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Cited by 338Circadian rhythm and melatoninPancreatic function and diabetesMetabolism, Diabetes, and Cancer

Circadian control of glucose metabolism

Open access
Kalsbeek, Andries, la Fleur, Susanne, Fliers, Eric·2014·Molecular Metabolism
DOI 10.1016/j.molmet.2014.03.002PMC PMC4060304
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Abstract

The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM. Recent evidence from basal studies has further sparked interest in the involvement of daily rhythms (and their disruption) in the development of obesity and T2DM. Most living organisms have molecular clocks in almost every tissue, which govern rhythmicity in many domains of physiology, such as rest/activity rhythms, feeding/fasting rhythms, and hormonal secretion. Here we present the latest research describing the specific role played by the molecular clock mechanism in the control of glucose metabolism and speculate on how disruption of these tissue clocks may lead to the disturbances in glucose homeostasis.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that molecular circadian clocks in the suprachiasmatic nucleus (SCN) and peripheral tissues regulate glucose homeostasis, and that their disruption contributes to obesity and type 2 diabetes. Tissue-specific clock knockout studies especially implicate pancreatic clocks in insulin release and liver clocks in glucose tolerance, while roles for adipose and muscle clocks remain less direct or unresolved.

Key findings

  • Whole-body clock gene knockouts produce diverse metabolic phenotypes: *Clock* mutant mice are hyperphagic, obese, hyperleptinemic, hyperlipidemic, hyperglycemic, and hypoinsulinemic; *Bmal1* KO mice show fasting hypoglycemia, reduced plasma insulin, and increased adiposity; *Cry1−/−/Cry2−/−* mice have impaired glucose clearance; *Per2* mutants show reduced fasting glycemia and impaired gluconeogenesis. However, the paper notes that genetic background strongly affects these phenotypes, and many null mutations are associated with leanness despite normophagia or hyperphagia.
  • The SCN directly influences daily glucose rhythms independent of feeding: with a 6-meals-a-day schedule (identical meal every 4 h), meals during the dark period produced larger glucose and insulin responses than during the light period, and the basal plasma glucose rhythm persisted during fasting. The SCN signals via the PVN and sympathetic innervation of the liver; perifornical orexin neurons can increase hepatic glucose production.
  • Tissue-specific clocks have distinct roles: liver-specific *Bmal1* disruption increases glucose tolerance; liver-specific *Cry* KO inhibits glucagon-induced gluconeogenesis; pancreatic *Bmal1* or *Clock* ablation causes type 2 diabetes-like defective β-cell insulin secretion; adipocyte-specific *Bmal1* KO leads to obesity but not direct glucose homeostasis changes; a note added in proof reports muscle-specific *Bmal1* KO mice show reduced GLUT4 and impaired insulin-stimulated glucose uptake.
  • Human evidence links circadian gene variants to glucose homeostasis: *Clock* and *Bmal1* polymorphisms are associated with obesity and type 2 diabetes susceptibility, *Npas2* and *Per2* polymorphisms with high fasting glucose, and *CRY2* variants with glucose levels. Shift work and disrupted sleep are consistently associated with increased type 2 diabetes risk. The review also notes that over 350 circadian transcripts have been identified in liver, 10% of which maintain rhythmicity without a functional hepatocyte clock, and that after a meal >80% of glucose is taken up by muscle.

Methods

  • Design: narrative review/synthesis of basic, genetic, physiological, and epidemiological literature on circadian control of glucose metabolism; no systematic review or meta-analysis is described.
  • Data/sample: rodent whole-body and tissue-specific clock gene knockouts, SCN lesion/stimulation studies, scheduled feeding and autonomic denervation experiments, tracer/isotope and PET-FDG studies, human genetic association studies, and epidemiological studies of shift work and sleep disruption.
  • Main analysis: qualitative integration of findings across central and peripheral clocks, with no new primary data reported.

