A major breakthrough in diabetes research! Both artemisinin and GABA allow alpha cells to produce insulin
December 13, 2016 Source: Bio Valley
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)]; Over the years, in order to induce this transformation, scientists around the world have tried a variety of methods using stem cells or adult cells. Their efforts have led to a basic understanding of the molecular mechanisms involved in beta cell development, but compounds that succeed in achieving this are lacking.
Stefan Kubicek, team leader of the CeMM Center for Molecular Medicine Research at the Austrian Academy of Sciences, and his team eventually took the lead: in their latest study published in the Cell Journal (doi:10.1016/j.cell.2016.11.010), they confirmed Artemisin promotes this transformation. Using a specially designed, fully automated test method, they tested the effects of a representative drug library on alpha cells cultured in vitro and found that this antimalarial drug was able to meet the requirements. Stefan Kubicek explains, "Through our research, we were able to confirm that artemisinin alters the epigenetic processes of glucagon-producing alpha cells and induces profound changes in their biochemical functions."
In the islets of the pancreas, alpha and beta cells are formed together with at least three other highly specialized cell types, which are the central control centers for regulating blood glucose in the body. As a hormone produced by β cells, insulin indicates a decrease in blood sugar, and glucagon produced by α cells has an opposite effect. But these cells are flexible: previous studies have shown that alpha cells can replenish insulin-producing cells after a large beta cell loss. The epigenetic major regulator Arx was identified as a molecule that plays a key role in this transformation.
Stefan Kubicek said, "Arx regulates many genes that play a vital role in the function of alpha cells. Previous studies by our collaborators, Patrick Collombat, have demonstrated that gene knockout of Arx leads to the conversion of alpha cells to beta. Cells." However, this effect is only observed in living model organisms - it is completely unclear whether additional factors from surrounding cells or even distant organs also work. To rule out these factors, the Kubicek team worked with the team of Jacob Hecksher Sorensen from Novo Nordisk to design special alpha and beta cell lines to analyze them in isolation from their environment. They confirmed that the Arx deletion is sufficient to alter alpha cell identity without relying on in vivo effects.
Using these cell lines, researchers are now able to test their compound libraries and found that artemisinin exerts the same effect as the Arx deletion. Working closely with Christoph Bock, Giulio Superti-Furga and Tibor Harkany, they revealed the molecular mechanism of artemisinin remodeling alpha cells: this compound binds to a protein called gephyrin Above, where the bridge protein activates the GABA receptor. Subsequently, a series of biochemical reaction changes lead to insulin production. Another Patrick Collombat study published in the same issue of Cell in the same period (doi:10.1016/j.cell.2016.11.002) confirmed that in model mice, injection of GABA also resulted in the conversion of alpha cells to beta cells, suggesting that these two The substances target the same mechanism.
In addition to these cell line experiments, the effects of this anti-malarial drug were also confirmed in model organisms: the Stefan Kubicek team and their collaborators observed in the diabetic model zebrafish, mice and rats once injected into Artemisia annua It increases the number of beta cells and improves the homeostasis of blood glucose. Given that the molecular targets of artemisinin in zebrafish, rodents, and humans are very similar, the effects on alpha cells will also be higher in the human body. Stefan Kubicek said, "Significantly, the long-term effects of artemisinin need to be tested. In particular, the ability of human alpha cells to regenerate is still unknown to date. Furthermore, these new beta cells must be protected by the immune system. But we believe that the discovery of artemisinin and their mechanism of action can be the basis of a new type 1 diabetes treatment."
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