Researchers from the Liston lab have recently published a preventative therapeutic for diabetes in mice. The team has been able to prevent diabetes in mice by manipulating signalling pathways in pancreatic cells to prevent stress-induced cell death. The treatment targets a pathway common to both major types of diabetes and therefore could have huge therapeutic potential once translated into a clinical treatment.
Dr Kailsah Singh, former research fellow in the Liston lab, described their findings: “Our results show that MANF could prevent the beta cell damage by preventing the inflammation in islets, which is a hallmark of type 1 diabetes.”
For over 35 years there have been failed attempts to prevent type 1 diabetes development. 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 if there was more causing 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 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 disease.
Their hope was to find a way to stop this stress-related death, preventing the decline into diabetes without the need to focus solely on the immune system. First, the researchers had to know which pathways would influence the decision of life or death 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 sets the level of Manf in the cells. While 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.
In order 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 favour of continued survival. To test their treatment, the researchers treated mice susceptible to spontaneous development of autoimmune diabetes. Treating pre-diabetic mice resulted in a lower rate of diabetes development from 58% to 18%. This research in mice is a key first step in the development of treatments for human patients.
“A key advantage of targeting this particular pathway is the high likelihood 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 severe complications arise in patients where the beta cells of the pancreas have been chronically stressed by the need to make 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 the major adverse events in late-stage type 2 diabetes.”
Singh, K., et al. Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development. Biomolecules 2022, 12, 1493. https://doi.org/10.3390/biom12101493
Honor Pollard, Communications Officer, firstname.lastname@example.org
Slides showing treatment with AAV leads to upregulation of Manf, shown in green, specifically within the beta-cell compartment of the pancreas. Manf (green), insulin (red) or glucagon (red), and DAPI (blue).
Babraham Institute affiliated authors (in author order):
Kailash Singh, former research fellow, Liston lab
Orian Bricard, Postdoctoral researcher, Liston lab
James Dooley, Senior staff scientist, Liston lab
Adrian Liston, Group leader, Immunology research programme
This research was funded the Research Foundation – Flanders (FWO), the Vlaams Instituut voor Biotechnologie (VIB) and the Biotechnology and Biological Sciences Research Council (BBSRC).
Animal research statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The animal research included in this study was carried out at the University of Leuven. The research involved mouse models of type 1 diabetes. Mice underwent regular blood tests to see if they were diabetic.
Please follow the link for further details of our animal research and our animal welfare practices. http://www.babraham.ac.uk/about-us/animal-research
About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through Institute Strategic Programme Grants and an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
The Biotechnology and Biological Sciences Research Council (BBSRC) is part of UK Research and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government. BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
06 December 2022