Limitations

  • Stated in the paper: whole-body clock gene KOs cannot distinguish contributions of separate tissues; tissue-specific KO models were urgently needed; many mechanisms remain unresolved, including the exact role of glucocorticoid receptor signaling, autonomic innervation, and the muscle clock; integrative whole-animal/human studies are still required.
  • Stated in the paper: metabolic phenotypes of clock mutants depend heavily on genetic background, and human evidence is largely correlational/epidemiological rather than causal.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy or quantitative synthesis, and many conclusions rely on animal models and cited studies; the 2014 publication date means some tissue-specific findings, such as the muscle-specific *Bmal1* KO, appear only in a note added in proof.

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

Integrity signals

Registry

Crossref · 10.1016/j.molmet.2014.03.002

Cites

156 of 156 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 86 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    We did not find an obvious and direct influence of the SCN on basal plasma insulin or glucagon concentrations.

    “On the other hand, we did not find an obvious and direct influence of the SCN on basal plasma insulin or glucagon concentrations [58,59].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] La Fleur, 1999, An SCN generated rhythm in basal glucose levels, Journal of Neuroendocrinology source

      Not checked in the free run.

    • cites [59] Ruiter, 2003, The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior, Diabetes source

      Not checked in the free run.

  • Findingown data

    Rhythmicity was maintained in plasma glucose concentrations during fasting.

    “Another argument in favor of a direct influence of the SCN on glucose metabolism, independent of its effect on feeding behavior, was the fact that the rhythmicity was maintained in plasma glucose concentrations during fasting.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The SCN needs an intact sympathetic innervation of the liver to generate a daily rhythm in plasma glucose concentrations.

    “From these studies it became clear that the SCN does indeed need an intact sympathetic innervation of the liver to generate a daily rhythm in plasma glucose concentrations [63,66].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Kalsbeek, 2004, Suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver, Journal of Neuroscience source

      Not checked in the free run.

    • cites [66] Cailotto, 2005, The suprachiasmatic nucleus controls the daily variation of plasma glucose via the autonomic output to the liver: are the clock genes involved?, European Journal of Neuroscience source

      Not checked in the free run.

  • Findingcitation

    Anatomical tracing experiments revealed synaptic connections between the SCN and the liver via the autonomic nervous system.

    “Interestingly, our anatomical tracing experiments revealed synaptic connections between the SCN and the liver, via the autonomic nervous system (ANS) [62,63].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] La Fleur, 2000, Polysynaptic neural pathways between the hypothalamus, including the suprachiasmatic nucleus, and the liver, Brain Research source

      Not checked in the free run.

    • cites [63] Kalsbeek, 2004, Suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver, Journal of Neuroscience source

      Not checked in the free run.

  • Findingcitation

    In rats on a 6-meals-a-day feeding schedule, similar meals resulted in larger glucose and insulin responses when consumed during the dark period than during the light period.

    “The first experiments with this scheduled feeding regimen in rats revealed a clear daily rhythm in meal-induced responses in glucose and insulin, i.e., similar meals resulted in larger glucose and insulin responses when consumed during the dark period than when consumed during the light period (Figure 2; [57]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Kalsbeek, 1998, Circadian control of insulin secretion is independent of the temporal distribution of feeding, Physiology and Behaviour source

      Not checked in the free run.

  • May combine two claims. 27
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Findingcitation

    Glucose uptake showed a clear 24-h rhythm, with the highest uptake at the end of the light period.

    “Glucose uptake did indeed show a clear 24-h rhythm, but, surprisingly, with the highest uptake at the end of the light period (Figure 2; [60]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] La Fleur, 2001, A daily rhythm in glucose tolerance. A role for the suprachiasmatic nucleus, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liver glycogen content undergoes large daily fluctuations to sustain blood glucose levels, with glycogen synthesis and degradation recruited during activity/feeding and resting/starvation periods respectively.

    “In this process liver glycogen content undergoes large daily fluctuations to sustain blood glucose levels, as glycogen synthesis and degradation are specifically recruited during the activity/feeding and resting/starvation periods, respectively [9,10].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Peret, 1973, Schedule of protein ingestion, nitrogen and energy utilization and circadian rhythm of hepatic glycogen, plasma corticosterone and insulin in rats, Journal of Nutrition source

      Not checked in the free run.

