INDIANAPOLIS — New Indiana University School of Medicine research supports that Type 1 diabetes may be driven by the very cells the disease eventually destroys. In two studies recently published in Science Translational Medicine, scientists found that early failures in the stress responses of the insulin-producing beta cells in the pancreas may help trigger the disease instead of only being passive targets. These findings offer fresh perspectives on therapies aimed at preserving beta cell health before the damage becomes irreversible.
Type 1 diabetes is an autoimmune disease that progresses in stages, culminating in a Stage 3 clinical diagnosis. Once diagnosed, the majority of beta cells in people with Type 1 diabetes are too damaged to function, so they require lifelong insulin therapy to manage blood sugar levels and prevent life-threatening complications.
While it has been widely understood that the immune system mistakenly destroys beta cells, the researchers noticed qualities in the cells well before the immune attack began. Using advanced live-cell imaging of Type 1 diabetes models, they discovered that the beta cells develop defects in their self-protection systems.
"The main goal of this work was to understand how beta cells respond to stress before the disease is clinically diagnosed," said Amelia Linnemann, PhD, associate professor of pediatrics at the IU School of Medicine and lead author of the studies. "We found that these cells have defects in their cellular ‘cleanup’ and recycling pathways, as well as antiviral defense responses, which may leave them more vulnerable to immune attack and damage."
A surprising finding involved mitochondrial reactive oxygen species (ROS), which are molecules typically associated with cell damage. Their study revealed that a short, controlled burst of these molecules is actually necessary to activate a beta cell's antiviral defenses. Because the beta cells in diabetes-prone models already have impaired cleanup systems, or autophagy, they lose the ability to control this normally beneficial stress response. This pattern potentially links viral or inflammatory stress to early beta cell dysfunction.
Their findings point toward therapies that can restore healthy autophagy or treatments that can preserve the short ROS signal needed for beta cells to turn on their antiviral defenses. The discoveries could potentially translate beyond Type 1 diabetes.
"This work could influence other diseases such as neurodegenerative diseases, other autoimmune diseases or Type 2 diabetes, where viral and inflammatory signaling, mitochondrial stress or defective autophagy may play a role in the pathogenesis," said Linnemann, who is also a researcher at the Herman B Wells Center for Pediatric Research and the IU Center for Diabetes and Metabolic Diseases.
The research team plans to conduct long-term imaging studies to determine if these broken cleanup systems directly contribute to diabetes progression or if they simply serve as an early warning sign. Future studies will also examine how beta cells respond to chronic inflammatory stress compared to the early antiviral responses examined in their recent studies.
IU School of Medicine’s Leslie E. Wagner, Olha Melnyk, Alissa N. Muncy, Abigail Turner, Bryce E. Duffett, Charanya Muralidharan, Michelle M. Martinez-Irizarry, Matthew C. Arvin, Kara S. Orr, Wenting Wu and Jon D. Piganelli are co-authors on the study, "A mitochondrial ROS-dependent antiviral response promotes β cell resilience and is absent in donors with type 1 diabetes." Additional co-authors include Elisabetta Manduchi and Klaus H. Kaestner of University of Pennsylvania, Estefania Quesada-Masachs of University of Miami and Joseph T. Brozinick of Eli Lilly and Company.
IU School of Medicine’s Olha Melnyk, Charanya Muralidharan, Bryce E. Duffett, Alissa N. Muncy, Leslie E. Wagner, Matthew Austin, Jahnavi Aluri, Abdul S. Qadir, Yashu Battina, Rachael Morara, Glorian Perez-Aviles, Justin J. Crowder and Michelle M. Martinez are co-authors on the study, "Real time in vivo analysis of murine β cells reveals autophagic flux defects before onset of autoimmune diabetes." Additional co-authors include Sylvaine You and Roberto Mallone of Indiana Biosciences Research Institute and Université Paris Cité.
This research was supported by funding from the National Institutes of Health.
About the Indiana University School of Medicine
The IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability. According to the Blue Ridge Institute for Medical Research, the IU School of Medicine ranks No. 15 in 2025 National Institutes of Health funding among all public medical schools in the country.
Writer: Jackie Maupin, jacmup@iu.edu
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