American Diabetes Association (ADA) Pathway to Stop Diabetes® grant recipients Michael L. Stitzel, PhD, of the Jackson Laboratory, Stephen C.J. Parker, PhD, of the University of Michigan, and Praveen Sethupathy, PhD, of Cornell University, recently embarked on a collaborative research initiative empowered by the ADA Pathway to Stop Diabetes program. Bringing together diverse areas of expertise, their collaboration led to today’s report that establishes new detail about the genetic signatures of the cells that produce and release insulin, pancreatic beta (β) cells. The research, detailed in the article, “Multiomic profiling identifies cis-regulatory networks underlying human pancreatic β cell identity and function,” published online today in the scientific journal Cell Reports(DOI: 10.1016/j.celrep.2018.12.083), provides an integrated analysis of EndoC-βH1, a genetically engineered human β cell line, which is of significant importance to the diabetes research community.

Type 2 diabetes develops when pancreatic β cells produce an insufficient supply of insulin, often in the setting of a reduced ability to use the insulin that is produced. Risk for developing type 2 diabetes includes both genetic and environmental factors, such as nutrition and physical activity. Because of the central role of insulin-producing cells in development of diabetes, significant research efforts have focused on the genetic links to β cell development and function. Dr. Stitzel and his team, in an effort to motivate further functional studies of human β cell molecular biology and to guide the development of cellular models, worked to create extensive multi-faceted maps of the EndoC-βH1 molecular landscape.

By comparing these multilayered genomic maps of EndoC-βH1 to those generated from human islets in this and previous studies, the researchers identified shared and unique cis-regulatory elements (cis-RE) and expression features of protein-coding genes and non-coding RNAs. The resulting data, along with a web application created by the team, provide a valuable resource and guide for the design of future experiments to understand and manipulate the genetic programs governing β cell identity and (dys)function in diabetes. The researchers hope that making these tools publicly available will both motivate and enable fellow scientists to embrace this human cell line, which potentially offers more direct relevance to this human genetic disease compared to other widely used rodent β cell lines.

“Our results lay the groundwork for targeted and hypothesis-driven research projects that could ultimately reveal the connections linking a person’s genetics, β cell failure, and type 2 diabetes,” stated Drs. Stitzel, Parker and Sethupathy.

The research team for this project includes corresponding author Michael L. Stitzel, PhD, a 2018 recipient of the ADA’s Pathway to Stop Diabetes Accelerator grant. Dr. Stitzel is an assistant professor at the Jackson Laboratory, an independent, nonprofit biomedical research institution in Farmington, Connecticut. Co-senior author Stephen C.J. Parker, PhD, assistant professor of computational medicine and bioinformatics and assistant professor of human genetics at the University of Michigan, is a 2014 recipient of an ADA Pathway Initiator grant. Praveen Sethupathy, PhD, associate professor of biomedical sciences at Cornell University, is a 2016 recipient of an ADA Pathway Accelerator grant. The Pathway to Stop Diabetes program was launched in 2013 by the American Diabetes Association and has awarded more than $47 million to 29 leading scientists to pursue transformative diabetes-related research. Each awardee is selected from a highly competitive applicant pool of only one nominee per institution, with approximately 100 applications received each year. The Pathway program is supported by contributions from corporate sponsors, individual philanthropists and foundations. Current Pathway corporate sponsors include Novo Nordisk, