Groundbreaking study reveals beta cell dynamics in type 1 diabetes

Approximately 8 million people worldwide have type 1 diabetes (T1D). It is a chronic autoimmune disease in which the body attacks and destroys its own insulin-producing beta cells (pronounced “beta”) in the pancreas, causing a lack of insulin and an inability to regulate blood sugar levels. . It is unclear why the body suddenly recognizes its own beta cells as enemies. Some evidence suggests that environmental factors, such as viral infections, may trigger the development of T1D, and other evidence suggests that genetics may also play a role.

A groundbreaking study by researchers at the Joslin Diabetes Center sheds new light on specific changes that beta cells undergo during the onset of T1D.Their findings – published in natural cell biology-;Provides new avenues for targeted intervention against chronic autoimmune conditions.

In the field of type 1 diabetes, research has mainly focused on understanding the immune component, but our study argues that β cells play an important role. Our findings suggest that β-cells may initiate critical events that promote abnormal autoimmune mechanisms. It’s a paradigm-changing approach. ”

Rohit N. Kulkarni, MD, Margaret A. Congleton, Chair and Co-Director, Section of Islet and Regenerative Biology, Joslin Diabetes Center

In a series of experiments using a mouse model of T1D and beta cells from humans with established T1D, Kulkarni and colleagues uncovered a complex cascade of biochemical steps, called signaling pathways, that control the innate immune response during disease onset. I made it. T1D’s. The researchers identified one pathway that influences the immune properties of beta cells, acting like a control switch that distinguishes beta cells from friend or foe to the body. You can imagine these control switches as small tags. The researchers focused on one particular tag, called N6-methyladenosine (m6A), which plays a key role in the beta cell response during T1D onset. By adjusting these regulatory switches, the researchers were able to influence the levels of key proteins along this pathway, significantly slowing disease progression in a T1D mouse model.

Dario F. de Jesús, M.A., Ph.D., lead author of the study and a researcher in Kulkarni’s lab, identified METTL3, an enzyme important in regulating beta-cell antiviral defenses. At later stages of T1D, METTL3 levels were low, suggesting that high METTL3 levels protect β-cells from dysfunction. The research team was able to slow disease progression by boosting METTL3 production in a mouse model.

“This finding suggests that interventions that increase METTL3 levels are a potential strategy to protect beta cells and slow the progression of type 1 diabetes,” said de Jesús, also an instructor in medicine at Harvard Medical School. he emphasized.

Taken together, these several lines of evidence paint a clearer picture of the still-mysterious immune phenomena surrounding the development of T1D, including novel mechanisms available for beta-cell protection. They also demonstrated that the enzyme METTL3 may promote β-cell survival and function during disease progression.

“It’s worth noting that there are commercially available compounds in this pathway that are used in connection with other diseases,” said Kulkarni, who is also a professor at Harvard Medical School. “Although the targets are different, it is an approach that has been proven to be effective. The next steps will focus on identifying specific molecules and pathways that can be exploited to enhance beta-cell protection. ”

Co-authors include Natalie K. Brown, Lin Xiao, Jiang Hu, Garrett Fogarty, Sevim Karaman, and Giorgio Basile of the Joslin Diabetes Center. Zijie Zhang, Jiangbo Wei, and Chuan He from the University of Chicago; Xiaolu Li, Wei-Jun Qian, and Matthew J. Gaffrey of the Pacific Northwest National Laboratory; Tariq M. Rana of the University of California, San Diego; Clayton Matthews and Mark A. Atkinson of the University of Florida School of Medicine; Alvin C. Powers of Vanderbilt University Medical Center; Audrey V. Parent, University of California, San Francisco. Cyrano De Paganon of Harvard Medical School. his Decio L. Eizirik of the Free University of Bruxelles;

This research was supported by the National Institutes of Health (grants R01 DK67536, UC4 DK116278, RM1 HG008935, and R01 DK122160). A portion of the mass spectrometry work was performed at the Environmental Molecular Sciences Laboratory at the Pacific Northwest National Laboratory, a National Science User Facility sponsored by the Department of Energy under contract DE AC05-76RL0 1830. RNK acknowledges support from the Margaret A. Congleton Endowed Chair. CH is a Howard Hughes Medical Institute Investigator. DFDJ thanks Mary K. Iacocca for her Junior Postdoctoral Fellowship, support from the American Diabetes Association (grant #7-21-PDF-140, and her NIH K99 DK135927).