Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Circadian clocks and insulin resistance

Nature Reviews Endocrinology volume 15, pages 75–89 (2019)Cite this article

Subjects

Abstract

Insulin resistance is a main determinant in the development of type 2 diabetes mellitus and a major cause of morbidity and mortality. The circadian timing system consists of a central brain clock in the hypothalamic suprachiasmatic nucleus and various peripheral tissue clocks. The circadian timing system is responsible for the coordination of many daily processes, including the daily rhythm in human glucose metabolism. The central clock regulates food intake, energy expenditure and whole-body insulin sensitivity, and these actions are further fine-tuned by local peripheral clocks. For instance, the peripheral clock in the gut regulates glucose absorption, peripheral clocks in muscle, adipose tissue and liver regulate local insulin sensitivity, and the peripheral clock in the pancreas regulates insulin secretion. Misalignment between different components of the circadian timing system and daily rhythms of sleep–wake behaviour or food intake as a result of genetic, environmental or behavioural factors might be an important contributor to the development of insulin resistance. Specifically, clock gene mutations, exposure to artificial light–dark cycles, disturbed sleep, shift work and social jet lag are factors that might contribute to circadian disruption. Here, we review the physiological links between circadian clocks, glucose metabolism and insulin sensitivity, and present current evidence for a relationship between circadian disruption and insulin resistance. We conclude by proposing several strategies that aim to use chronobiological knowledge to improve human metabolic health.

Key points

  • The circadian timing system consists of a central brain clock in the hypothalamic suprachiasmatic nucleus and peripheral clocks in tissues, including the liver, muscle, adipose tissue and pancreas.

  • Misalignment between different components of the circadian timing system and daily rhythms of sleep–wake behaviour and food intake might contribute to the development of insulin resistance.

  • Strategies to improve metabolic health by circadian synchrony include modulating light exposure, modulating rhythmic behaviour and chronotherapy.

  • Circadian molecules are a promising new treatment option for insulin resistance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The circadian timing system.
Fig. 2: Circadian clocks regulate glucose metabolism, insulin sensitivity and insulin secretion.
Fig. 3: The central clock.
Fig. 4: The gut clock.
Fig. 5: The muscle clock.
Fig. 6: The white adipose tissue clock.
Fig. 7: The liver clock.
Fig. 8: The pancreas clock.
Fig. 9: Potential interventions promoting metabolic health through circadian synchrony.

Similar content being viewed by others

References

  1. World Health Organization. Global Report on Diabetes (WHO, 2016).

  2. American Diabetes Association. Standards of medical care in diabetes-2018. Diabetes Care 41, S1–S159 (2018).2018 Current guideline of the American Diabetes Association for the diagnosis and treatment of diabetes mellitus.

    Google Scholar 

  3. Ouyang, Y., Andersson, C. R., Kondo, T., Golden, S. S. & Johnson, C. H. Resonating circadian clocks enhance fitness in cyanobacteria. Proc. Natl Acad. Sci. USA 95, 8660–8664 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Woelfle, M. A., Ouyang, Y., Phanvijhitsiri, K. & Johnson, C. H. The adaptive value of circadian clocks: an experimental assessment in cyanobacteria. Curr. Biol. 14, 1481–1486 (2004).

    CAS  PubMed  Google Scholar 

  5. Dibner, C., Schibler, U. & Albrecht, U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517–549 (2010).

    CAS  PubMed  Google Scholar 

  6. Stenvers, D. J., Jonkers, C. F., Fliers, E., Bisschop, P. H. & Kalsbeek, A. Nutrition and the circadian timing system. Progress Brain Res. 199, 359–376 (2012).

    CAS  Google Scholar 

  7. Lowrey, P. L. & Takahashi, J. S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu. Rev. Genom. Hum. Genet. 5, 407–441 (2004).

    CAS  Google Scholar 

  8. Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002).

    CAS  PubMed  Google Scholar 

  9. Roberts, H. J. Afternoon glucose tolerance testing: a key to the pathogenesis, early diagnosis and prognosis of diabetogenic hyperinsulinism. J. Am. Geriatr. Soc. 12, 423–472 (1964).

    CAS  PubMed  Google Scholar 

  10. Van Cauter, E., Polonsky, K. S. & Scheen, A. J. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr. Rev. 18, 716–738 (1997).Seminal review on the diurnal rhythms of human glucose metabolism.

    PubMed  Google Scholar 

  11. Gibson, T. & Jarrett, R. J. Diurnal variation in insulin sensitivity. Lancet 2, 947–948 (1972).

    CAS  PubMed  Google Scholar 

  12. Boden, G., Ruiz, J., Urbain, J. L. & Chen, X. Evidence for a circadian rhythm of insulin secretion. Am. J. Physiol. 271, E246–E252 (1996).

    CAS  PubMed  Google Scholar 

  13. Saad, A. et al. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes 61, 2691–2700 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Morris, C. J. et al. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. Proc. Natl Acad. Sci. USA 112, E2225–E2234 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Stephan, F. K. & Zucker, I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc. Natl Acad. Sci. USA 69, 1583–1586 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Czeisler, C. A., Weitzman, E., Moore-Ede, M. C., Zimmerman, J. C. & Knauer, R. S. Human sleep: its duration and organization depend on its circadian phase. Science 210, 1264–1267 (1980).

    CAS  PubMed  Google Scholar 

  17. Saper, C. B., Scammell, T. E. & Lu, J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437, 1257–1263 (2005).

    CAS  PubMed  Google Scholar 

  18. Strubbe, J. H. & van Dijk, G. The temporal organization of ingestive behaviour and its interaction with regulation of energy balance. Neurosci. Biobehav. Rev. 26, 485–498 (2002).

    PubMed  Google Scholar 

  19. Scheer, F. A., Morris, C. J. & Shea, S. A. The internal circadian clock increases hunger and appetite in the evening independent of food intake and other behaviors. Obesity 21, 421–423 (2013).First study showing the control of human appetite by the endogenous circadian timing system.

    PubMed  Google Scholar 

  20. Herrera-Moro Chao, D. et al. The suprachiasmatic nucleus modulates the sensitivity of arcuate nucleus to hypoglycemia in the male rat. Endocrinology 157, 3439–3451 (2016).

    CAS  PubMed  Google Scholar 

  21. Blancas-Velazquez, A., Mendoza, J., Garcia, A. N. & la Fleur, S. E. Diet-induced obesity and circadian disruption of feeding behavior. Front. Neurosci. 11, 23 (2017).

