Common protein is important player in diabetes

An egg white that is common in the body plays an important role in regulating glucose levels, says new research conducted in the Cell Signal Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) and Riken Center of Integrative Medical Sciences . Called CNOT3, this egg white was found to secrete a set of genes that would otherwise cause insulin-producing cells, which is related to the development of diabetes.

Diabetes is a common disorder that causes very high blood glucose levels. Untreated, it can lead to serious health problems such as kidney failure, heart disease, and vision loss. This disorder occurs when there is not enough insulin in the body or when insulin-induced responses are weakened. Insulin normally releases glucose into cells for energy use and thus, without it, builds up glucose in the blood. Insulin deficiency is often due to the failure of the pancreatic beta cells, which normally synthesize and secrete insulin, to stop functioning.

“We know that deficiencies in beta cells can lead to high blood glucose levels and, ultimately, diabetes.” said Dr. Dina Mostafa, former PhD candidate in the Unit and first author of the paper published in Communication Biology. “Our results suggest that CNOT3 has a hand in this and plays an important role in maintaining normal beta cell function.”

Disabling CNOT3 found to lead to diabetes in mice:

CNOT3 is a jack-of-all-trades. Many organs in the body express it, and it regulates different genes in different tissues. But its activity has a common basis – it helps keep cells alive, healthy, and functioning properly. It does this through several different mechanisms, such as producing the right proteins or suppressing certain genes.

Here, researchers examined their function in islet cells from pancreatic tissue in mice. These islands are supposedly difficult to work with, and take up only one to two percent of the panko, but they are where the beta cells lie.

The researchers first looked at whether CNOT3 expression differed in diabetic mice compared to non-diabetic mice. Looking at these islands, they found that there was a significant reduction in CNOT3 in the diabetic islands as opposed to the non-diabetic ones.

To further investigate the function of the protein, the researchers blocked their production in the beta cells of otherwise normal mice. At four weeks the animals’ metabolism functioned normally, but by the eighth week they had developed an intolerance to glucose, and by 12 weeks they had complete diabetes.

Without CNOT3, the researchers found that some genes, which are normally eliminated in beta cells, turn on and start producing proteins. Under normal circumstances, these genes are silenced because once activated, they cause all sorts of problems for the beta cells, such as stopping the secretion of insulin in response to glucose.

“We do not yet know much about these types of genes, such as what their normal function is and the mechanism involved in their silencing,” said Drs. Mostafa. “So, it was very nice to find that CNOT3 was an important factor in keeping them off.”

The messenger RNA connection:

Further research into the cellular mechanisms behind this found a surprising link between CNOT3 and the messenger RNA of these normally disabled genes. A messenger RNA (mRNA) is a single-stranded molecule that corresponds to the genetic sequence of a gene and is essential for synthesizing egg whites.

Under normal circumstances, the mRNA of these genes is barely released. But once CNOT3 was removed, the researchers found that the mRNA was much more stable. In fact, egg white was produced from the stabilized mRNA, which has adverse effects on normal tissue function. This suggests that at least one way in which these genes are eliminated is through the destabilization of their mRNA, driven by CNOT3.

“This study is a step towards understanding the molecular mechanisms that regulate normal beta cell function,” said Drs. Mostafa. “Ultimately, it may contribute to new ways to prevent and treat diabetes.”

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Reference: “Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA death assay” by Dina Mostafa, Akiko Yanagiya, Eleni Georgiadou, Yibo Wu, Theodoros Stylianides, Guy A. Rutter, Toru Suzuki and Tadashi Yamamoto, 28 August 2020, Communication Biology.
DOI: 10.1038 / s42003-020-01201-y

Besides Dr. Mostafa included the research group Dr. Akiko Yanagiya and Professor Tadashi Yamamoto of the Cell Signal Unit of OIST, Dr. Eleni Georgiadou and Professor Guy A. Rutter of Imperial College London, Dr. Yibo Wu and Dr. Toru Suzuki of Riken Center of Integrative Medical Sciences, and Dr. Theodoros Stylianides of Loughborough University.