Type 1 Diabetes Development Mechanisms in the Pancreas Uncovered

Woman injecting insulin, daily diabetes care during COVID-19
Credit: martin-dm/Getty Images

University of Pennsylvania School of Medicine researchers show that during the development of type 1 diabetes (T1D), the cells lining the pancreatic duct reprogram themselves in an attempt to suppress autoimmune T-cell responses that cause the autoimmune disorder.

In T1D, immune cells called T lymphocytes attack and destroy insulin-secreting pancreatic beta cells and the pancreas stops producing insulin. “T1D is an autoimmune disease in which immune cells destroy insulin-producing beta cells,” the researchers wrote in their study, which is published in the journal Nature Metabolism.

“The etiology of this complex disease is dependent on the interplay of multiple heterogeneous cell types in the pancreatic environment. Here, we provide a single-cell atlas of pancreatic islets of 24 T1D, autoantibody-positive and nondiabetic organ donors across multiple quantitative modalities including ~80,000 cells using single-cell transcriptomics, ~7,000,000 cells using cytometry by time of flight, and ~1,000,000 cells using in situ imaging mass cytometry.”

“The first events that occur in a patient heading towards T1D, the events that trigger autoimmunity, have been difficult for researchers to pin down because of our inability to biopsy the pancreas, and the fact that clinical diagnosis is only made once massive beta cell destruction has occurred,” said senior author Golnaz Vahedi, PhD, an associate professor of genetics and member of the Institute for Diabetes, Obesity, and Metabolism at the Perelman School of Medicine at the University of Pennsylvania.

“Although it might be an ultimately unsuccessful attempt of the pancreas to limit the adaptive T-cell response responsible for destroying beta cells, this finding that the ductal cells are capable of playing this suppressive role towards autoimmune T-cell responses is unprecedented,” said co-senior author Klaus Kaestner, PhD, the Thomas and Evelyn Suor Butterworth professor in genetics. “Our study shows that these cells, which had never previously been linked to immunity, may change themselves to protect the pancreas.”

“Our study took those quality tissue samples and created high-resolution measurements of millions of cells from patients at various stages of T1D progression, resulting in a single-cell atlas of pancreatic islets,” said co-senior author R. Babak Faryabi, PhD, an assistant professor of pathology and laboratory medicine and a core member of Epigenetics Institute at Penn.

“Our study is the first to show that even when a person is not clinically considered to have T1D, high levels detected in their GAD test indicate large-scale transcriptional remodeling of their beta cells,” said Ali Naji, MD, PhD, the J. William White professor of surgical research and a study co-senior author. “It solidifies to clinicians to closely monitor patients with increasing levels of GAD, as we now know what cellular and molecular changes are in motion in relation to those levels.”

Further studies are needed. However, the discovery of molecular phenotypic changes in pancreatic cells advances the understanding of early pancreatic changes occurring in T1D.

“Our multimodal analyses delineate cell types and processes that may contribute to T1D immunopathogenesis and provide an integrative procedure for exploration and discovery of human pancreatic function,” concluded the researchers.

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