    • cites [10] Armstrong, 1980, A chronometric approach to the study of feeding behavior, Neuroscience and Biobehavioural Reviews source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CLOCK and BMAL1 are transcription factors that act as positive regulators of circadian gene expression and activate expression of the negative regulators CRY and PER families.

    “CLOCK and BMAL1 are transcription factors that act as positive regulators of circadian gene expression and activate the expression of the negative regulators of circadian gene expression: cryptochrome (CRY1 and CRY2) and period (PER1, PER2, PER3) families.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Reppert, 2001, Molecular analysis of mammalian circadian rhythms, Annual Review of Physiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During the activity/feeding period blood glucose is mainly of dietary origin, whereas during resting/starvation glucose is recruited from endogenous glucose production in the liver.

    “whereas during the activity/feeding period blood glucose is mainly of dietary origin, during the resting/starvation period glucose is progressively recruited from endogenous glucose production in the liver to maintain blood glucose levels within a relatively narrow range.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Peret, 1973, Schedule of protein ingestion, nitrogen and energy utilization and circadian rhythm of hepatic glycogen, plasma corticosterone and insulin in rats, Journal of Nutrition source

      Not checked in the free run.

    • cites [10] Armstrong, 1980, A chronometric approach to the study of feeding behavior, Neuroscience and Biobehavioural Reviews source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rhythmic feeding is both necessary and sufficient to drive the circadian expression of liver genes.

    “Indeed, it was shown that rhythmic feeding is both necessary and sufficient to drive the circadian expression of liver genes [7,8]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Hara, 2001, Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus, Genes to Cells source

      Not checked in the free run.

    • cites [8] Kornmann, 2007, System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock, PLoS Biology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT is expressed rhythmically and interacts with CLOCK:BMAL1 heterodimers, leading to rhythmic deacetylation of CLOCK:BMAL1, histone H3, and PER2.

    “SIRT is expressed rhythmically and interacts with CLOCK:BMAL1 heterodimers, leading to rhythmic deacetylation of CLOCK:BMAL1, histone H3, and PER2 [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Asher, 2008, SIRT1 regulates circadian clock gene expression through PER2 deacetylation, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ID2 knockout mice show increased glucose tolerance and insulin sensitivity.

    “LD2 KO mice not only show increased light-induced phase-shifts [33], but also increased glucose tolerance and insulin sensitivity [34].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Duffield, 2009, A role for Id2 in regulating photic entrainment of the mammalian circadian system, Current Biology source

      Not checked in the free run.

    • cites [34] Mathew, 2013, Ablation of the ID2 gene results in altered circadian feeding behavior, and sex-specific enhancement of insulin sensitivity and elevated glucose uptake in skeletal muscle and brown adipose tissue, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite being hypophagic on a high-fat diet, Cry double knockout animals become obese rapidly, probably because of increased insulin release and lipid storage.

    “Despite being hypophagic on the high-fat diet the dKO animals become obese rapidly, probably because of an increased insulin release and lipid storage [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Barclay, 2013, High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice, American Journal of Physiology – Endocrinology and Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Per2 mutant mice show a reduction in fat pad mass and plasma lipid levels.

    “as well as a reduction in fat pad mass and plasma lipid levels [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Grimaldi, 2010, PER2 controls lipid metabolism by direct regulation of PPARgamma, Cell Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Per2 null mice exhibit no glucocorticoid oscillations, indicating that PER2 may impact glucocorticoid receptor-dependent glucose metabolism.

    “Per2 null mice exhibit no glucocorticoid oscillations, indicating that PER2 may also impact glucocorticoid receptor (GR)-dependent glucose metabolism [24,25].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] So, 2009, Glucocorticoid regulation of the circadian clock modulates glucose homeostasis, Proceedings of the National Academy of Sciences of the United States of America source

      Not checked in the free run.