    PubMed  PubMed Central  Google Scholar 

  22. Buckley, T. M. & Schatzberg, A. F. On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J. Clin. Endocrinol. Metab. 90, 3106–3114 (2005).

    CAS  PubMed  Google Scholar 

  23. van Raalte, D. H. & Diamant, M. Steroid diabetes: from mechanism to treatment? Neth. J. Med. 72, 62–72 (2014).

    PubMed  Google Scholar 

  24. Ramracheya, R. D. et al. Function and expression of melatonin receptors on human pancreatic islets. J. Pineal Res. 44, 273–279 (2008).

    CAS  PubMed  Google Scholar 

  25. Tuomi, T. et al. Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metab. 23, 1067–1077 (2016).

    CAS  PubMed  Google Scholar 

  26. Claustrat, B., Brun, J. & Chazot, G. The basic physiology and pathophysiology of melatonin. Sleep Med. Rev. 9, 11–24 (2005).

    PubMed  Google Scholar 

  27. Moller, N. & Jorgensen, J. O. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr. Rev. 30, 152–177 (2009).

    PubMed  Google Scholar 

  28. Morris, C. J., Aeschbach, D. & Scheer, F. A. Circadian system, sleep and endocrinology. Mol. Cell. Endocrinol. 349, 91–104 (2012).

    CAS  PubMed  Google Scholar 

  29. Willoughby, J. O. & Martin, J. B. The suprachiasmatic nucleus synchronizes growth hormone secretory rhythms with the light-dark cycle. Brain Res. 151, 413–417 (1978).

    CAS  PubMed  Google Scholar 

  30. La Fleur, S. E., Kalsbeek, A., Wortel, J., Fekkes, M. L. & Buijs, R. M. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Diabetes 50, 1237–1243 (2001).

    PubMed  Google Scholar 

  31. Coomans, C. P. et al. The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity. Diabetes 62, 1102–1108 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Morris, C. J., Purvis, T. E., Mistretta, J. & Scheer, F. A. Effects of the internal circadian system and circadian misalignment on glucose tolerance in chronic shift workers. J. Clin. Endocrinol. Metab. 101, 1066–1074 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Morris, C. J. et al. The human circadian system has a dominating role in causing the morning/evening difference in diet-induced thermogenesis. Obesity 23, 2053–2058 (2015).

    PubMed  Google Scholar 

  34. Krauchi, K. & Wirz-Justice, A. Circadian rhythm of heat production, heart rate, and skin and core temperature under unmasking conditions in men. Am. J. Physiol. 267, R819–R829 (1994).

    CAS  PubMed  Google Scholar 

  35. Moran-Ramos, S. et al. The suprachiasmatic nucleus drives day-night variations in postprandial triglyceride uptake into skeletal muscle and brown adipose tissue. Exp. Physiol. 102, 1584–1595 (2017).

    CAS  PubMed  Google Scholar 

  36. Amir, S., Shizgal, P. & Rompre, P. P. Glutamate injection into the suprachiasmatic nucleus stimulates brown fat thermogenesis in the rat. Brain Res. 498, 140–144 (1989).

    CAS  PubMed  Google Scholar 

  37. Bamshad, M., Song, C. K. & Bartness, T. J. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am. J. Physiol. 276, R1569–R1578 (1999).

    CAS  PubMed  Google Scholar 

  38. Hussain, M. M. & Pan, X. Circadian regulation of macronutrient absorption. J. Biol. Rhythms 30, 459–469 (2015).

    CAS  PubMed  Google Scholar 

  39. Scheving, L. A. Biological clocks and the digestive system. Gastroenterology 119, 536–549 (2000).

    CAS  PubMed  Google Scholar 

  40. Hoogerwerf, W. A. Role of clock genes in gastrointestinal motility. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G549–G555 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Iwashina, I., Mochizuki, K., Inamochi, Y. & Goda, T. Clock genes regulate the feeding schedule-dependent diurnal rhythm changes in hexose transporter gene expressions through the binding of BMAL1 to the promoter/enhancer and transcribed regions. J. Nutr. Biochem. 22, 334–343 (2011).

    CAS  PubMed  Google Scholar 

  42. Nishida, T., Saito, M. & Suda, M. Parallel between circadian rhythms of intestinal disaccharidases and food intake of rats under constant lighting conditions. Gastroenterology 74, 224–227 (1978).

    CAS  PubMed  Google Scholar 

  43. Saito, M., Kato, H. & Suda, M. Circadian rhythm of intestinal disaccharidases of rats fed with adiurnal periodicity. Am. J. Physiol. 238, G97–G101 (1980).

    CAS  PubMed  Google Scholar 

  44. Hansen, J. et al. Synchronized human skeletal myotubes of lean, obese and type 2 diabetic patients maintain circadian oscillation of clock genes. Sci. Rep. 6, 35047 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Perrin, L. et al. Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretion. Mol. Metab. 4, 834–845 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Guo, H., Brewer, J. M., Lehman, M. N. & Bittman, E. L. Suprachiasmatic regulation of circadian rhythms of gene expression in hamster peripheral organs: effects of transplanting the pacemaker. J. Neurosci. 26, 6406–6412 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Guo, H., Brewer, J. M., Champhekar, A., Harris, R. B. & Bittman, E. L. Differential control of peripheral circadian rhythms by suprachiasmatic-dependent neural signals. Proc. Natl Acad. Sci. USA 102, 3111–3116 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Yamanaka, Y., Honma, S. & Honma, K. Scheduled exposures to a novel environment with a running-wheel differentially accelerate re-entrainment of mice peripheral clocks to new light-dark cycles. Genes Cells 13, 497–507 (2008).

    CAS  PubMed  Google Scholar 

  49. Wolff, G. & Esser, K. A. Scheduled exercise phase shifts the circadian clock in skeletal muscle. Med. Sci. Sports Exercise 44, 1663–1670 (2012).

    Google Scholar 

  50. Reznick, J. et al. Altered feeding differentially regulates circadian rhythms and energy metabolism in liver and muscle of rats. Biochim. Biophys. Acta 1832, 228–238 (2013).

    CAS  PubMed  Google Scholar 

  51. Opperhuizen, A. L. et al. Feeding during the resting phase causes profound changes in physiology and desynchronization between liver and muscle rhythms of rats. Eur. J. Neurosci. 44, 2795–2806 (2016).

    PubMed  Google Scholar 

  52. Feneberg, R. & Lemmer, B. Circadian rhythm of glucose uptake in cultures of skeletal muscle cells and adipocytes in Wistar-Kyoto, Wistar, Goto-Kakizaki, and spontaneously hypertensive rats. Chronobiol. Int. 21, 521–538 (2004).

