A new study published in Cell Reports, co-led by University of Florida’s J. Crayton Pruitt Family Department of Biomedical Engineering associate professor Edward A. Phelps, Ph.D., and College of Veterinary Medicine chair and professor Clayton E. Mathews, Ph.D., reveals that beta cell dysfunction occurs independently of immune cell infiltration in the pancreas during the onset of type 1 diabetes (T1D). The collaborative research involved key partners from the Network for Pancreatic Organ Donors with Diabetes (nPOD), directed by Mark A. Atkinson, Ph.D.
Traditionally, the loss of insulin-producing beta cells in T1D has been attributed to immune-mediated destruction. This study demonstrates that even when beta cells remain, they are already dysfunctional at diagnosis—regardless of whether T cells are present in the islets.
Using live human pancreas slices from nPOD organ donors, the team found that beta cells from individuals with T1D showed diminished calcium mobilization and insulin secretion in response to glucose. These defects were observed in both inflamed and non-inflamed islets. Gene and protein profiling further revealed reduced activity in pathways responsible for glucose metabolism and insulin release.
“Our findings suggest that the pathogenesis of type 1 diabetes is not solely a matter of immune attack,” said Phelps. “There is also a parallel metabolic defect in beta cells that contributes to disease progression and to the clinical symptoms patients experience at diagnosis.”
The paper’s first author, Mollie K. Huber, Ph.D., completed her doctoral training in the UF Biomedical Sciences (BMS) program, co-mentored by Phelps, Mathews, and Atkinson. Huber conducted much of the research during her time in the Phelps Lab and is now a postdoctoral fellow at the Joslin Diabetes Institute at Harvard Medical School.
The Phelps Lab applies engineering approaches to challenges in health and biology, with a particular emphasis on pancreatic islet function in both normal and disease states. The team specializes in light microscopy, cell physiology, hydrogel engineering, and immune engineering. Adrienne Widener, Ph.D., a co-author on the paper, completed her Ph.D. in the Phelps Lab and is now a postdoctoral fellow in the UF College of Pharmacy working with Holger Russ, Ph.D.
This discovery opens the door to developing new biomarkers and therapies targeting beta cell metabolism, which could complement immunotherapies aimed at preserving beta cell mass.
Paper details
Title: Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis
Journal: Cell Reports
Authors: Mollie K. Huber, Adrienne E. Widener, Alexandra E. Cuaycal, Dylan Smurlick, Elizabeth A. Butterworth, Nataliya I. Lenchik, Jing Chen, Maria Beery, Helmut Hiller, Ellen Verney, Irina Kusmartseva, Marjan Slak Rupnik, Martha Campbell-Thompson, Ivan C. Gerling, Mark A. Atkinson, Clayton E. Mathews*, and Edward A. Phelps*
*Co-equal contribution.