Review of Trends Neurosci︱Research progress on biological clock and circadian rhythm of blood glucose

Written by ︱ Peng Fei ︱ Sizhen Wang The biological clock provides signals for the circadian rhythm of baseline blood glucose and the circadian rhythm of glucose tolerance
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The central circadian clock is located in the suprachiasmatic nucleus (SCN) within the hypothalamus
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SCN rhythm signaling regulates the physiological circadian rhythm of endogenous glucose production and hepatic insulin sensitivity through neuroendocrine mechanisms
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Disturbances in the molecular circadian clock are associated with prolonged dawn phenomenon in patients with type 2 diabetes
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The dawn phenomenon refers to early morning-specific hyperglycemia without nighttime hypoglycemia, which affects nearly half of diabetic patients and lacks targeted treatment
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A variety of neural and secretory factors may play important roles in the physiological circadian rhythm and dawn phenomenon of glucose metabolism
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 On April 21, 2022, the team of Zheng Sun from Baylor College of Medicine published a review article titled "Circadian clock, diurnal glucose metabolic rhythm, and dawn phenomenon" in Trends in Neurosciences, summarizing the role of the central circadian clock in blood glucose metabolism day and night.
The regulation of rhythm, to explore the mechanism of the dawn phenomenon of diabetes
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Research Advances Biological clocks and environmental changes work together to generate behavioral, hormonal, and metabolic circadian rhythms
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The mammalian molecular circadian clock consists of interlocking transcription-translation feedback loops [1]
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The transcription factors BMAL1 and CLOCK form heterodimers and bind to E-box elements in the promoter/enhancer regions of target genes and activate their transcription
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BMAL1/CLOCK target genes include the clock gene Period (PER), Cryptochrome (CRY) and REV-ERB
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PER and CRY proteins form heterodimers that interact with BMAL1/CLOCK and counteract BMAL1/CLOCK-mediated transcriptional activation, while the nuclear receptor REV-ERB interacts with the ROR element (RORE) in the BMAL1 promoter/enhancer region.
) to inhibit BMAL1 transcription
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Due to negative feedback regulation, the levels of PER, CRY, and REV-ERB transcripts and proteins begin to decay once they reach a certain threshold until the point at which they fail to repress BMAL1/CLOCK, followed by another wave of transcriptional activation with a rhythm cycle of approximately for 24 hours
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Clock genes are also involved in other transcription factors [2]
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Clock genes generate signal outputs through various downstream target genes, providing temporal cues for various physiological processes consistent with changes in the circadian environment
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 In mammals, the circadian clock consists of a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks in other tissues [3]
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The SCN central clock can direct peripheral clocks through behavioral changes or neurohumoral signals, the exact mechanism being unclear
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The SCN mainly contains gamma-aminobutyric acid (GABA) neurons
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The spontaneous firing activity of SCNGABA neurons exhibited a cell-autonomous circadian rhythm, peaking during the day and troughing at night
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The SCN transmits light-transmitted temporal information to other parts of the brain through direct or indirect neural projections or secreted factors
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The SCN directly or indirectly innervates about several brain regions, including the paraventricular zone (SPZ), paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), and arcuate nucleus (ARC) [4]
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The PVN is an important relay center that transmits SCN signals to the autonomic nervous system (ANS) nuclei via the intermediolateral cell column (IML), sympathetic nucleus, and dorsal motor nucleus of the vagus (DMV), parasympathetic nerves [5, 6]
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Both the autonomic nervous system and various hormones may be involved in the signal output of the SCN (Figure 1)
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Figure 1 The SCN central circadian clock can regulate peripheral metabolic organs and endogenous glucose production (EGP) through multiple neurohumoral pathways (Image source: Peng F et al.
, Trends Neurosci, 2022) In patients with dawn phenomenon, although early morning insulin requirements increased, but no changes in insulin levels or insulin clearance [7,8], suggesting that the dawn may be caused by insulin resistance rather than abnormal insulin secretion or clearance
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The dawn phenomenon is associated with an abnormal increase in endogenous glucose production (EGP) in the liver in the morning [9,10]
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Continuous glucose monitoring found that T2D patients with dawn phenomenon showed different REV-ERBα/β expression rhythms compared with type 2 diabetes (T2D) patients without dawn phenomenon [11]
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REV-ERBα/β knockout (REV-GABA-KO) in GABAergic neurons in the mouse brain results in glucose intolerance and hepatic insulin resistance only during wakefulness but not during sleep, similar to prolonged dawn phenomenon
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In a population study, sleep quality and clock gene expression were associated with the dawn phenomenon in T2D [12], supporting a role for the neural circadian clock in the dawn phenomenon in T2D
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 Basal blood glucose rhythm: Baseline preprandial blood glucose levels in animals and healthy humans exhibit a circadian rhythm under a regular light/dark cycle, peaking during wakefulness and troughing during sleep [13–15] 
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In SCN-injured animals, the circadian rhythm of baseline glucose disappeared [13,16], and the rhythm of PEPCK expression in the liver was also disrupted [17]
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SCN lesions or hepatic sympathectomy, but not hepatic parasympathectomy, blocked PVN GABA agonist-induced hyperglycemia [18]
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In another study, either hepatic sympathectomy or hepatic parasympathectomy abolished baseline glucose circadian rhythms without affecting glucocorticoid levels [15,19]
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At the same time, complete denervation of sympathetic and parasympathetic inputs to the liver had no effect [19]
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Compared with normal healthy subjects, the phase of fasting glucose fluctuations in prediabetic patients is altered, and the peak blood glucose level is shifted to the evening [20]
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Analysis of postmortem hypothalamic tissue showed that T2D patients had a reduced number of SCN neurons compared with normal subjects [21], suggesting a possible SCN signaling blockade in T2D
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REV-ERB knockdown or molecular manipulation of SCNGABA neurons did not abrogate the circadian rhythm of baseline hepatic endogenous glucose production nor did it alter baseline glucose levels
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Therefore, a clock gene output pathway independent of REV-ERB might explain baseline glucose circadian regulation
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 Postprandial blood glucose rhythms: Human and animal studies have shown that glucose tolerance peaks during wakefulness and troughs during sleep [11, 22–24]
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Glucose-clamp CLAMP analysis in mice revealed that the circadian rhythm of insulin sensitivity can be attributed to increased sensitivity to insulin-mediated EGP inhibition during wakefulness [11,24]
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The co-occurrence of high baseline glucose and high insulin sensitivity during wakefulness may seem counterintuitive, but it is understandable from an evolutionary perspective
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The need for EGP to maintain euglycemia gradually increases as the body goes through sleep/fasting phases and peaks shortly after waking up before meals, as EGP is required to support cognitive and motor activity during fasting foraging behavior
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And once a meal is eaten, it would be beneficial to effectively inhibit EGP to prevent postprandial hyperglycemia
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This complex regulation is achieved by accumulating the potential for EGP to be inhibited by insulin, allowing baseline EGP to rise continuously during sleep before breakfast, and the arrival of insulin after breakfast exploits this potential to rapidly complete the transition from high baseline EGP levels The transition to low postprandial EGP levels
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If this mechanism is disturbed, the high baseline EGP levels after the arousal meal do not fall back quickly, resulting in the prolonged dawn phenomenon after breakfast (Figure 2)
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Depletion of REV-ERBα/β in mouse GABAergic neurons (REV-GABA-KO) resulted in glucose intolerance and hepatic insulin resistance only during wakefulness, but not during sleep
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Induction of specific REV-ERBα re-expression in SCNGABA neurons of REV-GABA-KO mice rescues time-dependent glucose resistance [11]
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These results suggest that the SCN clock gene is required for the circadian rhythm of glucose tolerance and hepatic insulin sensitivity
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Figure 2.
Baseline endogenous glucose production (EGP) and its sensitivity to insulin both peak during normal physiological arousal
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(Source: Peng F et al.
, Trends Neurosci, 2022) Summary and Outlook In conclusion, under normal physiological conditions, baseline endogenous glucose production and its sensitivity to insulin show similar circadian rhythms, reaching peak
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The brain's central circadian clock controls the rise in hepatic insulin sensitivity upon awakening in anticipation of eating after awakening
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Disruption of circadian clock-mediated anticipatory regulation may contribute to the prolonged dawn phenomenon in type 2 diabetes
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How the central circadian clock controls peripheral metabolic organs to coordinate systemic insulin sensitivity through neurohumoral mechanisms requires further investigation
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 Link to the original text: https://doi.
org/10.
1016/j.
tins.
2022.
03.
010 Exchange doctoral students Peng Fei and postdoctoral fellows Li Xin from Baylor College of Medicine, Dr.
Xiao Fang from the Second Affiliated Hospital of Shandong University and Dr.
Zhao Ruxing from Qilu Hospital of Shandong University Participated in the writing of the review, and Professor Sun Zheng was the corresponding author of the article
.

