

    “The concentration is controlled by the SCN both indirectly, via controlling feeding rhythms (which effect glucose and insulin rhythms), and directly, by affecting glucose production and utilization and insulin sensitivity in tissues like liver, muscle and pancreas 17, 21, 75.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Stenvers DJ, Scheer FAJL, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. Nat Rev Endocrinol 2019; 15: 75– 89. 30531917 source

      Not checked in the free run.

    • cites [21] Jha PK, Challet E, Kalsbeek A. Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals. Mol Cell Endocrinol 2015; 418: 74– 88. 25662277 source

      Not checked in the free run.

    • cites [75] Panda S. Circadian physiology of metabolism. Science 2016; 354: 1008– 15. 27885007 PMC7261592 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Better oxygenation through night-time continuous positive air pressure reduces nocturnal hypertension and reduces catecholamines and aldosterone secretion.

    “Further, better oxygenation through night‐time continuous positive air pressure reduces nocturnal hypertension 65 and reduces catecholamines and aldosterone secretion 66.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Schein AS, Kerkhoff AC, Coronel CC, Plentz RD, Sbruzzi G. Continuous positive airway pressure reduces blood pressure in patients with obstructive sleep apnea; a systematic review and meta‐analysis with 1000 patients. J Hypertens 2014; 32: 1762– 73. 24979300 source

      Not checked in the free run.

    • cites [66] Casitas R et al The effect of treatment for sleep apnoea on determinants of blood pressure control. Eur Respir J 2017; 50: 1701261. 29146604 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This rhythm is independent of food availability and depends on a functioning central clock.

    “This rhythm is independent of food availability and depends on a functioning central clock 21, 76, 77.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Jha PK, Challet E, Kalsbeek A. Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals. Mol Cell Endocrinol 2015; 418: 74– 88. 25662277 source

      Not checked in the free run.

    • cites [76] Coomans CP et al The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity. Diabetes 2013; 62: 1102– 8. 23274903 PMC3609590 source

      Not checked in the free run.

    • cites [77] Kalsbeek A, la Fleur S, Fliers E. Circadian control of glucose metabolism. Mol Metab 2014; 3: 372– 83. 24944897 PMC4060304 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is mounting evidence to link cardio-metabolic risk factors and comorbidities with circadian rhythm disturbances, suggesting all or the majority of cluster components could have a common aetiology.

    “There is mounting evidence to link these cardio‐metabolic risk factors and the comorbidities with circadian rhythm disturbances which suggests all, or the majority, of the cluster components could have a common aetiology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Timing of treatment to body rhythms is a means of individualizing and optimizing the treatment of hypertension and may constitute an effective option to reduce CVD risk.

    “Timing of treatment to body rhythms is a means of individualizing and optimizing the treatment of hypertension and may a constitute an effective option to reduce CVD risk 67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Hermida RC et al Circadian rhythms in blood pressure regulation and optimization of hytertension treatment with ACE inhibitor and ARB medications. Am J Hypertens 2011; 24: 383– 91. 20930708 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human and animal studies suggest that circadian clocks are important drivers of rhythms in CVD physiology and pathology and for disease prevention and management.

    “Human and animal studies suggest that circadian clocks are not only important drivers of rhythms in CVD physiology and pathology but also for disease prevention and management 19, 61.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Crnko S, Du Pré BC, Sluijter JPG, Van Laake LW. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nat Rev Cardiol 2019 10.1038/s41569-019-0167-4 30796369 source

      Not checked in the free run.

    • cites [61] Durgan DJ, Young ME. The cardiomyocyte circadian clock emerging roles in health and disease. Circ Res 2010; 106: 647– 58. 20203314 PMC3223121 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood pressure dips at night, typically at the end of the night, and on arousal, blood pressure surges.

    “Blood pressure dips at night, typically at the end of the night, and on arousal, blood pressure surges 30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Smolensky MH, Hermida RC, Castriotta RJ, Portaluppi F. Role of sleep‐wake cycle on blood pressure circadian rhythms and hypertension. Sleep Med 2007; 8: 668– 80. 17383936 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood glucose levels are higher in the afternoon, indicating that glucose tolerance is impaired during the evening hours because of the body's circadian rhythm.

    “Blood glucose levels were higher in the afternoon indicating that glucose tolerance is impaired during the evening hours because of the body's circadian rhythm.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Zimmet PZ, Wall JR, Rome R, Stimmler L, Jarrett RJ. Diurnal variation in glucose tolerance: associated changes in plasma insulin, growth hormone, and non‐esterified. BMJ 1974; 1: 485– 8. 4817159 PMC1633483 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Circadian oscillations have been reported for physiological CVD regulation including heart rate and blood pressure, for cardiac disorders including arrhythmias, and there is circadian variation in frequency of onset of myocardial infarction and sudden cardiac death.

    “Circadian oscillations have been reported for both physiological CVD regulation including heart rate and blood pressure 57, for cardiac disorders including arrythmias 58, 59, and there is circadian variation in frequency of onset of myocardial infarction and sudden cardiac death 19, 60.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [57] Van Laake LW, Luscher TF, Young ME. The circadian clock in cardiovascular regulation and disease: lessons from the nobel prize in physiology or medicine 2017. Eur Heart J 2018; 39: 2326– 9. 29309706 PMC6012474 source

      Not checked in the free run.

    • cites [58] Thosar SS, Butler MP, Shea SA. Role of the circadian system in cardiovascular disease. J Clin Invest 2018; 128: 2157– 67. 29856365 PMC5983320 source

      Not checked in the free run.

    • cites [59] Shaw E, Tofler GH. Circadian rhythm and cardiovascular disease. Curr Atheroscler Rep 2009; 11: 289– 95. 19500492 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    The Metabolic Syndrome only recognizes a few of the aetiological components of the proposed Circadian Syndrome and says virtually nothing about its actual aetiology.

    “The Metabolic Syndrome only recognizes a few of the aetiological components of what constitutes those of our proposed Circadian Syndrome and it says virtually nothing about its actual aetiology.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    There is uncertainty whether there is a common and central aetiological feature to explain the clustering of the risk factors and comorbidities.

    “Nevertheless, an important issue still remained as to the uncertainty whether there is a common and central aetiological feature to explain the clustering of these risk factors. Not only this but also the accompanying commonly associated comorbidities of sleep disturbance, depression and NAFLD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Light therapy and other treatments affecting the circadian clock are used as a therapy for depression.

    “Depression is related to disturbances of the circadian clock, and light therapy and other treatment affecting the circadian clock are used as a therapy for depression 83, 88, 89, 90, 91, 92, 93, 94, 95, 96.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [83] Bilu C, Einat H, Kronfeld‐Schor N. Utilization of diurnal rodents in the research of depression. Drug Dev Res 2016; 77: 336– 45. 27654112 source

      Not checked in the free run.

    • cites [88] Brouwer A et al Light therapy for better mood and insulin sensitivity in patients with major depression and type 2 diabetes: a randomised, double‐blind, parallel‐arm trial. BMC Psychiatry 2015; 15 10.1186/s12888-015-0543-5 PMC4513382 26204994 source

      Not checked in the free run.

    • cites [89] Dietzel M, Saletu B, Lesch OM, Sieghart W, Schjerve M. Light treatment in depressive illness. Polysomnographic, psychometric and neuroendocrinological findings. Eur Neurol 1986; 25: 93– 103. 3758132 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Circadian medicine, through timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in maintenance of individual and population health in the future.

    “With the increased recognition of the ‘Circadian Syndrome’, circadian medicine, through the timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in the maintenance of both individual and population health in the future.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Laboratory conditions are similar in many ways to conditions in modern societies, where ambient temperature and light exposure are controlled, food is available ad libitum, and there is no connection to rhythms of other species.

    “Laboratory conditions are similar in many ways to the conditions we live in modern societies, where we control our ambient temperature and light exposure, where food is available ad libitum and where we have no connection to rhythms of other species – food, competitors or predators 104.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Kronfeld‐Schor N, Visser ME, Salis L, van Gils JA. Chronobiology of interspecific interactions in a changing world. Philos Trans R Soc Lond B Biol Sci 2017; 372 10.1098/rstb.2016.0248 PMC5647275 28993492 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NAFLD is now the commonest chronic liver disease in Western nations.