    CAS  PubMed  Google Scholar 

  53. Dyar, K. A. et al. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock. Mol. Metab. 3, 29–41 (2014).

    CAS  PubMed  Google Scholar 

  54. Liu, J. et al. CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1 in male mice. Endocrinology 157, 2259–2269 (2016).

    CAS  PubMed  Google Scholar 

  55. Hong, S. et al. Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat. Med. 23, 223–234 (2017).

    CAS  PubMed  Google Scholar 

  56. Verrillo, A. et al. Differential roles of splanchnic and peripheral tissues in determining diurnal fluctuation of glucose tolerance. Am. J. Physiol. 257, E459–E465 (1989).

    CAS  PubMed  Google Scholar 

  57. van Moorsel, D. et al. Demonstration of a day-night rhythm in human skeletal muscle oxidative capacity. Mol. Metab. 5, 635–645 (2016).

    PubMed  PubMed Central  Google Scholar 

  58. Otway, D. T., Frost, G. & Johnston, J. D. Circadian rhythmicity in murine pre-adipocyte and adipocyte cells. Chronobiol. Int. 26, 1340–1354 (2009).

    CAS  PubMed  Google Scholar 

  59. Ramanathan, C. et al. Cell type-specific functions of period genes revealed by novel adipocyte and hepatocyte circadian clock models. PLOS Genet. 10, e1004244 (2014).

    PubMed  PubMed Central  Google Scholar 

  60. Huang, T. S. et al. Induction of circadian rhythm in cultured human mesenchymal stem cells by serum shock and cAMP analogs in vitro. Chronobiol. Int. 26, 242–257 (2009).

    CAS  PubMed  Google Scholar 

  61. Gomez-Santos, C. et al. Circadian rhythm of clock genes in human adipose explants. Obesity 17, 1481–1485 (2009).

    CAS  PubMed  Google Scholar 

  62. Kolbe, I. et al. The SCN clock governs circadian transcription rhythms in murine epididymal white adipose tissue. J. Biol. Rhythms 31, 577–587 (2016).

    CAS  PubMed  Google Scholar 

  63. Wehrens, S. M. T. et al. Meal timing regulates the human circadian system. Curr. Biol. 27, 1768–1775 (2017).Study demonstrating the effect of meal timing on adipose tissue clock gene expression in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Su, Y., Foppen, E., Zhang, Z., Fliers, E. & Kalsbeek, A. Effects of 6-meals-a-day feeding and 6-meals-a-day feeding combined with adrenalectomy on daily gene expression rhythms in rat epididymal white adipose tissue. Genes Cells 21, 6–24 (2016).

    CAS  PubMed  Google Scholar 

  65. Loboda, A. et al. Diurnal variation of the human adipose transcriptome and the link to metabolic disease. BMC. Med. Genom. 2, 7 (2009).

    Google Scholar 

  66. Carrasco-Benso, M. P. et al. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. FASEB J. 30, 3117–3123 (2016).First study showing a circadian rhythm in insulin signalling in cultured white adipose tissue explants from humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Gliniak, C. M., Brown, J. M. & Noy, N. The retinol-binding protein receptor STRA6 regulates diurnal insulin responses. J. Biol. Chem. 292, 15080–15093 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Delezie, J. et al. The nuclear receptor REV-ERBalpha is required for the daily balance of carbohydrate and lipid metabolism. FASEB J. 26, 3321–3335 (2012).

    CAS  PubMed  Google Scholar 

  69. Shostak, A., Meyer-Kovac, J. & Oster, H. Circadian regulation of lipid mobilization in white adipose tissues. Diabetes 62, 2195–2203 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. van der Veen, D. R., Shao, J., Chapman, S., Leevy, W. M. & Duffield, G. E. A diurnal rhythm in glucose uptake in brown adipose tissue revealed by in vivo PET-FDG imaging. Obesity 20, 1527–1529 (2012).

    PubMed  Google Scholar 

  71. Lee, P. et al. Brown adipose tissue exhibits a glucose-responsive thermogenic biorhythm in humans. Cell Metab. 23, 602–609 (2016).

    CAS  PubMed  Google Scholar 

  72. Sakamoto, K. et al. Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain. J. Biol. Chem. 273, 27039–27042 (1998).

    CAS  PubMed  Google Scholar 

  73. Akhtar, R. A. et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550 (2002).

    CAS  PubMed  Google Scholar 

  74. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).

    CAS  PubMed  Google Scholar 

  75. Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

    CAS  PubMed  Google Scholar 

  76. Kornmann, B., Schaad, O., Bujard, H., Takahashi, J. S. & Schibler, U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLOS Biol. 5, e34 (2007).

    PubMed  PubMed Central  Google Scholar 

  77. Robles, M. S., Cox, J. & Mann, M. In-vivo quantitative proteomics reveals a key contribution of post-transcriptional mechanisms to the circadian regulation of liver metabolism. PLOS Genet. 10, e1004047 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. Mauvoisin, D. et al. Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver. Proc. Natl Acad. Sci. USA 111, 167–172 (2014).

    CAS  PubMed  Google Scholar 

  79. Gooley, J. J. & Chua, E. C. Diurnal regulation of lipid metabolism and applications of circadian lipidomics. J. Genet. Genomics 41, 231–250 (2014).

    CAS  PubMed  Google Scholar 

  80. Abbondante, S., Eckel-Mahan, K. L., Ceglia, N. J., Baldi, P. & Sassone-Corsi, P. Comparative circadian metabolomics reveal differential effects of nutritional challenge in the serum and liver. J. Biol. Chem. 291, 2812–2828 (2016).

    CAS  PubMed  Google Scholar 

  81. Krishnaiah, S. Y. et al. Clock regulation of metabolites reveals coupling between transcription and metabolism. Cell Metab. 25, 1206 (2017).

    CAS  PubMed  Google Scholar 

  82. Lamia, K. A., Storch, K. F. & Weitz, C. J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl Acad. Sci. USA 105, 15172–15177 (2008).Key study showing that the hepatic clock is essential to maintain euglycemia during the fasting period in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Rudic, R. D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLOS Biol. 2, e377 (2004).

