New innovative treatment prevents diabetes
Researchers from the Liston Laboratory at The Babraham Institute recently published a study on the preventive therapy of diabetes in mice. They were able to prevent 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 great therapeutic potential when translated into the 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 islet inflammation, which is a hallmark of type 1 diabetes.”
For more than 35 years, there have been failed 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 was something more causing it to worsen 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 therefore approached this problem by identifying the pathways that decide whether stressed insulin-producing pancreatic cells survive or die, and therefore determine the development of the disease.
They hoped to find a way to stop this stress-related death, preventing the descent into diabetes without having to focus solely on the immune system. First, the researchers needed to know which pathways would affect 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, which determines the level of Manf in cells. While type 1 and type 2 diabetes in patients usually have different causes and different genetics, the GLIS3-MANF pathway is a common feature of both conditions and is therefore an attractive target for treatment.
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 those cells to produce more of the pro-survival protein Manf, reversing the life-or-death decision in favor of continued survival. To test their treatment, the researchers treated mice susceptible to spontaneously developing autoimmune diabetes. Treatment of mice in a prediabetic state resulted in a lower rate of diabetes development from 58% to 18%. This research in mice is a crucial first step in developing treatments for human patients.
“The key advantage of targeting this particular pathway is that it is highly likely to work 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 serious complications arise in patients whose pancreatic beta cells are under chronic stress from the need to make more and more insulin. By treating early type 2 diabetes with this or a similar approach, we have the potential to prevent progression to the major side effects of late-stage type 2 diabetes.”
Reference: “Gene 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, November 16 Biomolecules.
The study was funded by the Research Council for Biotechnology and Biological Sciences, Vlaams Institutut voor Biotechnologie and The Research Foundation – Flanders.