Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes

Abstract

The circadian system generates endogenous rhythms of approximately 24 h, the synchronisation of which are vital for healthy bodily function. The timing of many physiological processes, including glucose metabolism, are coordinated by the circadian system, and circadian disruptions that desynchronise or misalign these rhythms can result in adverse health outcomes. In this review, we cover the role of the circadian system and its disruption in glucose metabolism in healthy individuals and individuals with type 2 diabetes mellitus. We begin by defining circadian rhythms and circadian disruption and then we provide an overview of circadian regulation of glucose metabolism. We next discuss the impact of circadian disruptions on glucose control and type 2 diabetes. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying the impact of circadian disruption on glucose metabolism may aid in improving glycaemic control.

Keywords: Beta cell function; Circadian disruption; Circadian misalignment; Circadian rhythm; Diabetes; Glucose control; Glucose metabolism; Glucose tolerance; Insulin sensitivity; Review; Type 2 diabetes mellitus.

Figures

Fig. 1

Circadian timekeeping and the alignment between environmental/behavioural rhythms and central/peripheral clocks. (a) Timing signals from the environment (e.g. light, as indicated by the image of the sun) and from behaviours (e.g. food intake, as indicated by the plate with knife and fork, and physical activity, as indicated by the runner) affect the rhythms of the central clock (i.e. the SCN) and/or peripheral clocks (shown for the pineal gland [orange], liver [brown], adrenal gland [yellow], pancreas [green], stomach [red], muscle [blue], white adipose tissue [purple] and gastrointestinal tract [grey]). Rhythms in the clock oscillators are represented by the cosine waves. Through hormonal/humoral, neural and temperature pathways (shown by the dashed blue arrows), temporal signals are also transmitted between the central clock and peripheral clocks. Through this relay of timing signals, the body’s rhythms entrain to external environmental and behavioural rhythms while, internally, the central and peripheral clocks maintain synchrony. (b) Alignment and misalignment between central clock and environmental/behavioural rhythms. Timing of the central clock, environment light exposure and behaviours are shown as yellow bars across a 24 h period. In the ‘aligned’ condition, the central clock is aligned with light exposure, wake, feeding and physically active period. In the ‘misaligned’ condition, the light exposure, wake, feeding and physical activity are shifted so that they are not aligned with the central clock. This misalignment between the central clock and the environmental and behavioural rhythms is a type of circadian disruption. (c) Alignment and misalignment between central and peripheral clocks. Timing of the central and peripheral clock rhythms are shown schematically as cosine waves across a 24 h period. In the aligned condition, the rhythms of the central and peripheral clocks are aligned. In the misaligned condition, the rhythms are dampened or flat and some rhythms are shifted such that not all are aligned. This misalignment between central and peripheral clocks is another form of circadian disruption, also called ‘internal misalignment’ or ‘internal desynchrony’. Note that the phases of the cosine waves do not necessarily show the rhythmic expression of specific clock genes but illustrate the concept of alignment (when the timing of different clocks occur at an optimal phase relationship, i.e. the timing within each rhythm’s cycle are in alignment with one another) vs misalignment (when these relationships are abnormal). GI, gastrointestinal; WAT, white adipose tissue. This figure is available as part of a downloadable slideset.

Fig. 2

Comparison of the alignment of environmental, circadian and behavioural rhythms in a modern diurnal lifestyle (a), during night-shift work (b) and during jet lag (c). Environmental light exposure patterns are determined by sunlight and artificial light. Sunlight is shown as varying by day and night; artificial light is shown as light (i.e. ‘on’) or dark (i.e. ‘off’). Endogenous circadian rhythms are illustrated by the endogenous clock and profiles of melatonin, varying by circadian day (when there is no circadian drive for melatonin production and melatonin levels are low) and circadian night (when there is circadian drive for melatonin production and melatonin levels are high). The green curve represents endogenous melatonin levels across the wake and sleep episodes, with behavioural rhythms shown as the wake and sleep episodes and feeding patterns (meals; illustrated by the plate with knife and fork). In the modern lifestyle (a), there is relative alignment between the daylight, artificial light, circadian day, wake period and meal timing. However, note that the sleep episode and, therefore, the artificial light exposure and circadian phase are typically delayed relative to the solar night, because of the choice by most to remain awake many hours after sun set and often awakening after sunrise. The melatonin curve shows robust rhythm and is aligned to the environmental and behavioural rhythms. During shift work (b), the wake period and meal ingestion occur during the circadian night, with artificial lighting during the wake episode. With this acute misalignment, there is a dampened melatonin rhythm. Jet lag (c) occurs in response to rapid shifts in time zone. While the sunlight and artificial light align with the wake period and meal ingestion in this scenario, they are inverted compared with the circadian day–night pattern and the melatonin profile is dampened. This figure is available as part of a downloadable slideset.

Fig. 3

Effect of misalignment between the central clock and the behavioural/environmental cycle on glucose tolerance. (a) In-laboratory experimental conditions designed to test the effect of alignment vs misalignment on glucose tolerance. In the alignment condition, room light and wake occur during the circadian day, when melatonin is low. A test meal (blue arrow) is given during the wake period to assess glucose tolerance during alignment. In the misalignment condition, room light and wake occur during the circadian night, when circadian drive for melatonin production is high. A test meal (orange arrow) is given during the wake period to assess glucose tolerance during misalignment. (b, c) Glucose tolerance is impaired in misaligned vs aligned conditions during in-laboratory experimental protocols of both gradual and rapid misalignment. In a forced desynchrony protocol (b), in which misalignment is gradual (see text for more details), postprandial glucose and late-phase postprandial insulin (timing of meal indicated by black bar) were higher in the misaligned (orange closed circles) vs aligned (blue open circles) condition (n = 10; mean ± SEM; p<0.001 and p<0.06, respectively, with statistical significance for effect of misalignment). In a simulated shift-work protocol (c), in which misalignment occurred rapidly (see text for more details), postprandial glucose and insulin were both higher in the misaligned (orange closed circles) vs aligned (blue open circles) condition (n = 14; mean ± SEM; p=0.013 and p=0.001, respectively). In both experimental protocols, the results indicated that circadian misalignment impaired glucose tolerance, in part via reduced insulin sensitivity. Data in (b, c) adapted from [20] and [21] under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium. This figure is available as part of a downloadable slideset.

Fig. 4

Diagram illustrating the impact of circadian and behavioural influences on glycaemic control and the potential transition to diabetes. The relationship between insulin secretion and insulin sensitivity is shown by the two hyperbolae for normoglycaemia (blue line) and dysglycaemia (orange line). When insulin sensitivity decreases, insulin secretion increases to maintain normoglycaemia (moving from right to left along the blue line). If and when insulin secretion is unable to compensate for decreased insulin sensitivity, the curve shifts to the left and impaired glucose tolerance develops (moving from right to left along the yellow line, insulin secretion does not rise sufficiently to counter the decrease in insulin sensitivity). Experimental evidence indicates that insulin sensitivity is impaired by circadian misalignment, sleep restriction and, with less strong evidencea, behavioural/environmental evening. Beta cell function is impaired by circadian evening and recent circadian misalignment with sleep restriction. Glucose tolerance has been shown to be impaired by circadian evening, circadian misalignment, substantial sleep restriction, recent circadian misalignment with sleep restriction, and behavioural/environmental evening. The circadian and behavioural impact on glycaemic control can, thus, affect the shift from normoglycaemia to dysglycaemia and the transition to diabetes. This figure is available as part of a downloadable slideset.