    PubMed  PubMed Central  Google Scholar 

  84. Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang, E. E. et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat. Med. 16, 1152–1156 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Jang, H. et al. SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding. Nat. Commun. 7, 12180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Tong, X. et al. DDB1-mediated CRY1 degradation promotes FOXO1-driven gluconeogenesis in liver. Diabetes 66, 2571–2582 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Macauley, M., Smith, F. E., Thelwall, P. E., Hollingsworth, K. G. & Taylor, R. Diurnal variation in skeletal muscle and liver glycogen in humans with normal health and Type 2 diabetes. Clin. Sci. 128, 707–713 (2015).

    CAS  Google Scholar 

  89. Peek, C. B. et al. Circadian clock interaction with HIF1α mediates oxygenic metabolism and anaerobic glycolysis in skeletal muscle. Cell Metab. 25, 86–92 (2017).

    CAS  PubMed  Google Scholar 

  90. Neufeld-Cohen, A. et al. Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins. Proc. Natl Acad. Sci. USA 113, E1673–E1682 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Jacobi, D. et al. Hepatic Bmal1 regulates rhythmic mitochondrial dynamics and promotes metabolic fitness. Cell Metab. 22, 709–720 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Vieira, E., Burris, T. P. & Quesada, I. Clock genes, pancreatic function, and diabetes. Trends Mol. Med. 20, 685–693 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Peschke, E. & Peschke, D. Evidence for a circadian rhythm of insulin release from perifused rat pancreatic islets. Diabetologia 41, 1085–1092 (1998).

    CAS  PubMed  Google Scholar 

  94. Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).Pivotal study showing that specific ablation of the pancreatic clock disrupts insulin secretion in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Qian, J., Block, G. D., Colwell, C. S. & Matveyenko, A. V. Consequences of exposure to light at night on the pancreatic islet circadian clock and function in rats. Diabetes 62, 3469–3478 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Pulimeno, P. et al. Autonomous and self-sustained circadian oscillators displayed in human islet cells. Diabetologia 56, 497–507 (2013).

    CAS  PubMed  Google Scholar 

  97. Saini, C. et al. A functional circadian clock is required for proper insulin secretion by human pancreatic islet cells. Diabetes Obes. Metab. 18, 355–365 (2016).Study demonstrating that CLOCK inhibition with small interfering RNA disrupts insulin secretion in cultured human pancreatic islet cells.

    CAS  PubMed  Google Scholar 

  98. Buijs, R. M., Chun, S. J., Niijima, A., Romijn, H. J. & Nagai, K. Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J. Comp. Neurol. 431, 405–423 (2001).

    CAS  PubMed  Google Scholar 

  99. Perelis, M. et al. Pancreatic beta cell enhancers regulate rhythmic transcription of genes controlling insulin secretion. Science 350, aac4250 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. Sadacca, L. A., Lamia, K. A., deLemos, A. S., Blum, B. & Weitz, C. J. An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 54, 120–124 (2011).

    CAS  PubMed  Google Scholar 

  101. Lee, J. et al. Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in β-cells. Islets 3, 381–388 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. Defronzo, R. A. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58, 773–795 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Shulman, G. I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Shulman, G. I. et al. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N. Engl. J. Med. 322, 223–228 (1990).

    CAS  PubMed  Google Scholar 

  105. Reaven, G. M., Chen, Y. D., Donner, C. C., Fraze, E. & Hollenbeck, C. B. How insulin resistant are patients with noninsulin-dependent diabetes mellitus? J. Clin. Endocrinol. Metab. 61, 32–36 (1985).

    CAS  PubMed  Google Scholar 

  106. Winocour, P. H. et al. A randomized cross-over study of the effects of proinsulin on lipid metabolism in type 2 diabetes. Diabet. Med. 8, 22–27 (1991).

    CAS  PubMed  Google Scholar 

  107. Meek, S. E., Nair, K. S. & Jensen, M. D. Insulin regulation of regional free fatty acid metabolism. Diabetes 48, 10–14 (1999).

    CAS  PubMed  Google Scholar 

  108. Unger, R. H. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 144, 5159–5165 (2003).

    CAS  PubMed  Google Scholar 

  109. Jarrett, R. J. & Keen, H. Diurnal variation of oral glucose tolerance: a possible pointer to the evolution of diabetes mellitus. Br. Med. J. 2, 341–344 (1969).First study showing an altered daily rhythm in glucose tolerance in patients with type 2 diabetes mellitus.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).First study to show metabolic disease in a clock gene knockout mouse.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Arble, D. M., Bass, J., Laposky, A. D., Vitaterna, M. H. & Turek, F. W. Circadian timing of food intake contributes to weight gain. Obes.(Silver. Spring) 17, 2100–2102 (2009).

    Google Scholar 

  112. Scheer, F. A., Hilton, M. F., Mantzoros, C. S. & Shea, S. A. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc. Natl Acad. Sci. USA 106, 4453–4458 (2009).First study demonstrating that humans develop reduced glucose tolerance when subjected to conditions of circadian misalignment.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Bass, J. & Takahashi, J. S. Circadian integration of metabolism and energetics. Science 330, 1349–1354 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Lee, J. et al. Bmal1 and β-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced beta-cell failure in mice. Mol. Cell. Biol. 33, 2327–2338 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Harfmann, B. D. et al. Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis. Skelet. Muscle 6, 12 (2016).

    PubMed  PubMed Central  Google Scholar 

  116. Paschos, G. K. et al. Obesity in mice with adipocyte-specific deletion of clock component Arntl. Nat. Med. 18, 1768–1777 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Oishi, K. et al. Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice. FEBS Lett. 580, 127–130 (2006).

    CAS  PubMed  Google Scholar 

  118. Zani, F. et al. PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and G L expression. Mol. Metab. 2, 292–305 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Grimaldi, B. et al. PER2 controls lipid metabolism by direct regulation of PPARgamma. Cell Metab. 12, 509–520 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Stenvers, D. J. et al. Dim light at night disturbs the daily sleep-wake cycle in the rat. Sci. Rep. 6, 35662 (2016).

    PubMed  Google Scholar 

  121. Shamsi, N. A. et al. Metabolic consequences of timed feeding in mice. Physiol. Behav. 128, 188–201 (2014).

    PubMed  Google Scholar 

  122. Sherman, H. et al. Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J. 26, 3493–3502 (2012).

    CAS  PubMed  Google Scholar 

  123. Kalsbeek, A., la Fleur, S. & Fliers, E. Circadian control of glucose metabolism. Mol. Metab. 3, 372–383 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Eckel-Mahan, K. & Sassone-Corsi, P. Metabolism and the circadian clock converge. Physiol. Rev. 93, 107–135 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fonken, L. K. & Nelson, R. J. The effects of light at night on circadian clocks and metabolism. Endocr. Rev. 35, 648–670 (2014).

