Researchers at the Babraham Institute’s Liston lab recently published a study on a preventive therapy for diabetes in mice. They were able to prevent the onset of diabetes in mice by modifying signaling pathways in pancreatic cells to prevent stress-induced cell death. The therapy targets a pathway common to both types of diabetes, making it a promising treatment option with enormous therapeutic potential when translated to a clinical setting.
Dr. Kailsah Singh, a former research associate in the Liston lab, described their findings: “Our results show that MANF can prevent beta cell damage by preventing the inflammation in 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 focused on the autoimmune nature of the disease, but Dr. Adrian Liston, senior group leader in the Immunology research program, wanted to investigate whether there were more causes for the deterioration in later stages than just the immune response.
The Liston lab sought to understand the role of cell death in the development of diabetes, and so approached this problem by identifying the pathways that decide whether stressed insulin-producing cells of the pancreas live or die, and therefore determine the development of disease.
They hoped to find a way to stop this stress-related death and prevent the decline in diabetes without having to focus solely on the immune system. First, the researchers needed to know which pathways would influence the life-or-death decision for the beta cell. 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 the cells. Although type 1 and 2 diabetes in patients usually have different causes and different genetics, the GLIS3-MANF pathway is a common feature for both conditions and therefore an attractive target for treatments.
To manipulate the Manf pathway, the researchers developed a gene delivery system based on a modified virus known as an AAV gene delivery system. The AAV targets beta cells and allows these cells to make more of the pro-survival protein Manf, tipping the life-or-death decision in favor of continued survival. To test their treatment, the researchers treated mice susceptible to the spontaneous development of autoimmune diabetes. Treating pre-diabetic mice resulted in a lower development of diabetes from 58% to 18%. This study in mice is an important first step in the development of treatments for human patients.
“An important advantage of targeting this particular pathway is the high probability that it works in both type 1 and type 2 diabetes,” explains Dr Adrian Liston. “In type 2 diabetes, while the initial problem is insulin insensitivity in the liver, most of the serious complications occur in patients whose pancreatic beta cells are chronically stressed by the need to produce more and more insulin . By treating early-stage type 2 diabetes with this or a similar approach, we have the potential to block progression to the major side effects of late-stage type 2 diabetes.”
Reference: “Gen Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development” by Kailash Singh, Orian Bricard, Jason Haughton, Mikaela Bjorkqvist, Moa Thorstensson, Zhengkang Luo, Loriana Mascali, Emanuela Pasciuto, Chantal Mathieu, James Dooley and Adrian Liston, Nov. 16 Biomolecules.
The study was funded by the Research Council of Biotechnology and Biological Sciences, Flemish Institute for Biotechnology and The Research Foundation – Flanders.