A surprising protein player in diabetes

Date:
August 28, 2020
Source:
Okinawa Institute of Science and Technology (OIST) Graduate
University
Summary:
A study of pancreatic beta cells has found a link between a commonly
found protein, a subset of switched-off genes and the development
of diabetes.



FULL STORY ==========================================================================
A protein that's common throughout the body plays a key 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 protein was found to silence a set of genes that would otherwise
cause insulin-producing cells to malfunction, which is related to the development of diabetes.


========================================================================== Diabetes is a common disorder that causes very high blood glucose
levels. Left untreated, it can lead to serious health problems like kidney failure, heart disease, and vision loss. This disorder occurs when there
isn't enough insulin in the body or when insulin-induced responses are weakened. Insulin normally lets glucose into cells for energy-use and so, without it, glucose builds up in the blood instead. A lack of insulin
is often because the pancreatic beta cells, which normally synthesize
and secrete insulin, have stopped functioning correctly.

"We know that defects in beta cells can lead to high levels of glucose
in the blood and, eventually, diabetes." said Dr. Dina Mostafa, former
PhD student in the Unit and first author of the paper published in Communications Biology.

"Our results suggest that CNOT3 has a hand in this and plays a key
role in maintaining normal beta cell function." Knocking out CNOT3
found to lead to diabetes in mice CNOT3 is a jack-of-all-trades. Many
organs throughout the body express it, and it regulates different genes
in different tissues. But its activity has a common basis -- it helps
to keep cells alive, healthy, and functioning correctly. It does this
through several different mechanisms, such as producing the right proteins
or suppressing certain genes.

Here, researchers studied its function in islet cells from pancreatic
tissue in mice. These islets are notoriously difficult to work with,
taking up just only one to two percent of the pancreas, but they're
where the beta cells are located.



==========================================================================
The researchers first looked at whether CNOT3 expression differed in
diabetic mice compared with non-diabetic mice. By looking at these
islets, they found that there was a significant decrease in the CNOT3
in the diabetic islets as opposed to the non-diabetic ones.

To further investigate the protein's function, the researchers blocked its production in the beta cells of otherwise normal mice. For 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 full-blown diabetes.

Without CNOT3, the researchers found that some genes, which are normally switched off in beta cells, switch on and start to produce proteins. Under normal circumstances, these genes are silenced because once they switch
on, they cause all kinds of problems for the beta cells, such as stopping
them from secreting insulin in response to glucose.

"We still don't know that much about these kinds of genes, such as what
their normal function is and the mechanism that's involved in their
silencing," Dr.

Mostafa said. "So, it was very rewarding to find that CNOT3 in an
important factor in keeping them switched 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 switched-off genes.

A messenger RNA (mRNA) is a single strand molecule that corresponds to
the genetic sequence of a gene and is essential for synthesizing proteins.

Under normal circumstances, the mRNA of these genes hardly expresses. But
once CNOT3 was removed, the researchers found that the mRNA was much
more stable. In fact, protein was produced from the stabilized mRNA,
which have unfavorable effects on normal tissue function. This suggests
that at least one way that these genes are kept switch off is through
the destabilization of their mRNA, driven by CNOT3.

"This study is a step towards understanding the molecular mechanisms
that govern normal beta cell function," Dr. Mostafa said. "Ultimately,
it could contribute to new ways of preventing and treating diabetes."

========================================================================== Story Source: Materials provided by Okinawa_Institute_of_Science_and_Technology_(OIST)
Graduate_University. Original written by Lucy Dickie. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Dina Mostafa, Akiko Yanagiya, Eleni Georgiadou, Yibo Wu, Theodoros
Stylianides, Guy A. Rutter, Toru Suzuki, Tadashi Yamamoto. Loss of
b-cell identity and diabetic phenotype in mice caused by disruption
of CNOT3- dependent mRNA deadenylation. Communications Biology,
2020; 3 (1) DOI: 10.1038/s42003-020-01201-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200828081042.htm

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