    CAS  PubMed  Google Scholar 

  126. Woon, P. Y. et al. Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc. Natl Acad. Sci. USA 104, 14412–14417 (2007).First study showing an association between a clock gene single nucleotide polymorphism and type 2 diabetes mellitus.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Scott, E. M., Carter, A. M. & Grant, P. J. Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int. J. Obes. 32, 658–662 (2008).

    CAS  Google Scholar 

  128. Sookoian, S. et al. Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity. Am. J. Clin. Nutr. 87, 1606–1615 (2008).

    CAS  PubMed  Google Scholar 

  129. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Barker, A. et al. Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children. Diabetes 60, 1805–1812 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Ruano, E. G., Canivell, S. & Vieira, E. REV-ERB ALPHA polymorphism is associated with obesity in the Spanish obese male population. PLOS ONE 9, e104065 (2014).

    PubMed  PubMed Central  Google Scholar 

  132. Dashti, H. S. et al. Gene-environment interactions of circadian-related genes for cardiometabolic traits. Diabetes Care 38, 1456–1466 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Dashti, H. S. et al. CRY1 circadian gene variant interacts with carbohydrate intake for insulin resistance in two independent populations: Mediterranean and North American. Chronobiol. Int. 31, 660–667 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Garcia-Rios, A. et al. Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome. Chronobiol. Int. 31, 401–408 (2014).

    CAS  PubMed  Google Scholar 

  135. Garaulet, M. et al. CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids. Am. J. Clin. Nutr. 90, 1466–1475 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Loria-Kohen, V. et al. Polymorphism in the CLOCK gene may influence the effect of fat intake reduction on weight loss. Nutrition 32, 453–460 (2016).

    CAS  PubMed  Google Scholar 

  137. Corella, D. et al. CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial. Cardiovasc. Diabetol. 15, 4 (2016).

    PubMed  PubMed Central  Google Scholar 

  138. Ando, H. et al. Clock gene expression in peripheral leucocytes of patients with type 2 diabetes. Diabetologia 52, 329–335 (2009).

    CAS  PubMed  Google Scholar 

  139. Otway, D. T. et al. Rhythmic diurnal gene expression in human adipose tissue from individuals who are lean, overweight, and type 2 diabetic. Diabetes 60, 1577–1581 (2011).First study comparing in vivo clock gene expression rhythms between healthy participants, participants with obesity and patients with type 2 diabetes mellitus.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Wright, K. P. Jr. et al. Entrainment of the human circadian clock to the natural light-dark cycle. Curr. Biol. 23, 1554–1558 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Fonken, L. K. et al. Light at night increases body mass by shifting the time of food intake. Proc. Natl Acad. Sci. USA 107, 18664–18669 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Obayashi, K. et al. Exposure to light at night, nocturnal urinary melatonin excretion, and obesity/dyslipidemia in the elderly: a cross-sectional analysis of the HEIJO-KYO study. J. Clin. Endocrinol. Metab. 98, 337–344 (2013).

    CAS  PubMed  Google Scholar 

  143. McFadden, E., Jones, M. E., Schoemaker, M. J., Ashworth, A. & Swerdlow, A. J. The relationship between obesity and exposure to light at night: cross-sectional analyses of over 100,000 women in the Breakthrough Generations study. Am. J. Epidemiol. 180, 245–250 (2014).

    PubMed  Google Scholar 

  144. Obayashi, K., Saeki, K., Iwamoto, J., Ikada, Y. & Kurumatani, N. Independent associations of exposure to evening light and nocturnal urinary melatonin excretion with diabetes in the elderly. Chronobiol. Int. 31, 394–400 (2014).

    CAS  PubMed  Google Scholar 

  145. Cheung, I. N. et al. Morning and evening blue-enriched light exposure alters metabolic function in normal weight adults. PLOS ONE 11, e0155601 (2016).

    PubMed  PubMed Central  Google Scholar 

  146. Albreiki, M. S., Middleton, B. & Hampton, S. M. A single night light exposure acutely alters hormonal and metabolic responses in healthy participants. Endocr. Connect. 6, 100–110 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Versteeg, R. I. et al. Acute effects of morning light on plasma glucose and triglycerides in healthy men and men with type 2 diabetes. J. Biol. Rhythms 32, 130–142 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Opperhuizen, A. L. et al. Light at night acutely impairs glucose tolerance in a time-, intensity- and wavelength-dependent manner in rats. Diabetologia 60, 1333–1343 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Lewy, A. J. & Sack, R. L. The dim light melatonin onset as a marker for circadian phase position. Chronobiol. Int. 6, 93–102 (1989).

    CAS  PubMed  Google Scholar 

  150. Rubio-Sastre, P., Scheer, F. A., Gomez-Abellan, P., Madrid, J. A. & Garaulet, M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep 37, 1715–1719 (2014).

    PubMed  PubMed Central  Google Scholar 

  151. Cagnacci, A. et al. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin. Endocrinol. (Oxf.) 54, 339–346 (2001).

    CAS  Google Scholar 

  152. Garaulet, M. et al. Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. Metabolism 64, 1650–1657 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Bonnefond, A. & Froguel, P. The case for too little melatonin signalling in increased diabetes risk. Diabetologia 60, 823–825 (2017).

    CAS  PubMed  Google Scholar 

  154. McMullan, C. J., Schernhammer, E. S., Rimm, E. B., Hu, F. B. & Forman, J. P. Melatonin secretion and the incidence of type 2 diabetes. JAMA 309, 1388–1396 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Bonnefond, A. et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat. Genet. 44, 297–301 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Shan, Z. et al. Sleep duration and risk of type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 38, 529–537 (2015).Meta-analysis demonstrating an association between sleep duration and the incidence of type 2 diabetes mellitus.

    PubMed  Google Scholar 

  157. Stamatakis, K. A. & Punjabi, N. M. Long sleep duration: a risk to health or a marker of risk? Sleep Med. Rev. 11, 337–339 (2007).

    PubMed  PubMed Central  Google Scholar 

  158. Cappuccio, F. P., D’Elia, L., Strazzullo, P. & Miller, M. A. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 33, 414–420 (2010).

    PubMed  Google Scholar 

  159. Bosy-Westphal, A. et al. Influence of partial sleep deprivation on energy balance and insulin sensitivity in healthy women. Obes. Facts 1, 266–273 (2008).

