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Monday, July 13, 2020 - 08:00

Tackling Type 1 diabetes from prevention to better treatments

At the Translational Research Institute, a Mater Research group led by Professor Josephine Forbes is at the international forefront of Type 1 diabetes research.

  • Developing a preventative medication for Type 1 diabetes, which is slated for clinical trials in humans in 2022
  • Preparing to run a Phase Ib clinical trial in 2021 to test a potential new treatment developed with Mater Young Adults Health Centre for diabetic kidney disease in young adults
  • Part of the Australian-wide, Environmental Determinants of Islet Autoimmunity (ENDIA) study to identify environmental factors contributing to Type 1 diabetes

Professor Forbes, who has been researching diabetes for more than 20 years, is currently preparing to trial a potential new therapeutic to prevent the disease developing and a possible new treatment for chronic kidney disease in diabetic patients. Her team is also involved in a major study to identify environmental factors triggering diabetes.

“These are my three most high profile projects, but I always have irons in the fire for other projects. It’s important to continue the joy of discovery,” said Professor Forbes.  

A new therapeutic to prevent Type 1 diabetes

Featuring high on the list of research priorities for Professor Forbes is developing a preventative medication for Type 1 diabetes.

With a research grant from the Juvenile Diabetes Research Foundation (JDRF), her team is collaborating with Yale University and an industry partner on a preclinical trial to assess three potential drug candidates. The drugs, including a biological therapeutic developed by Professor Forbes’ team, all target the cell surface ‘Receptor for Advance Glycation End-products’ also known as RAGE.

Professor Forbes has shown it is possible to prevent Type 1 diabetes developing in animal models by blocking RAGE early in the onset of diabetes, when the first autoantibodies are present.

“RAGE plays an important role in the immune system and activating the inflammatory response. In diabetes, we believe it is involved in initiation as well as sustaining the immune dysfunction which culminates in the disease,” she said.

Using a biological compound developed by the Forbes laboratory, the researchers were able to block RAGE at a critical point in the onset of Type 1 diabetes in animal models. After just two weeks, they found they had reprogrammed the immune system and slowed down the incidence of diabetes by 90%.

“In humans, this same critical point occurs when you begin losing efficacy in the immune system, and it’s at this point we are looking to deliver a drug and stop the runaway train.

“We have three viable options to trial in individuals at risk of developing diabetes, but we are looking to see which one shows the best potential in our laboratory models. We will then sit around the table with JDRF and decide on the next step, and that could be trialling a single drug or combination of the drugs.”

Depending on the outcome of the study, the team may be able to go straight to a much later stage clinical trial as one of the therapeutics they are looking at has been trialled already in diabetic patients with Alzheimer’s disease and it has passed the safety requirements.

About RAGE: RAGE is a receptor found on cell surfaces, particularly in the gut and mucus linings. It has a role in fighting bacterial and viral infections. The gene for RAGE is found in the regions of our DNA that link with susceptibility to diseases such as type 1 diabetes. RAGE can bind compounds known as ‘glycation end products’ or AGEs, which have been increasingly consumed from processed foods since the 1970s. AGEs give processed foods a brown/yellow colour along with enhanced aroma, taste and a longer shelf life. They also feed the body’s reward pathways. Professor Forbes first discovered a possible link between diabetes and RAGE in 1999 while looking at the impact of diet on overweight individuals. 

“When we gave patients a diet high in AGEs they had poorer glucose control and moved into the susceptibility range for diabetes. Those early studies also showed that chronic dietary consumption of AGEs jump started autoimmunity against the pancreas via interactions with the protein RAGE.”

A better treatment for diabetic kidney disease

The majority of the disease, deaths and costs associated with diabetes results from chronic vascular complications, with diabetic kidney disease the most common risk factor.

Professor Forbes is preparing to run a Phase Ib clinical trial in 2021 to test a potential new treatment developed with Mater Young Adults Health Centre for diabetic kidney disease in young adults. The treatment improves mitochondrial function and the Professor hopes it will either prevent or slow the development of diabetic kidney disease.

“Kidney disease develops early in Type 1 diabetes and the best available clinical management sta­bilises but doesn’t improve kidney function. There is a substantial treatment gap,” she said.

“Interestingly, the organs affected by diabetes all have high energy use, especially the kidneys, so that made us look more closely at the energy store house of cells, the mitochondria and we essentially found that young people with mitochondrial defects also have early signs of kidney disease.”

Following these results, Professor Forbes began searching for existing therapeutics treating mitochondrial dysfunction. Her subsequent trials in preclinical models provided strong support for her educated “hunch” that mitochondrial damage in diabetes can be pharmacologically repaired to improve kidney function.

The clinical trial will run at the Mater Young Adult Diabetes Centre, in Brisbane.

What is causing more children to develop Type 1 diabetes?

Professor Forbes and her team are part of the Australian-wide, Environmental Determinants of Islet Autoimmunity (ENDIA) study. Through this study, researchers hope to identify environmental factors contributing to Type 1 diabetes so that they can then find ways to prevent them.

In Australia, Type 1 diabetes in children is twice as common as it was 20 years ago.

Professor Forbes said that while there is a strong genetic link to Type I diabetes, genetics alone could not fully explain the rapid increase in cases over recent decades.

