Researcher at Liston Institute Babraham Institute Recently, we published a study on preventive therapy for diabetes in mice. They were able to prevent the development of diabetes in mice by altering signaling pathways in pancreatic cells to prevent stress-induced cell death. This therapy targets pathways common to both types of diabetes, making it a promising treatment option with great therapeutic potential when translated into the clinical setting.
Dr. Kailsah Singh, a former researcher in the Liston lab, explains their findings:
For over 35 years, attempts to prevent the development of type 1 diabetes have failed. Previous approaches have sought to target the autoimmune nature of the disease, but Dr. Adrian Liston, senior group leader of the Immunology Research Program, believes that the immune response and other causes of late-stage exacerbation are more likely. I wanted to find out if there are any.
As the Liston lab sought to understand the role of cell death in the development of diabetes, the goal was to identify the pathways that determine whether stressed pancreatic insulin-producing cells live or die, thereby determining disease development. and I tackled this problem.
Their hope was to find a way to stop this stress-related death and prevent the progression to diabetes without having to focus solely on the immune system. I needed to know the route. In previous studies, they were able to identify Manf as a protective protein against stress-induced cell death and Glis3, which sets the level of her Manf in cells. Although the patient’s type 1 and type 2 diabetes usually have different causes and different genetics, the GLIS3-MANF pathway is an attractive target for treatment because it is a common feature of both conditions.
To manipulate the Manf pathway, researchers developed a modified virus-based gene delivery system known as the AAV gene delivery system. AAV targets beta cells, enabling these cells to make more of the pro-survival protein Manf, favoring life-or-death decisions for continued survival. To test their treatment, the researchers treated mice susceptible to spontaneous development of autoimmune diabetes. Treatment of prediabetic mice reduced the incidence of diabetes from 58% to 18%. This study in mice is an important first step toward developing therapeutics for human patients.
“A major advantage of targeting this particular pathway is that it likely works in both type 1 and type 2 diabetes,” explains Dr. Adrian Liston. “In type 2 diabetes, the primary problem is insulin insensitivity in the liver, but most of the serious complications are chronic stress on pancreatic beta cells from the need to make more and more insulin. “Treatment of early stage type 2 diabetes with this or a similar approach may prevent progression to the major adverse events of late stage type 2 diabetes.”
See also: “Gene delivery of Manf into pancreatic islet beta cells protects NOD mice from developing type 1 diabetes” Kailas Singh, Orian Bricard, Jason Horton, Mikaela Björkvist, More Thorstenson, Cheng Kang Luo, Loriana Mascari , Emanuela Passing, Chantal Mathieu, James Dooley, Adrian Liston, 16 November 2022, biomolecules.
This work was funded by the Biotechnology and Biological Sciences Research Council, the Vlaams Instituut voor Biotechnologie, and the Research Foundation – Flanders.