    • cites [25] Yang, 2009, The role of mPer2 clock gene in glucocorticoid and feeding rhythms, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When subjected to daytime feeding, the liver of Parp-1 knockout mice shows a significantly delayed phase inversion of clock gene expression compared with wild type, suggesting PARP-1 activity is implicated in phase entrainment of peripheral oscillators.

    “When subjected to daytime feeding the liver of Parp-1 KO mice showed a significantly delayed phase inversion of clock gene expression, when compared with wild type mice, suggesting that PARP-1 activity is indeed implicated in the phase entrainment of peripheral oscillators [48].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Asher, 2010, Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Per2 mutant mice show reduced fasting glycemia, loss of rhythmic glycogen accumulation in the liver, elevated plasma insulin levels and impaired gluconeogenesis.

    “Per2 mutant mice show reduced fasting glycemia, a loss of rhythmic glycogen accumulation in the liver, elevated plasma insulin levels and impaired gluconeogenesis [20–22]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] Schmutz, 2010, The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors, Genes & Development source

      Not checked in the free run.

    • cites [21] Zani, 2013, PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and G L expression, Molecular Metabolism source

      Not checked in the free run.

    • cites [22] Zhao, 2012, Loss of mPer2 increases plasma insulin levels by enhanced glucose-stimulated insulin secretion and impaired insulin clearance in mice, FEBS Letters source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clock mutant mice described by Turek et al. show severely disturbed daily feeding rhythms, hyperphagia, obesity, hyperleptinemia, hyperlipidemia, hyperglycemia and hypoinsulinemia.

    “Turek et al. [12] described a pronounced metabolic phenotype in Clock mutant mice. Not only did these animals show severely disturbed daily feeding rhythms, they were also hyperphagic, obese, hyperleptinemic, hyperlipidemic, hyperglycemic and hypoinsulinemic.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Turek, 2005, Obesity and metabolic syndrome in circadian Clock mutant mice, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cAMP is not solely an output of the SCN, but an integral component of the SCN pacemaker, regulating transcriptional cycles.

    “O'Neill et al. [43] showed that cAMP is not solely an output of the SCN, but an integral component of the SCN pacemaker, regulating transcriptional cycles.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] O'Neill, 2008, cAMP-dependent signaling as a core component of the mammalian circadian pacemaker, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other Clock mutant mouse models show different metabolic results, including lack of obesity or weight loss despite lipid imbalance, suggesting the importance of genetic background.

    “However, different results have been reported in other Clock mutant mouse models as also lack of obesity or even weight loss, despite lipid imbalance, has been reported suggesting the importance of the genetic background when analyzing the metabolic effects of the Clock gene [13–16].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13] Oishi, 2006, Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice, FEBS Letters source

      Not checked in the free run.

    • cites [14] Kudo, 2007, Attenuating effect of clock mutation on triglyceride contents in the ICR mouse liver under a high-fat diet, Journal of Biological Rhythms source

      Not checked in the free run.

    • cites [15] Kennaway, 2007, Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues, American Journal of Physiology

      Not checked in the free run.

    • cites [16] Rudic, 2004, BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis, PLoS Biology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cry1−/−/Cry2−/− double knockout mice exhibit elevated blood glucose in response to acute feeding after an overnight fast and severely impaired glucose clearance in a glucose tolerance test.

    “Cry1−/−/Cry2−/− (double KO) mice exhibit elevated blood glucose in response to acute feeding after an overnight fast and severely impaired glucose clearance in a glucose tolerance test.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Lamia, 2011, Cryptochromes mediate rhythmic repression of the glucocorticoid receptor, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rev-erbα−/− mice display increased adiposity and mild hyperglycemia, but without insulin resistance.

    “Indeed, Rev-erbα−/− mice displayed increased adiposity and mild hyperglycemia, but without insulin resistance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Yin, 2007, Rev-erba, a heme sensor that coordinates metabolic and circadian pathways, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of p75NTR alters the circadian oscillation of clock genes in the SCN, liver and fibroblasts, as well as glucose and lipid homeostasis genes.