“There are strong environmental risk factors. Cross-sectional studies suggest that exposure to certain viruses, dietary components or factors such as weight gain in infancy and microbiome alterations may trigger diabetes in genetically predisposed individuals,” she said.

“We’re also seeing a growing numbers of individuals presenting without a family history of the disease and a greater prevalence of adult‐onset Type 1 diabetes, which is very unusual. It is very rare to develop this disease later in life if you don’t have antibody with the first three years of life.

“In ENDIA, an extensive range of factors including the gut microbiome, viruses are being examined by teams across Australia. Our role will be examining RAGE and its effect on the immune system during Type 1 diabetes development”

The trial has enrolled 1500 children in the study and will follow them from birth to three years of age. Many ENDIA participants are being studied locally by a fabulous clinical team at the Mater Mother’s Hospital.

About Type I diabetes: Diabetes affects 425 million people worldwide. Type 1 diabetes accounts for about 10% of diabetes cases, and its prevalence is increasing at a rate of 3% per year globally. In Australia, this form of diabetes affects 150,000 children and adolescents. Type 1 diabetes is an incurable autoimmune disease. It occurs following destruction of the pancreatic beta cells by a person's own immune system. This results in an inability to produce the sugar storage hormone, insulin. Patients require lifelong insulin replacement and have significantly increased risk for heart disease, blindness and kidney failure and mental health issues. According to Professor Forbes, diabetes has become so prevalent that it touches all of our lives.

“There are no therapies available to prevent or treat diabetes and it has significant annual healthcare costs in excess of $570 million nationally,” she said.  

About Professor Forbes

Professor Forbes is a Program Leader of the Chronic Disease Biology and Care research theme at Mater Research. A National Health and Medical Research Council (NHMRC) Senior Research Fellow, Professor Forbes also leads her own research group, ‘Glycation and Diabetes Complications’, with a team of 10 researchers. Her lab is investigating new treatments for diabetes and the devastating chronic complications associated with it such as kidney disease, blindness, amputations and heart disease. With this research, she aims to build a greater understanding of the biological basis of diabetes in connection with a broad range of chronic diseases and develop preventative strategies and innovative treatments to improve patient outcomes.

Professor Forbes has been studying diabetes since she completed her PhD in Nephrology in 1999 and has worked at Royal Children's Hospital, the University of Melbourne and Baker IDI Heart and Diabetes Institute in Melbourne Australia. She has held research grants from the NHMRC, the Juvenile Diabetes Research Foundation (JDRF) and the National Institutes of Health (USA). She has also received awards including the TJ Neale Award in 2017 for outstanding contribution to nephrological science, the Commonwealth Health Minister’s Award for Excellence in medical research in 2010, an NHMRC Achievement Award in 2009, a Young Tall Poppy Award in 2008 and a Young Investigator Award from the International Diabetes Federation in 2002. Professor Forbes is the author of over 160 scientific publications.

Research projects

Recent journal publications on this body of research

Forbes J.M., “Prolyl hydroxylase inhibitors: a breath of fresh air for diabetic kidney disease?”, Kidney International, May 2020; 97(5): 855-857. https://doi.org/10.1016/j.kint.2020.01.038

Tan S.M., Ziemann M., Thallas-Bonke V., et al, “Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility”, Diabetes, 2020 Jan; 69(1): 83-98.https://doi.org/10.2337/db19-0043

Lindblom R.S.J., Higgins G.C., Nguyen T-V, et al "Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D", Clin Sci , 2020; 134(2): 239–259. https://doi.org/10.1042/CS20190787

Leung S.S., Borg D.J., McCarthy D.A., et al, "Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes", bioRxiv, Posted January 11, 2020 doi: https://doi.org/10.1101/2020.01.10.902627

Bagge S.L.,  Fotheringham A.K., Leung S.S., Forbes J.M., "Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes",  Medical Research Reviews, 28 February 2020. https://doi.org/10.1002/med.21654

Balmer L.A., Whiting R., Rudnicka C., et al, “Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease”, Kidney international, 2019; 96(4): 918-926

Fotheringham A.K., Gallo L.A., Forbes J. M., “Dietary AGEs in the development and progression of chronic kidney disease”, Dietary AGEs and their role in health and disease, 2018, Edited by Jaime Uribarri. Boca Raton, FI, United States: CRC Press.213-224.https://doi.org/10.1201/9781315120041

Fotheringham A.K., , Bagger J.I., Borg D.J., “Exploring AGE and sRAGE regulation in response to oral and intravenous glucose loads in individuals with recently diagnosed type 2 diabetes”, Diabetologia, 2019; 62:S542-S54

Hagiwara S., Sourris K., Ziemann M., et al, “RAGE Deletion Confers Renoprotection by Reducing Responsiveness to Transforming Growth Factor-β and Increasing Resistance to Apoptosis”, Diabetes 2018 May; 67(5): 960-973.https://doi.org/10.2337/db17-0538

Flemming N.B., Gallo L.A, Forbes J.M., “Mitochondrial dysfunction and signaling in diabetic kidney disease: oxidative stress and beyond”, Seminars in Nephrology, 2018; 38(2):101-110. https://doi.org/10.1016/j.semnephrol.2018.01.001

TRI would like to thank Mater Research and thesugarscience.com for providing additional material for this profile.