New Innovative Treatment Prevents Diabetes

Diabetes is a chronic condition characterized by high levels of sugar (glucose) in the blood. It is caused by a problem with the hormone insulin, which regulates the amount of glucose in the body. There are two main types of diabetes: Type 1, in which the body does not produce enough insulin, and Type 2, in which the body does not properly use the insulin it does produce.

Researchers from the Liston lab at the Babraham Institute have 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 that is common to both types of diabetes, making it a promising treatment option with great therapeutic potential when translated into a clinical setting.

Dr. Kailsah Singh, a former researcher in Liston’s lab, described their findings: “Our results show that MANF can prevent damage to beta cells by preventing inflammation in the islets, 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 sought to target the autoimmune nature of the disease, but Dr. Adrian Liston, Senior Group Leader in the Immunology research programme, wanted to investigate whether there were more triggers for late-stage deterioration than just the immune response.

Liston’s laboratory 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 cells of the pancreas live or die, and therefore determine the development of the disease. .

Their hope was to find a way to stop this stress-related death by preventing the onset of diabetes without having to focus solely on the immune system. First, the researchers needed to know which pathways would affect 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 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 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. AAV targets beta cells and allows these 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 prediabetic mice resulted in a lower rate of diabetes development from 58% to 18%. This research in mice is a key first step in developing treatments for human patients.

“A major advantage of targeting this particular pathway is the high likelihood that it will 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 where the beta cells of the pancreas are chronically stressed by the need to produce more and more insulin. By treating early type 2 diabetes with this approach, or a similar one, we have the potential to block progression to major adverse events in late-stage type 2 diabetes.”

Reference: “Manf gene delivery in pancreatic islet beta cells protects NOD mice from developing type 1 diabetes” by Kailash Singh, Orian Bricard, Jeason Haughton, Mikaela Björkqvist, Moa Thorstensson, Zhengkang Luo, Loriananto Changeci Mathieu, James Dooley and Adrian Liston, 16 Nov 2022, Biomolecules.
DOI: 10.3390/biom12101493

The study was funded by the Biotechnology and Biological Sciences Research Council, the Vlaams Instituut voor Biotechnologie and the Research Foundation – Flanders.