    “which is now the commonest chronic liver disease in Western nations 78.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Yu JS, Marsh S, Hu JB, Feng WK, Wu CD. The pathogenesis of nonalcoholic fatty liver disease: interplay between diet, gut microbiota, and genetic background. Gastroenterol Res Pract 2016 10.1155/2016/2862173 PMC4876215 27247565 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metabolic homeostasis is linked to the circadian clock with the clock involved in regulation of hepatic triglyceride accumulation, inflammation, oxidative stress and mitochondrial dysfunction, all of which may contribute to the pathogenesis of NAFLD.

    “Metabolic homeostasis is linked to the circadian clock with the clock involved in regulation of hepatic triglyceride accumulation, inflammation, oxidative stress and mitochondrial dysfunction 29, all of which may contribute to the pathogenesis of NAFLD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Reinke H, Asher G. Circadian clock control of liver metabolic functions. Gastroenterology 2016; 150: 574– 80. 26657326 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The escalating global epidemics of CVD and T2DM and dramatic changes in societies over recent decades are pivotal in the pathogenesis of obesity, T2DM and CVD.

    “We see this scenario as pivotal in the pathogenesis of obesity, T2DM and CVD and in the light of the modern epidemics of NCDs 8, 55.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Zimmet PZ, Magliano DJ, Herman WH, Shaw JE. Diabetes: a 21st century challenge. Lancet Diabetes Endocrinol 2014; 2: 56– 64. 24622669 source

      Not checked in the free run.

    • cites [55] Zimmet PZ, Alberti KGM. Epidemiology of diabetes—status of a pandemic and issues around metabolic surgery. Diabetes Care 2016; 39: 878– 83. 27222545 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease.

    “The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The current environment increases the risk of chronic metabolic diseases and CVD.

    “Furthermore, Gluckman and his colleagues point out that the current environment increases the risk of chronic metabolic diseases and CVD 39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Alberti KGM, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet 2005; 366: 1059– 62. 16182882 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The sand rat (Psammomys obesus) is a diurnal, well-accepted and extensively studied model for T2DM.

    “A diurnal, well‐accepted and extensively studied model for T2DM 48, 51, 100, 101, 102, 103 is the sand rat, (Psammomys obesus).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [48] Keating ST, Plutzky J, El‐Osta A. Epigenetic changes in diabetes and cardiovascular risk. Circ Res 2016; 118: 1706– 22. 27230637 PMC5593074 source

      Not checked in the free run.

    • cites [51] Kaspi A et al Diet during pregnancy is implicated in the regulation of hypothalamic RNA methylation and risk of obesity in offspring. Mol Nutr Food Res 2018; 62: e1800134 10.1002/mnfr.201800134 29882289 source

      Not checked in the free run.

    • cites [100] Barnett M, Collier GR, Zimmet P, Odea K. The effect of restricting energy‐intake on diabetes in Psammomys‐obesus. Int J Obes Relat Metab Disord 1994; 18: 789– 94. 7894516

      Not checked in the free run.

    • cites [101] Schmidt‐Nielsen K, Haines HB, Hackel DB. Diabetes mellitus in the sand rat induced by standard laboratory diets. Science 1964; 143: 689– 90. 14081240 source

      Not checked in the free run.

    • cites [102] Kalman R, Ziv E, Lazarovici G, Shafrir E. The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents. London: Academic Press, 2012; 1171– 90.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [103] Kaiser N, Cerasi E, Leibowitz G. Diet‐induced diabetes in the sand rat (Psammomys obesus)In Animal Models in Diabetes Research. Totowa, NJ: Humana Press, 2012; (pp. 89– 102). 22893403 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA methylation is an important determinant of epigenetic change and regulates tissue-specific expression of genes described recently in adipose tissue after one night of sleep loss.

    “For example, DNA methylation, an important determinant of epigenetic change regulates tissue‐specific expression of genes described recently in adipose tissue after one night of sleep loss 56.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Cedernaes J et al Acute sleep loss results in tissue‐specific alterations in genome‐wide DNA methylation state and metabolic fuel utilization in humans. Sci Adv 2018; 4 10.1126/sciadv.aar8590 PMC6105229 30140739 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Recent developments in epigenetics may provide the basis for a better understanding of the pathophysiological mechanisms underlying the Metabolic Syndrome.

