Circadian clock gene Rev-erb linked to daybreak phenomenon in sort 2 diabetes

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Researchers at Baylor College of Medicine may have found an explanation for the phenomenon of dawn, an abnormal rise in blood sugar only in the morning that has been seen in many patients with type 2 diabetes. Photo credit: Baylor College of Medicine

Researchers at Baylor College of Medicine, Shandong University in China, and other institutions may have found an explanation for the dawn phenomenon, an abnormal rise in blood sugar only in the morning that has been seen in many patients with type 2 diabetes. They report in the journal Nature that mice lacking the circadian clock gene called Rev-erb in the brain have properties similar to those of the dawn phenomenon.

The researchers then examined Rev-erb gene expression in patients with type 2 diabetes and compared a group with twilight phenomenon to a group without diabetes. They found that gene expression followed a different temporal pattern between these two groups. The results support the idea that an altered daily rhythm of expression of the Rev-erb gene could underlie the dawn phenomenon. Future investigations may lead to therapies.

“We started this study to investigate the function of Rev-erb in the brain,” said co-author Dr. Zheng Sun, Associate Professor of Medical Endocrinology, Diabetes and Metabolism in Baylor. “We are interested in this gene because it is a ‘druggable’ part of the circadian clock with potential clinical uses. Rev-erb is only expressed during the day but not at night. When we started we didn’t know where it would be lead us. “

The researchers first developed a mouse model by turning off the Rev-erb gene in GABA neurons. They chose this approach because the expression of the gene is highly enriched in a specific area of ​​the brain called the suprachiasmatic nucleus, which is mainly composed of GABA neurons.

An unexpected finding

“We saw something very interesting in these mice,” said Sun. “They were only glucose intolerant in the evenings – that is, they had high levels of glucose – mice are nocturnal, which means they get active in the evening like humans do in the morning.”

When the body wakes up and ingests food, insulin is secreted from the pancreas to signal the body to lower blood sugar. Insulin is more effective at waking up at this task than at other times of the day. This high insulin sensitivity is probably due to the fact that the body anticipates the feeding behavior when it wakes up. Mice have a high level of insulin sensitivity in the evening, and humans in the morning.

Sun and colleagues found that the abnormally higher glucose levels observed in Rev-erb knockout mice in the evening were due to insufficient suppression of liver glucose production by insulin. Their data show an essential role of the neural Rev-erb in regulating the insulin sensitivity rhythm in the liver, independent of eating behavior or the basal glucose production in the liver.

Next, the researchers wanted to understand how defects in Rev-erb gene expression in the brain can lead to changes in the liver’s ability to respond to insulin. They discovered that the suprachiasmatic core GABA neurons in Rev-erb knockout mice had higher fire activity than the neurons of normal mice when the animals woke up, and that this neuronal hyperactivity was sufficient and necessary to cause glucose intolerance in the evening cause.

In normal mice, these GABA neurons drop their fire activity in the evening, which lowers blood sugar levels. Interestingly, through the re-expression of Rev-erb in the knockout mice, the researchers found that Rev-erb expression is only required during the day, but not at night, which corresponds to the strongly oscillating expression pattern of endogenous Reverb. inheritance in normal condition.

Connection with the phenomenon of dawn

Mice with higher glucose levels in the evening reminded Sun and colleagues of the dawn phenomenon seen in people with type 2 diabetes. “Given the similarities of the phenomenon in mice and humans, we thought that this gene we are studying could possibly be linked to the biology of dawn phenomena in diabetics,” said Sun, a member of the Dan L Duncan Comprehensive Cancer Center and from Baylor to the Huffington Center on Aging.

Working with Shandong University’s Qilu Hospital in China, researchers tracked 27 type 2 diabetes patients with continuous glucose monitoring. They found that although the patients had diabetes of similar severity in terms of their baseline glucose levels, obesity, and other parameters, about half of the patients had a twilight phenomenon while the other half did not.

“We collected patients’ blood at different times of the day and measured expression in white blood cells of the Rev-erb gene, which has been reported to correlate well with the central clock in the brain,” Sun said. “Interestingly, we found that expression of the gene followed a temporal pattern that was different between those with and without dawn,” said Sun. “We propose that the altered temporal expression pattern of this gene could explain twilight phenomena in humans. It is possible that a drug will be used in the future to regulate this gene to treat the disease.”

A gatekeeper against insulin resistance in the brain

More information:
Guolian Ding et al., REV-ERB in GABAergic Neurons, Control the Daily Insulin Sensitivity of the Liver, Nature (2021). DOI: 10.1038 / s41586-021-03358-w Provided by Baylor College of Medicine

Quote: The circadian clock gene Rev-erb related to the phenomenon of dawn in type 2 diabetes (2021, March 25) was found on March 25, 2021 from https://medicalxpress.com/news/2021-03-circadian- clock-gene-rev-erb- retrieved. linked.html

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