Circadian clocks and insulin resistance

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.

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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.

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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.

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Correspondence to Andries Kalsbeek.

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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.

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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.

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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

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