    PubMed  PubMed Central  Google Scholar 

  160. Nedeltcheva, A. V. et al. Sleep curtailment is accompanied by increased intake of calories from snacks. Am. J. Clin. Nutr. 89, 126–133 (2009).

    CAS  PubMed  Google Scholar 

  161. Reutrakul, S. & Mokhlesi, B. Obstructive sleep apnea and diabetes: a state of the art review. Chest 152, 1070–1086 (2017).

    PubMed  PubMed Central  Google Scholar 

  162. Spiegel, K., Leproult, R. & Van Cauter, E. Impact of sleep debt on metabolic and endocrine function. Lancet 354, 1435–1439 (1999).Seminal experimental study showing the detrimental effect of sleep debt on glucose metabolism.

    CAS  PubMed  Google Scholar 

  163. Donga, E. et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J. Clin. Endocrinol. Metab. 95, 2963–2968 (2010).

    CAS  PubMed  Google Scholar 

  164. Broussard, J. L., Ehrmann, D. A., Van Cauter, E., Tasali, E. & Brady, M. J. Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study. Ann. Intern. Med. 157, 549–557 (2012).

    PubMed  PubMed Central  Google Scholar 

  165. Buxton, O. M. et al. Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes 59, 2126–2133 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Cedernaes, J. et al. A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men. J. Sleep Res. 25, 5–10 (2016).

    PubMed  Google Scholar 

  167. Rao, M. N. et al. Subchronic sleep restriction causes tissue-specific insulin resistance. J. Clin. Endocrinol. Metab. 100, 1664–1671 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. van Leeuwen, W. M. et al. Prolonged sleep restriction affects glucose metabolism in healthy young men. Int. J. Endocrinol. 2010, 108641 (2010).

    PubMed  PubMed Central  Google Scholar 

  169. Robertson, M. D., Russell-Jones, D., Umpleby, A. M. & Dijk, D. J. Effects of three weeks of mild sleep restriction implemented in the home environment on multiple metabolic and endocrine markers in healthy young men. Metabolism 62, 204–211 (2013).

    CAS  PubMed  Google Scholar 

  170. St-Onge, M. P., O’Keeffe, M., Roberts, A. L., RoyChoudhury, A. & Laferrere, B. Short sleep duration, glucose dysregulation and hormonal regulation of appetite in men and women. Sleep 35, 1503–1510 (2012).

    PubMed  PubMed Central  Google Scholar 

  171. Tasali, E., Leproult, R., Ehrmann, D. A. & Van Cauter, E. Slow-wave sleep and the risk of type 2 diabetes in humans. Proc. Natl Acad. Sci. USA 105, 1044–1049 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Stamatakis, K. A. & Punjabi, N. M. Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 137, 95–101 (2010).

    CAS  PubMed  Google Scholar 

  173. Herzog, N. et al. Selective slow wave sleep but not rapid eye movement sleep suppression impairs morning glucose tolerance in healthy men. Psychoneuroendocrinology 38, 2075–2082 (2013).

    CAS  PubMed  Google Scholar 

  174. Lee, S. W. H., Ng, K. Y. & Chin, W. K. The impact of sleep amount and sleep quality on glycemic control in type 2 diabetes: A systematic review and meta-analysis. Sleep Med. Rev. 31, 91–101 (2017). Systematic review showing the relationship between sleep and glycaemic control in patients with type 2 diabetes mellitus.

    PubMed  Google Scholar 

  175. Merikanto, I. et al. Associations of chronotype and sleep with cardiovascular diseases and type 2 diabetes. Chronobiol. Int. 30, 470–477 (2013).

    PubMed  Google Scholar 

  176. Yu, J. H. et al. Evening chronotype is associated with metabolic disorders and body composition in middle-aged adults. J. Clin. Endocrinol. Metab. 100, 1494–1502 (2015).

    CAS  PubMed  Google Scholar 

  177. Vetter, C. et al. Mismatch of sleep and work timing and risk of type 2 diabetes. Diabetes Care 38, 1707–1713 (2015). Study demonstrating the association between social jet lag and the risk of type 2 diabetes mellitus.

    PubMed  PubMed Central  Google Scholar 

  178. Parsons, M. J. et al. Social jetlag, obesity and metabolic disorder: investigation in a cohort study.Int. J. Obes. 39, 842–848 (2015).

    CAS  Google Scholar 

  179. Koopman, A. D. M. et al. The association between social jetlag, the metabolic syndrome, and type 2 diabetes mellitus in the general population: the New Hoorn study. J. Biol. Rhythms 32, 359–368 (2017).

    PubMed  PubMed Central  Google Scholar 

  180. Reutrakul, S. et al. Chronotype is independently associated with glycemic control in type 2 diabetes. Diabetes Care 36, 2523–2529 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Osonoi, Y. et al. Morningness-eveningness questionnaire score and metabolic parameters in patients with type 2 diabetes mellitus. Chronobiol. Int. 31, 1017–1023 (2014).

    CAS  PubMed  Google Scholar 

  182. Gan, Y. et al. Shift work and diabetes mellitus: a meta-analysis of observational studies. Occupat. Environ. Med. 72, 72–78 (2015). Meta-analysis showing the association between shift work and diabetes mellitus.

    Google Scholar 

  183. Vetter, C. et al. Night shift work, genetic risk, and type 2 diabetes in the UK biobank. Diabetes Care 41, 762–769 (2018).

    PubMed  PubMed Central  Google Scholar 

  184. Leproult, R., Holmback, U. & Van Cauter, E. Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss. Diabetes 63, 1860–1869 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Qian, J., Dalla Man, C., Morris, C. J., Cobelli, C. & Scheer, F. A. Differential effects of the circadian system and circadian misalignment on insulin sensitivity and insulin secretion in humans. Diabetes Obes. Metab. 20, 2481–2485 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Wefers, J. et al. Circadian misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle. Proc. Natl Acad. Sci. USA 115, 7789–7794 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Opperhuizen, A. L., van Kerkhof, L. W., Proper, K. I., Rodenburg, W. & Kalsbeek, A. Rodent models to study the metabolic effects of shiftwork in humans. Front. Pharmacol. 6, 50 (2015).

    PubMed  PubMed Central  Google Scholar 

  188. Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).

    CAS  PubMed  Google Scholar 

  189. Riemersma-van der Lek, R. F. et al. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 299, 2642–2655 (2008).

    CAS  PubMed  Google Scholar 

  190. Hu, K. et al. Progression of dementia assessed by temporal correlations of physical activity: results from a 3.5-Year, longitudinal randomized controlled trial. Sci. Rep. 6, 27742 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Sander, B., Markvart, J., Kessel, L., Argyraki, A. & Johnsen, K. Can sleep quality and wellbeing be improved by changing the indoor lighting in the homes of healthy, elderly citizens? Chronobiol. Int. 32, 1049–1060 (2015).