    “Loss of p75NTR alters the circadian oscillation of clock genes in the SCN, liver and fibroblasts, as well as glucose and lipid homeostasis genes [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Baeza-Raja, 2013, p75 neurotrophin receptor is a clock gene that regulates oscillatory components of circadian and metabolic networks, Journal of Neuroscience source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-body Bmal1 knockout mice show fasting hypoglycemia, reduced plasma insulin levels and increased adiposity.

    “whole-body knockout (KO) mice of Bmal1 show fasting hypoglycemia, reduced plasma insulin levels, increased adiposity [16–18].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Rudic, 2004, BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis, PLoS Biology source

      Not checked in the free run.

    • cites [17] Marcheva, 2010, Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes, Nature source

      Not checked in the free run.

    • cites [18] Kennaway, 2013, Global loss of bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A high-fat diet may alter the function of the circadian clock, with an altered period of the locomotor activity rhythm and changes in the rhythms of core clock genes in adipose and liver tissue.

    “Even a high-fat diet may alter the function of the circadian clock, with an altered period of the locomotor activity rhythm and changes in the rhythms of the core clock genes in adipose and liver tissue [35–40,49].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [35] Kohsaka, 2007, High-fat diet disrupts behavioral and molecular circadian rhythms in mice, Cell Metabolism source

      Not checked in the free run.

    • cites [36] Barnea, 2009, High-fat diet delays and fasting advances the circadian expression of adiponectin signaling components in mouse liver, Endocrinology source

      Not checked in the free run.

    • cites [37] Hsieh, 2010, Abnormal expressions of circadian-clock and circadian clock-controlled genes in the livers and kidneys of long-term, high-fat-diet-treated mice, International Journal of Obesity (London) source

      Not checked in the free run.

    • cites [38] Mendoza, 2008, High-fat feeding alters the clock synchronization to light, Journal of Physiology source

      Not checked in the free run.

    • cites [39] Pendergast, 2013, High-fat diet acutely affects circadian organisation and eating behavior, European Journal of Neuroscience source

      Not checked in the free run.

    • cites [40] Coomans, 2013, Detrimental effects of constant light exposure and high-fat diet on circadian energy metabolism and insulin sensitivity, FASEB Journal source

      Not checked in the free run.

    • cites [49] Coomans, 2013, The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity, Diabetes source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    FDG-PET analysis revealed increased glucose uptake by skeletal muscle and brown adipose tissue in ID2 knockout mice.

    “Fluorodeoxyglucose-positron emission tomography (FDG-PET) analysis revealed increased glucose uptake by skeletal muscle and brown adipose tissue in the LD2 KO mice [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Mathew, 2013, Ablation of the ID2 gene results in altered circadian feeding behavior, and sex-specific enhancement of insulin sensitivity and elevated glucose uptake in skeletal muscle and brown adipose tissue, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The majority of null mutations in circadian clock components are associated with leanness, despite normophagia or hyperphagia, indicating that global clock gene disruption affects energy metabolism in a complex manner.

    “In fact, the majority of null mutations in the circadian clock components are associated with leanness, despite normophagia or hyperphagia, indicating that global clock gene disruption affects energy metabolism in a complex manner.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Both Clock mutant and Bmal1 knockout mice exhibit delayed recovery from insulin-induced hypoglycemia, impaired glucose tolerance and blunted insulin sensitivity.

    “Both Clock mutant and Bmal1 KO mice exhibit delayed recovery from insulin-induced hypoglycemia, impaired glucose tolerance and blunted insulin sensitivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Feeding behavior and/or glucose concentrations are more important to set basal insulin and glucagon secretion than a direct SCN input.

    “Clearly, feeding behavior and/or glucose concentrations are more important to set basal insulin and glucagon secretion than a direct SCN input.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Muscle-specific Bmal1 KO animals showed reduced protein levels of GLUT4 and an impaired insulin-stimulated glucose uptake in their muscles.

    “These animals showed reduced protein levels of GLUT4 and an impaired insulin-stimulated glucose uptake in their muscles.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Dyar, 2014, Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock, Molecular Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The hyperglycemia observed in whole body KO animals may be due primarily to a reduced insulin release and not so much to insulin resistance.

