New Molecular Mechanism That Regulates Insulin Uncovered

Scientists at the Research Center for Molecular Medicine of the Austrian Academy of Sciences have demonstrated that targeting the chromatin protein SMNDC1 will stimulate alpha cells to produce insulin.

The study findings are published in the journal Cell Reports in a paper titled, “SMNDC1 links chromatin remodeling and splicing to regulate pancreatic hormone expression.”

“Insulin expression is primarily restricted to the pancreatic β cells, which are physically or functionally depleted in diabetes,” wrote the researchers. “Identifying targetable pathways repressing insulin in non-β cells, particularly in the developmentally related glucagon-secreting α cells, is an important aim of regenerative medicine. Here, we perform an RNA interference screen in a murine α cell line to identify silencers of insulin expression.”

Previous research has shown that alpha cells can be converted into beta cells by genetic overexpression involving a combination of transcription factors.

Tamara Casteels, a PhD student in the lab of Stefan Kubicek, PhD, investigated the question of which factors repress insulin production in alpha cells, to identify factors that when inhibited could induce the expression of this important hormone.

Casteels was able to show that reducing the expression of the chromatin protein SMNDC1 leads to the insulin gene being switched on in alpha cells.

This effect was observed not only in a mouse cell line, but also in primary human islets of Langerhans.

Kubicek explained: “Splicing is a step in mRNA processing in which the noncoding intron sequences are cut out of the pre-mRNA. We have shown that the knockdown of SMNDC1 leads to splicing changes at hundreds of genes. Interestingly, one of these genes encodes the chromatin remodeler ATRX, to which SMNDC1 also binds directly. We find that loss of SMNDC1 reduces the abundance of both ATRX mRNA and ATRX protein. This, in turn, causes upregulation of the important beta cell transcription factor PDX1, which is well-known to stimulate insulin production.”

The findings reveal fundamental insights into the regulation of insulin in alpha cells. Initial attempts to regulate SMNDC1 in beta cells further indicate that the protein also influences insulin production there.

“The amount of insulin induced in alpha cells after SMNDC1 had been knocked-down, are significantly lower than those induced in beta cells,” Kubicek said. “And as an essential gene, complete loss of SMNDC1 can impair the viability of most cell types.”

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