    PubMed  PubMed Central  Google Scholar 

  192. Chang, A.-M., Aeschbach, D., Duffy, J. F. & Czeisler, C. A. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proc. Natl Acad. Sci. 112, 1232–1237 (2015).

    CAS  PubMed  Google Scholar 

  193. Tan, X., van Egmond, L., Chapman, C. D., Cedernaes, J. & Benedict, C. Aiding sleep in type 2 diabetes: therapeutic considerations. Lancet Diabetes Endocrinol. 6, 60–68 (2018).

    PubMed  Google Scholar 

  194. Young, T. Increasing sleep duration for a healthier (and less obese?) population tomorrow. Sleep 31, 593–594 (2008).

    PubMed  PubMed Central  Google Scholar 

  195. Leproult, R., Deliens, G., Gilson, M. & Peigneux, P. Beneficial impact of sleep extension on fasting insulin sensitivity in adults with habitual sleep restriction. Sleep 38, 707–715 (2015).

    PubMed  PubMed Central  Google Scholar 

  196. Cizza, G., Piaggi, P., Rother, K. I. & Csako, G. & Sleep Extension Study, G. Hawthorne effect with transient behavioral and biochemical changes in a randomized controlled sleep extension trial of chronically short-sleeping obese adults: implications for the design and interpretation of clinical studies. PLOS ONE 9, e104176 (2014).

    PubMed  PubMed Central  Google Scholar 

  197. Riemann, D. et al. European guideline for the diagnosis and treatment of insomnia. J. Sleep Res. 26, 675–700 (2017).

    PubMed  Google Scholar 

  198. Chen, L. et al. Continuous positive airway pressure and diabetes risk in sleep apnea patients: a systemic review and meta-analysis. Eur. J. Intern. Med. 39, 39–50 (2017).Meta-analysis investigating a potential relation between obstructive sleep apnoea treatment and the risk of developing type 2 diabetes mellitus.

    PubMed  Google Scholar 

  199. Zhu, B., Ma, C., Chaiard, J. & Shi, C. Effect of continuous positive airway pressure on glucose metabolism in adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Sleep Breath. 22, 287–295 (2017).

    PubMed  Google Scholar 

  200. Martinez-Ceron, E. et al. Effect of continuous positive airway pressure on glycemic control in patients with obstructive sleep apnea and type 2 diabetes. A randomized clinical trial. Am. J. Respir. Crit. Care Med. 194, 476–485 (2016).

    PubMed  Google Scholar 

  201. Mokhlesi, B., Grimaldi, D., Beccuti, G. & Van Cauter, E. Effect of one week of CPAP treatment of obstructive sleep apnoea on 24-hour profiles of glucose, insulin and counter-regulatory hormones in type 2 diabetes. Diabetes Obes. Metab. 19, 452–456 (2017).

    CAS  PubMed  Google Scholar 

  202. Colberg, S. R. et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care 39, 2065–2079 (2016).

    PubMed  PubMed Central  Google Scholar 

  203. Buxton, O. M., Lee, C. W., L’Hermite-Baleriaux, M., Turek, F. W. & Van Cauter, E. Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R714–R724 (2003).

    CAS  PubMed  Google Scholar 

  204. Kredlow, M. A., Capozzoli, M. C., Hearon, B. A., Calkins, A. W. & Otto, M. W. The effects of physical activity on sleep: a meta-analytic review. J. Behav. Med. 38, 427–449 (2015).

    PubMed  Google Scholar 

  205. Mattson, M. P. et al. Meal frequency and timing in health and disease. Proc. Natl Acad. Sci. USA 111, 16647–16653 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. St-Onge, M. P. et al. Meal timing and frequency: implications for cardiovascular disease prevention: a scientific statement from the American Heart Association. Circulation 135, e96–e121 (2017).Statement from the American Heart Association on the effects of meal timing and frequency for metabolic health.

    PubMed  PubMed Central  Google Scholar 

  207. Jakubowicz, D., Barnea, M., Wainstein, J. & Froy, O. High caloric intake at breakfast versus dinner differentially influences weight loss of overweight and obese women. Obesity 21, 2504–2512 (2013).

    CAS  PubMed  Google Scholar 

  208. Farshchi, H. R., Taylor, M. A. & Macdonald, I. A. Beneficial metabolic effects of regular meal frequency on dietary thermogenesis, insulin sensitivity, and fasting lipid profiles in healthy obese women. Am. J. Clin. Nutr. 81, 16–24 (2005).

    CAS  PubMed  Google Scholar 

  209. Farshchi, H. R., Taylor, M. A. & Macdonald, I. A. Deleterious effects of omitting breakfast on insulin sensitivity and fasting lipid profiles in healthy lean women. Am. J. Clin. Nutr. 81, 388–396 (2005).

    CAS  PubMed  Google Scholar 

  210. Chowdhury, E. A. et al. The causal role of breakfast in energy balance and health: a randomized controlled trial in obese adults. Am. J. Clin. Nutr. 103, 747–756 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Betts, J. A. et al. The causal role of breakfast in energy balance and health: a randomized controlled trial in lean adults. Am. J. Clin. Nutr. 100, 539–547 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Versteeg, R. I. et al. Meal timing effects on insulin sensitivity and intrahepatic triglycerides during weight loss. Int. J. Obes. 42, 156–162 (2017).

    Google Scholar 

  213. Gill, S. & Panda, S. A. Smartphone app reveals erratic diurnal eating patterns in humans that can be modulated for health benefits. Cell Metab. 22, 789–798 (2015).Study demonstrating chaotic diurnal eating patterns in humans, as well as the potential clinical benefits of time-restricted feeding.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Sutton, E. F. et al. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab. 27, 1212–1221 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Holman, R. R., Sourij, H. & Califf, R. M. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 383, 2008–2017 (2014).

    CAS  PubMed  Google Scholar 

  216. Um, J. H. et al. Activation of 5′-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. J. Biol. Chem. 282, 20794–20798 (2007).

    CAS  PubMed  Google Scholar 

  217. Barnea, M. et al. Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner. Biochim. Biophys. Acta 1822, 1796–1806 (2012).

