Researchers from Liston’s lab Babraham Institute Recently, a study on the preventive treatment of diabetes mellitus in rats. They were able to prevent the onset of diabetes in mice by modulating signaling pathways in pancreatic cells to prevent stress-induced cell death. The therapy targets a common pathway for both types of diabetes, making it a promising treatment option with huge therapeutic potential when translated into a clinical setting.
Dr. Kelsa Singh, a former research fellow in Liston’s lab, described their findings: “Our results show that Manv can prevent beta-cell damage by blocking inflammation in the islets, which is a hallmark of type 1 diabetes.”
For more than 35 years, there have been unsuccessful attempts to prevent the development of type 1 diabetes. Previous approaches have sought to target the autoimmune nature of the disease, but Dr. Adrian Liston, Senior Group Chair in the Immunology Research Program, wanted to investigate whether there was more to the late-stage deterioration than just the immune response.
Liston’s lab sought to understand the role of cell death in the development of diabetes, and thus approached this problem by identifying the pathways that decide whether insulin-producing cells in the pancreas live or die, and thus determine the progression of the disease.
Their hope was to find a way to stop this stress-related death, and prevent a descent into diabetes without having to focus solely on the immune system. First, the researchers had to figure out which pathways would influence the beta cell’s life-or-death decision. In previous research, they were able to identify Manf as a protective protein against stress-induced cell death, and Glis3 that determines the level of Manf in cells. While type 1 and type 2 diabetes usually have different causes and different heritabilities, the GLIS3-MANF pathway is a common feature of both conditions and is therefore an attractive target for treatment.
In order to manipulate the Manf pathway, the researchers developed a gene delivery system based on a modified virus known as the AAV gene delivery system. AAV targets beta cells, and allows these cells to produce more of the pro-survival protein Manf, altering the life-or-death decision in favor of continued survival. To test their treatment, the researchers treated mice prone to spontaneous development of autoimmune diabetes. Treating mice with prediabetes reduced the incidence of diabetes from 58% to 18%. This research in mice is a major first step in developing treatments for human patients.
“The main advantage of specifically targeting this pathway is the high likelihood of action in both type 1 and type 2 diabetes,” explains Dr. Adrian Liston. “In type 2 diabetes, while the initial problem is insulin sensitivity in the liver, the most severe complications appear in patients who suffer from chronic stress of beta cells in the pancreas due to the need to produce more and more insulin. By treating diabetes of Early Type 2 With this approach, or a similar method, we have the potential to prevent progression to major adverse events in late-stage type 2 diabetes.”
Reference: “Gene delivery from MANV to beta cells in pancreatic islets protects NOD mice from developing type 1 diabetes” By Kailash Singh, O’Rian Brikart, Jason Hutton, Michaela Björkvist, Moa Thorstenson, Zhengkang Lu, Loriana Maskali, Emanuela Pasciotto, Chantal Mathew, James Dooley, Adrienne Liston, November 16 , Biomolecules.
The study was funded by the Biotechnology and Biological Sciences Research Council, the Flemish Institute for Biotechnology, and the Research Foundation – Flanders.