    “Recent developments in epigenetics may also provide the basis for a better understanding of the pathophysiological mechanisms underlying what to date we have called the Metabolic Syndrome 4, 47.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Orozco‐Solis R, Sassone‐Corsi P. Epigenetic control and the circadian clock: linking metabolism to neuronal responses. Neuroscience 2014; 264: 76– 87. 24486964 PMC6501790 source

      Not checked in the free run.

    • cites [47] Barres R, Zierath JR. DNA methylation in metabolic disorders. Am J Clin Nutr 2011; 93: 897S– 900S. 21289222 source

      Not checked in the free run.

24 of 24

  • The paper relies on this without support.

    Risk of obesity, T2DM and Metabolic Syndrome is elevated in people who suffer from chronic sleep loss or are shift workers.

    “Risk of obesity, T2DM and Metabolic Syndrome is elevated in people who suffer from chronic sleep loss or are shift workers.”

  • The paper relies on this without support.

    To date, no explanation has revealed a potential mechanism that could explain the possible common factor(s) underlying Metabolic Syndrome components and comorbidities.

    “Yet to date, no explanation has revealed a potential mechanism that could explain the possible factor/s.”

  • The paper relies on this without support.

    Metabolic Syndrome, including T2DM and depression, is associated with disturbances of circadian rhythms.

    “Although the Metabolic Syndrome, including type 2 diabetes mellitus (T2DM) and depression, is associated with disturbances of circadian rhythms, most studies of these diseases use nocturnal mice and rats whilst modelling diurnal humans.”

  • The paper relies on this without support.

    Most studies of Metabolic Syndrome, T2DM and depression use nocturnal mice and rats whilst modelling diurnal humans.

    “Although the Metabolic Syndrome, including type 2 diabetes mellitus (T2DM) and depression, is associated with disturbances of circadian rhythms, most studies of these diseases use nocturnal mice and rats whilst modelling diurnal humans.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Depression is alternately included in and associated with the Metabolic Syndrome

    Minor

    The conclusion describes depression as included in the Metabolic Syndrome, whereas the earlier definition describes it as an associated comorbidity that the authors propose adding to a new Circadian Syndrome.

  • Diabetes and cardiovascular disease are called syndrome components

    Minor

    The paper calls obesity, type 2 diabetes, cardiovascular disease and hypertension all components of the Metabolic Syndrome. Its own definition instead lists central obesity, blood pressure, dyslipidaemia and fasting glucose as the components; diabetes and cardiovascular disease are described elsewhere as outcomes.

  • Table 1 credits the wrong reference

    Minor

    The text identifies reference 45 as the harmonized Metabolic Syndrome statement used to define Table 1, but the table note says it was adapted from reference 49, which is a paper on epigenetic programming.

3 of 3

Cites

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Zimmet, P., Alberti, K. G. M. M., Stern, N., Bilu, C., El‐Osta, A., Einat, H., & Kronfeld‐Schor, N.
Affiliations
  • Tel Aviv Sourasky Medical Center (IL)
  • Imperial College London (GB)
  • Tel Aviv University (IL)
  • The University of Melbourne (AU)
  • Academic College of Tel Aviv-Yafo (IL)
Corresponding author
Zimmet, P.
ORCID
Venue
Journal of Internal Medicine
Publisher
Wiley
Published
2019-06-10
Volume
286
Issue
2
Pages
181-191
ISSN
  • 0954-6820 (ISSN-L)
  • 1365-2796
DOI
10.1111/joim.12924
PMC
PMC6851668
OpenAlex
W2946781915
Semantic Scholar
0372cd9051b089e2107f2e10bfea4f5179d65b52
Cited by
387
References
112
Citations by year
2026: 58 · 2025: 68 · 2024: 80 · 2023: 69 · 2022: 39 · 2021: 40 · 2020: 23 · 2019: 10
FWCI
3.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Internal Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Monash University Research Portal (Monash University) (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
Israel Science Foundation (866/17)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
  • Health Sciences › Medicine › Physiology › Dietary Effects on Health
Keywords
circadian syndrome, circadian rhythm disruption, metabolic syndrome, circadian system, type 2 diabetes, cardiovascular disease, sleep disorders, depression, steatohepatitis, cognitive impairment, circadian medicine, chrononutrition, light exposure
MeSH terms
Circadian Rhythm, Cognition Disorders, Depression, Fatty Liver, Humans, Life Style, Risk Factors, Sleep Disorders, Circadian Rhythm, Metabolic Syndrome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review