Circadian System and Glucose Metabolism: Implications for Physiology and Disease

Abstract

The circadian system serves one of the most fundamental properties present in nearly all organisms: it generates 24-h rhythms in behavioral and physiological processes and enables anticipating and adapting to daily environmental changes. Recent studies indicate that the circadian system is important in regulating the daily rhythm in glucose metabolism. Disturbance of this circadian control or of its coordination relative to the environmental/behavioral cycle, such as in shift work, eating late, or due to genetic changes, results in disturbed glucose control and increased type 2 diabetes risk. Therefore, an in-depth understanding of the mechanisms underlying glucose regulation by the circadian system and its disturbance may help in the development of therapeutic interventions against the deleterious health consequences of circadian disruption.

Keywords: circadian rhythms; food timing; glucose metabolism; melatonin; sleep; type 2 diabetes.

Figure 1. Protocols to assess circadian effects

A) An inverted sleep-wake cycle protocol includes a period of extended wakefulness where sleep is displaced to the daytime (e.g., by 12 hr in this example). Study participants are sometimes required to have minimal physical activity, constant body posture, and/or constant nutritional state (e.g., constant glucose infusion). B) The Constant Routine (CR) protocol requires participants to remain awake, at rest, in a constant posture, with isocaloric intake distributed at equal intervals and under dim light conditions (to prevent the influence of light on the circadian system). CR protocols last longer than 24 hr allowing assessment of an entire circadian cycle after removal of the first few (transition) hr. C) The Forced Desynchrony (FD) protocol includes non-24-hr behavioral cycles (e.g., 28 or 20 hr, including sleep/wake and fasting/feeding cycles) under dim light conditions. The sleep:wake ratio is typically (although not necessarily) maintained at a 1:2 ratio. D) A misalignment protocol that simulates night work is compared with an alignment protocol simulating day work using a within-participant, cross-over design in randomized order. The independent effects are assessed by i) averaging breakfast (B_A and B_M) and dinner (D_A and D_M) values separately (behavioral effect); ii) averaging (B_A and D_M) and (D_A and B_M) values separately (circadian phase effect); iii) averaging (B_A and D_A) and (B_M and D_M) values within each protocol (circadian misalignment effect). The concentric circles indicate the phase relationship among environmental cycle (grey), behavioral cycle (blue), and the central clock (green) in each protocol. A filled grey/blue circle means constant environment/behaviors.

Figure 2. Different strategies to study the adverse effects of circadian disruption in rodents and humans

1) Light is the strongest Zeitgeber for the central clock. Light/dark cycles are widely used in both human and rodent experimental studies to modulate and disturb the circadian system. Environmental light conditions are often considered in human observational studies. 2) In experimental studies, behavioral misalignment with the central clock is achieved by manipulation of specific behavioral cycles. Lifestyles related to circadian disruption (as shown) are often assessed in human observational studies. 3) Considering the importance of melatonin in the circadian system, melatonin administration and suppression of endogenous melatonin (e.g. bright light treatment, pinealectomy) can be used as experimental approaches to alter the circadian system. Low nocturnal melatonin levels have also been found in T2D patients [99]. In rodent, SCN lesioning has been used as a circadian disruption model. In human postmortem studies, changes in the anatomy of the SCN has been found in Alzheimer's patients who are also known to display circadian deficits. 4) Rodent models with genetic mutations in core clock genes have been used to study the role of molecular clock. Studying the function of clock genes in human is difficult. One approach is to study polymorphisms in those genes. Another is by manipulating clock gene expression in human isolated tissues.

Figure 3. Circadian disruption at different levels

First, at a systemic level, circadian disruption occurs when environmental cycles (black square wave, e.g., light/dark cycle; which we refer to as “environmental misalignment”) and/or behavioral cycles (green square wave, e.g., sleep/wake, fasting/feeding, rest/activity cycle; “behavioral misalignment”) are misaligned relative to the central clock in the SCN (red cosine). Alternatively, exposure to light at night can shift the central clock, which can cause misalignment of the central clock with the behavioral cycle if the behavioral cycle doesn't shift, which may occur in an intensive care unit. Second, at an organismal level, circadian disruption can be caused by internal misalignment (also called “internal desynchrony”) between the central clock and peripheral clocks (blue cosine), which can be induced by, e.g., misaligned eating (although direct evidence in humans is missing). It also refers to misalignment among peripheral clocks in different organs, where peripheral clocks are in abnormal phase relationships with each other. At a tissue level, circadian disruption can be caused by desynchronization among cells within a tissue (clocks in each individual organs and/or cells are represented as black cosine) Finally, at cellular level, expression of clock genes should also follow particular phase relationships that can be disturbed. Note that the illustrated phases of the cosine/square wave curves in the Figure does not necessarily convey the time of the highest levels, but conveys a conceptual illustration of alignment (when the acrophases, or timing of peaks, occur at an optimal phase relationship) versus misalignment (when the relationships between acrophases are abnormal).