Professor Sun Zheng's laboratory welcomes students and scholars to exchange, visit and cooperate: https:// 
.

If you are interested, please contact: zheng.
sun@bcm.
edu Talent recruitment [1] "Logical Neuroscience" is looking for an associate editor/editor/operation position (online office) Selected articles from previous issues [1] Front Aging Neurosci Review︱Star Double-edged sword role of glial cells in neurovascular unit after cerebral ischemia [2] HBM︱ Region-based method for spatial standardization of brain MRI images to achieve accurate registration of brain regions [3] J Neuroinflammation︱ Ying Peng's group Revealing the regulatory role of microglia mitophagy in morphine-induced central nervous system inflammatory suppression【4】Curr Biol︱The relationship between novelty detection and surprise and recency in the primate brain【5】Neurosci Bull︱Qian Ling Jia's research group revealed that homocysteine ​​affects cognitive function by regulating DNA methylation during chronic stress [6] Front Aging Neurosci︱Ma Tao's team revealed that traditional Chinese medicine compounds can improve Alzheimer's disease through multiple pathways and multiple targets Mechanism of energy metabolism in disease【7】Aging Cell︱Gao Xu’s team found that good sleep quality can delay the accelerated aging caused by air pollution【8】Autophagy︱Shen Hanming’s research group revealed that autophagy-related protein WIPI2 regulates mitochondrial outer membrane protein degradation and mitochondrial The new mechanism of autophagy [9] Neuron's heavy review ︱ Sheng Zuhang's team focused on the important role of axonal mitochondrial maintenance and energy supply in neurodegenerative diseases and post-neural injury repair [10] Cell Death Dis︱ Kong Hui et al.
The role of the P2X7/NLRP3 inflammasome pathway in early diabetic retinopathy recommended for high-quality scientific research training courses [1] Symposium on Patch Clamp and Optogenetics and Calcium Imaging Technologies May 14-15 Tencent Conference [2] Research Skills︱Part 4th NIR Brain Function Data Analysis Class (Online: 2022.
4.
18~4.
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