    CAS  PubMed  Google Scholar 

  218. Henriksson, E. et al. The liver circadian clock modulates biochemical and physiological responses to metformin. J. Biol. Rhythms 32, 345–358 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Baker, I. A. & Jarrett, R. J. Diurnal variation in the blood-sugar and plasma-insulin response to tolbutamide. Lancet 2, 945–947 (1972).

    CAS  PubMed  Google Scholar 

  220. Webb, I. C., Lehman, M. N. & Coolen, L. M. Diurnal and circadian regulation of reward-related neurophysiology and behavior. Physiol. Behav. 143, 58–69 (2015).

    CAS  PubMed  Google Scholar 

  221. Ter Horst, K. W. et al. Striatal dopamine regulates systemic glucose metabolism in humans and mice. Sci. Transl Med. 10, eaar3752 (2018).

    PubMed  Google Scholar 

  222. Liang, W. et al. Efficacy and safety of bromocriptine-QR in type 2 diabetes: a systematic review and meta-analysis. Horm. Metab. Res. 47, 805–812 (2015).

    CAS  PubMed  Google Scholar 

  223. Garfinkel, D. et al. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab. Syndr. Obes. 4, 307–313 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Holleman, F. & Gale, E. A. Nice insulins, pity about the evidence. Diabetologia 50, 1783–1790 (2007).

    CAS  PubMed  Google Scholar 

  225. Wallia, A. & Molitch, M. E. Insulin therapy for type 2 diabetes mellitus. JAMA 311, 2315–2325 (2014).

    PubMed  Google Scholar 

  226. Stenvers, D. J., DeVries, J. H. & la Fleur, S. E. What’s the time? Does the artificial pancreas need to know? Diabetes 62, 2173–2174 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Thabit, H. et al. Closed-loop insulin delivery in inpatients with type 2 diabetes: a randomised, parallel-group trial. Lancet Diabetes Endocrinol. 5, 117–124 (2016).

    PubMed  Google Scholar 

  228. Johannsson, G. et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J. Clin. Endocrinol. Metab. 97, 473–481 (2012).

    CAS  PubMed  Google Scholar 

  229. Quinkler, M., Miodini Nilsen, R., Zopf, K., Ventz, M. & Oksnes, M. Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. Eur. J. Endocrinol. 172, 619–626 (2015).

    CAS  PubMed  Google Scholar 

  230. Giordano, R. et al. Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison’s disease. Endocr 51, 360–368 (2016).

    CAS  Google Scholar 

  231. Zhang, E. E. et al. A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Cell 139, 199–210 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Chen, Z. et al. Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc. Natl Acad. Sci. USA 109, 101–106 (2012).

    CAS  PubMed  Google Scholar 

  233. Chen, Z., Yoo, S. H. & Takahashi, J. S. Development and therapeutic potential of small-molecule modulators of circadian systems. Annu. Rev. Pharmacol. Toxicol. 58, 231–252 (2018).

    CAS  PubMed  Google Scholar 

  234. Solt, L. A. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012).Study demonstrating beneficial metabolic effects of targeting the molecular clock with REV-ERB agonists in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. He, B. et al. The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab. 23, 610–621 (2016).Study demonstrating that nobiletin improves metabolic health in mouse models of the metabolic syndrome by strengthening the molecular clock.

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Humphries, P. S. et al. Carbazole-containing sulfonamides and sulfamides: discovery of cryptochrome modulators as antidiabetic agents. Bioorg. Med. Chem. Lett. 26, 757–760 (2016).

    CAS  PubMed  Google Scholar 

  237. Humphries, P. S. et al. Carbazole-containing amides and ureas: discovery of cryptochrome modulators as antihyperglycemic agents. Bioorg. Med. Chem. Lett. 28, 293–297 (2017).

  238. Laing, E. E. et al. Blood transcriptome based biomarkers for human circadian phase. eLife 6, e20214 (2017).

    PubMed  PubMed Central  Google Scholar 

  239. Woller, A., Duez, H., Staels, B. & Lefranc, M. A. Mathematical model of the liver circadian clock linking feeding and fasting cycles to clock function. Cell Rep. 17, 1087–1097 (2016).

    CAS  PubMed  Google Scholar 

  240. Samuel, V. T. & Shulman, G. I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J. Clin. Invest. 126, 12–22 (2016).

    Google Scholar 

  241. Wallace, T. M., Levy, J. C. & Matthews, D. R. Use and abuse of HOMA modeling. Diabetes Care 27, 1487–1495 (2004).

    PubMed  Google Scholar 

  242. Sperling, L. S. et al. The CardioMetabolic Health Alliance: working toward a new care model for the metabolic syndrome. J. Am. College Cardiol. 66, 1050–1067 (2015).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands

    Dirk Jan Stenvers, Susanne E. la Fleur & Andries Kalsbeek

  2. Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

    Frank A. J. L. Scheer

  3. Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA

    Frank A. J. L. Scheer

  4. Department of Nutrition and Movement Sciences, NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands

    Patrick Schrauwen

  5. Laboratory for Endocrinology, Department of Clinical Chemistry, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands

    Susanne E. la Fleur & Andries Kalsbeek

  6. Netherlands Institute for Neuroscience (NIN), Royal Dutch Academy of Arts and Sciences (KNAW), Amsterdam, Netherlands

    Susanne E. la Fleur & Andries Kalsbeek

Authors
  1. Dirk Jan Stenvers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank A. J. L. Scheer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick Schrauwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susanne E. la Fleur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andries Kalsbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.J.S. researched data for article, all authors provided a substantial contribution to discussion of content and wrote the article, F.A.J.L.S., P.S., S.E.L.F. and A.K. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Andries Kalsbeek.

Ethics declarations

Competing interests

F.A.J.L.S. received speaker fees from Bayer Healthcare, Kellogg Company, Philips, Pfizer, Sentara Healthcare and Vanda Pharmaceuticals. F.A.J.L.S. was supported in part by NIH grants R01DK099512, R01HL118601, R01DK102696, R01DK105072 and R01HL140574. The other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Period

The time difference between two consecutive peaks or troughs, or any other fixed point in the rhythm. In the case of daily or circadian rhythms, this period is exactly or approximately 24 h, respectively. The period of the rhythm in constant conditions is called the free-running period and is denoted by the Greek letter τ.

Amplitude

On a line graph, the amplitude is half the distance between the peak and trough of a daily or circadian rhythm.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stenvers, D.J., Scheer, F.A.J.L., Schrauwen, P. et al. Circadian clocks and insulin resistance. Nat Rev Endocrinol 15, 75–89 (2019). https://doi.org/10.1038/s41574-018-0122-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-018-0122-1

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing