Wang Lab Study Finds Early Islet Transcriptional Signature is Associated with Local Inflammation in Type 1 Diabetes
Date Posted: Monday, November 21, 2022
Non-inflamed rat islet and insulitis islet with T cell infiltration (white). Red indicates the inflammation signal. Green shows insulin-producing beta cells. Images by Adediwura Arowosegbe, PhD Candidate, UMass Chan Morningside Graduate School of Biomedical Sciences, Translational Science Program
Viral infections continue to be linked to the development of type 1 diabetes (T1D), yet human immune responses to viruses and how that leads to the destruction of insulin-producing beta cells in the pancreas is still unknown.
Using a rat model of diabetes, the laboratory of Jennifer Wang, MD, investigated inflammatory pathways because viruses can trigger inflammation that damages the pancreas. The research focused on early events leading to autoimmune responses to viruses with the ultimate goal of therapeutics that could target inflammation before T1D manifests.
Published in Diabetes, the study includes single cell RNA-sequencing analysis of roughly 2000 pancreatic cells from five specific points over eleven days to observe how the autoimmune process was developing over time.
“The rats started developing insulitis many days before diabetes,” said Alan Derr, the bioinformatician who led the study for the Wang Lab at the UMass Chan Diabetes Center of Excellence. “That’s when we began to see inflammation of the pancreas, and eventually the autoimmune process kills nearly all of the insulin-producing beta cells.”
The data they collected allowed the scientists to observe snapshots of what was occurring in the pancreas at each time point during the autoimmune attack.
“As the days progressed, more T cells entered the pancreas and certain inflammation signals were only developing in the rats that were infected with virus,” said Derr.
They were also interested to determine if it was only a few islets that were getting inflamed, or if there was low-level inflammation occurring in all the islets throughout the pancreas. Additional experiments revealed that only a subset of islets expressed inflammation signals, with genes being turned on to alert the immune system that the body was under attack.
“Single cell and imaging technology has improved greatly, allowing us to get beautiful images to look at additional genes,” said Derr. “That analysis determined that it was individual islets that were being attacked by T cells. Something in those islets triggered them to alert the immune system, so the immune system sent those T cells to destroy the problem, except they end up killing the insulin-producing beta cells.”
Interestingly, the virus itself was not found inside the pancreas. Where and why the autoimmunity trigger occurs is still unknown. This study provided a better understanding of the trajectory of the destruction of the beta cells, and the fact that it’s not occurring in all islets, but in individual islets within the pancreas.
Insights into such early processes can assist in developing therapies and prevention strategies to help people living with T1D.
An Early Islet Transcriptional Signature is Associated with Local Inflammation in Autoimmune Diabetes. Derr AG, Arowosegbe A, Satish B, Redick SD, Qaisar N, Guo Z, Vanderleeden E, Trombly MI, Baer CE, Harlan DM, Greiner DL, Garber M, Wang JP. Diabetes. 2022 Nov 8:db220521. doi: 10.2337/db22-0521. Online ahead of print. PMID: 36346618