Nature | Biological Clock and Dawn Phenomenon——The Circadian Regulation Mechanism of Insulin Sensitivity

Editor | xi Under normal physiological conditions, liver sugar production peaks before and after awakening to prevent hypoglycemia during sleep and provide energy for neurocognitive and motor activities after awakening; at the same time, the liver inhibits insulin gluconeogenesis Sensitivity also peaks at the time of awakening to respond to anticipated upcoming eating behaviors, promote the absorption of dietary nutrients, and supplement energy reserves that are reduced during sleep.

These two mechanisms restrict each other, along with fluctuations in insulin levels, maintain the stability of blood sugar throughout the day.

How to regulate the circadian rhythm of insulin sensitivity? There is no clear answer to this physiological question.

On March 24, 2021, Professor Sun Zheng from Baylor College of Medicine and Professor Chen Li from Qilu Hospital of Shandong University jointly published a research paper entitled REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity in Nature, reporting on the hypothalamic optic chiasm The REV-ERB gene of GABA neurons in the nucleus (SCN) region controls the circadian rhythm of insulin suppression of liver gluconeogenesis.

This research is of great significance for our in-depth understanding of the timing and air conditioning control of peripheral glucose metabolism in the central nervous system.

(Image courtesy: Xiaodie Hu, Instagram ID: isabellamomomo) REV-ERB-α and REV-ERB-β are members of the nuclear receptor family and drug targets in the molecular biological clock.
Their expression is enriched in the GABA nerve in the SCN area of ​​the hypothalamus Yuan (SCNGABA).

The expression of REV-ERB presents a significant circadian rhythm and reaches a peak before awakening.

Glucose clamp analysis showed that wild-type (WT) mice have significant circadian rhythms in three aspects: systemic insulin sensitivity, insulin sensitivity to inhibit glycogen production, and the background level of liver sugar production.
The KO mice that specifically knocked out REV-ERB-α and REV-ERB-β by SCNGABA only showed the most significant impaired glucose tolerance during awakening.

This phenomenon is not affected by eating and exercise behavior.

Further research found that the firing activity of SCNGABA neurons in KO mice was consistent with the temporal rhythm of changes in glucose tolerance, and the increase in firing activity was mainly related to the increase in the amplitude of excitatory postsynaptic current (mEPSC).

REV-ERB in the hypothalamus regulates the expression of G protein signal transduction regulator Rgs16 and Takusan family genes.

The rhythmic expression of the above genes in SCN of KO mice is impaired.

In WT mice, specific activation of SCNGABA neurons or high expression of the above genes only causes impaired glucose tolerance during awakening.

For KO mice, specifically inhibiting SCNGABA neurons can improve impaired glucose tolerance during wakefulness.

More interestingly, the researchers induced the rhythmic expression of exogenous REV-ERB in SCNGABA neurons in KO mice.

When the rhythm of exogenous REV-ERB is in phase with the normal endogenous REV-ERB in WT mice, it can improve the glucose metabolism phenotype of KO mice during wakefulness; non-in-phase expression can not improve the glucose metabolism phenotype, which proves The importance of rhythmic expression.

The clinical significance of this study is to provide a molecular explanation for the "dawn phenomenon".

Dawn phenomenon refers to the fact that diabetic patients can control their blood sugar well and stable during most of the night or during the day, but have high blood sugar at dawn, especially after breakfast.

Dawn phenomenon is different from reactive hyperglycemia after night hypoglycemia caused by overdose of hypoglycemic agents (Su Mujie phenomenon).

REV-ERB KO mice only show abnormal glucose metabolism when they are awakened, suggesting that the circadian clock disturbance may lead to the dawn phenomenon.

The researchers used continuous dynamic blood glucose monitoring to divide the patients with type 2 diabetes into the dawn phenomenon group and the non-dawn phenomenon group.
The peripheral blood of the patients was collected at different time points to detect the dynamic expression of multiple circadian clock-related genes in peripheral blood lymphocytes.
Monitor the dynamic changes of serum insulin, melatonin, growth hormone, and cortisol levels.

Using the cardiopulmonary coupling-polysomnography recording system, it was found that in the case of no difference in sleep status, patients with dawn phenomenon compared with patients without dawn phenomenon, the expression rhythm of REV-ERB-α and REV-ERB-β existed Significant differences.

Therefore, the neuroregulation and molecular mechanism of insulin sensitivity rhythm revealed by this study is not only an explanation of physiological phenomena, but also helpful to the understanding and treatment of clinical phenomena.

Dr.
Guolian Ding from the Obstetrics and Gynecology Hospital of Fudan University, Dr.
Xin Li from Baylor College of Medicine, Dr.
Xinguo Hou from Qilu Hospital of Shandong University and Dr.
Wenjun Zhou from Baylor College of Medicine are the co-first authors of this article.
Other participating researchers include the First Affiliated Hospital of Nanjing Medical University Dr.
Yingyun Gong, Dr.
Wenbo Li from Baylor College of Medicine, Dr.
Fuqiang Liu and Jia Song and Jing Wang from Shandong University Qilu Hospital, Dr.
Yanlin He from Pennington Biomedical Research Center of Louisiana State University, Professor Yong Xu from Baylor College of Medicine, etc.

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