Diabetes is a chronic disease 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 produces.
Researchers from the Babraham Institute’s Liston Laboratory recently published a study of a preventive treatment for diabetes in mice. They were able to prevent the onset of diabetes in mice by altering 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 into a clinical setting.
Dr. Kailsah Singh, a former researcher at Liston’s lab, described their findings: “Our results show that MANF may prevent beta cell damage by preventing islet inflammation, 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 aimed to target the autoimmune nature of the disease, but Dr Adrian Liston, the program’s senior group leader of research in immunology, wanted to determine if there were more causes of 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 therefore addressed this problem by identifying the pathways that decide whether stressed insulin-producing cells in the pancreas live or die, and therefore determine the development of disease.
Their hope was to find a way to stop this stress-related death, preventing the decline of 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 which fixes the level of Manf in cells. While type 1 and 2 diabetes in patients generally have different causes and different genetics, the GLIS3-MANF pathway is a common feature of both conditions and therefore an attractive target for treatments.
In order 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 and allows these cells to produce 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 that could spontaneously develop autoimmune diabetes. Treatment of pre-diabetic mice reduced the rate of developing diabetes from 58% to 18%. This research in mice is a key first step in developing treatments for human patients.
“A key advantage of targeting this particular pathway is the high likelihood that it will work in both type 1 and type 2 diabetes,” says Dr. Adrian Liston. “In type 2 diabetes, while the initial problem is insensitivity to insulin in the liver, most serious complications occur in patients where pancreatic beta cells have been chronically stressed by the need to make insulin. more and more insulin.By treating early type 2 diabetes with this approach, or a similar approach, we have the potential to block progression to the major adverse events of late-stage type 2 diabetes.
Reference: “Manf gene delivery to 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, Loriana Mascali, Emanuela Pasciuto, Chantal Mathieu, James Dooley and Adrian Liston, November 16, 2022, Biomolecules.
DOI: 10.3390/biom12101493
The study was funded by the Research Council for Biotechnology and Biological Sciences, Vlaams Instituut voor Biotechnologie and The Research Foundation – Flanders.
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