    “For instance, the hyperglycemia observed in the whole body KO animals may be due primarily to a reduced insulin release and not so much to insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In humans, before waking, glucose production and glucose concentrations are increased while at the same time glucose utilization is high.

    “A similar situation occurs in humans; before waking, glucose production and glucose concentrations are increased while at the same time glucose utilization is high [61].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Bolli, 1984, The “Dawn-Phenomenon” – a common occurrence in both non-insulin-dependent and insulin-dependent diabetes mellitus, New England Journal of Medicine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Electrical stimulation of the SCN results in hyperglycaemia, an effect that can be prevented by blocking ANS activity with α and β-adrenergic blockers.

    “They showed that electrical stimulation of the SCN resulted in hyperglycaemia, an effect that could be prevented by blocking ANS activity by means of (i.p.) administration of α and β-adrenergic blockers [64,65].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Fujii, 1989, Involvement of adrenergic mechanism in hyperglycemia due to SCN stimulation, Hormone and Metabolic Research source

      Not checked in the free run.

    • cites [65] Nagai, 1988, Electrical stimulation of the suprachiasmatic nucleus of the hypothalamus causes hyperglycemia, Hormone and Metabolic Research source

      Not checked in the free run.

28 of 28

  • The paper relies on this without support.

    Disruption of biological rhythms, most profoundly with shift work, increases the risk of developing obesity and type 2 diabetes mellitus.

    “It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM.”

  • The paper relies on this without support.

    Skeletal muscle is the major site for glucose uptake in the organism, taking up more than 80% of glucose after a meal.

    “because skeletal muscle is the major site for glucose uptake in the organism, i.e., after a meal >80% of the glucose is taken up by muscle tissue.”

  • The paper relies on this without support.

    Whole body circadian gene KO animal observations were key in raising awareness of the role of the circadian clock in glucose metabolism, but were unable to distinguish the contribution of separate tissues.

    “The observations in whole body circadian gene KO animals were key in raising this awareness, but were unable to distinguish the contribution of separate tissues.”

  • The paper relies on this without support.

    Many KO animals are insulin sensitive at a young age.

    “many KO animals are insulin sensitive at a young age”

  • The paper relies on this without support.

    Many rhythms in the liver show a rapid phase-shift when the timing of food availability is shifted, unlike the SCN.

    “unlike the SCN many rhythms in the liver show a rapid phase-shift when the timing of food availability is shifted.”
5 of 5

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.

  • Whole-body Bmal1 knockout has opposing reported effects on insulin sensitivity

    Major

    The clock gene knock-out section says Bmal1 knockout mice have blunted insulin sensitivity, while the adipose tissue section says whole-body Bmal1 knockout increases insulin sensitivity. Neither statement qualifies the comparison by age or experimental condition.

  • ID2 knockout is called LD2 knockout

    Minor

    The text introduces the gene as ID2 and reference [34] describes ablation of ID2, but the corresponding knockout mice are called LD2 KO mice in the body text.

2 of 2

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Authors
Kalsbeek, A., la Fleur, S., & Fliers, E.
Affiliations
  • Netherlands Institute for Neuroscience (NL)
  • Amsterdam UMC Location University of Amsterdam (NL)
Corresponding author
Kalsbeek, Andries
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2014-07
Volume
3
Issue
4
Pages
372-383
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2014.03.002
PMC
PMC4060304
OpenAlex
W2140968650
Semantic Scholar
42607ad7a615a9c6d01bf6812457d7d6b37fcf9e
Cited by
338
References
156
Citations by year
2026: 24 · 2025: 29 · 2024: 31 · 2023: 29 · 2022: 32 · 2021: 27 · 2020: 33 · 2019: 28 · 2018: 27 · 2017: 29 · 2016: 23 · 2015: 22 · 2014: 4
FWCI
2.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by-nc-nd)
Funders
NWO-ZonMw (TOP91207036)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
circadian clock, glucose metabolism, glucose homeostasis, type 2 diabetes, obesity, insulin resistance, shift work, biological rhythms, beta-cell dysfunction, visceral fat

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 ›

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