Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans

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Abstract

Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show--by using two 8-d laboratory protocols--in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.

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Disruption of the Clock Components CLOCK and BMAL1 Leads to Hypoinsulinemia and Diabetes

Biliana Marcheva, Kathryn Moynihan Ramsey, Ethan D Buhr … (2010)

The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1–3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and while rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism, and insulin signaling is delayed in circadian mutant mice, and both Clock 5,6 and Bmal1 7 mutants exhibit impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival, and synaptic vesicle assembly. Remarkably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger onset of diabetes mellitus.

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Resetting of circadian time in peripheral tissues by glucocorticoid signaling.

A Balsalobre, S Brown, L Marcacci … (2000)

In mammals, circadian oscillators reside not only in the suprachiasmatic nucleus of the brain, which harbors the central pacemaker, but also in most peripheral tissues. Here, we show that the glucocorticoid hormone analog dexamethasone induces circadian gene expression in cultured rat-1 fibroblasts and transiently changes the phase of circadian gene expression in liver, kidney, and heart. However, dexamethasone does not affect cyclic gene expression in neurons of the suprachiasmatic nucleus. This enabled us to establish an apparent phase-shift response curve specifically for peripheral clocks in intact animals. In contrast to the central clock, circadian oscillators in peripheral tissues appear to remain responsive to phase resetting throughout the day.

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Slow-wave sleep and the risk of type 2 diabetes in humans.

Esra Tasali, Rachel Leproult, David A Ehrmann … (2008)

There is convincing evidence that, in humans, discrete sleep stages are important for daytime brain function, but whether any particular sleep stage has functional significance for the rest of the body is not known. Deep non-rapid eye movement (NREM) sleep, also known as slow-wave sleep (SWS), is thought to be the most "restorative" sleep stage, but beneficial effects of SWS for physical well being have not been demonstrated. The initiation of SWS coincides with hormonal changes that affect glucose regulation, suggesting that SWS may be important for normal glucose tolerance. If this were so, selective suppression of SWS should adversely affect glucose homeostasis and increase the risk of type 2 diabetes. Here we show that, in young healthy adults, all-night selective suppression of SWS, without any change in total sleep time, results in marked decreases in insulin sensitivity without adequate compensatory increase in insulin release, leading to reduced glucose tolerance and increased diabetes risk. SWS suppression reduced delta spectral power, the dominant EEG frequency range in SWS, and left other EEG frequency bands unchanged. Importantly, the magnitude of the decrease in insulin sensitivity was strongly correlated with the magnitude of the reduction in SWS. These findings demonstrate a clear role for SWS in the maintenance of normal glucose homeostasis. Furthermore, our data suggest that reduced sleep quality with low levels of SWS, as occurs in aging and in many obese individuals, may contribute to increase the risk of type 2 diabetes.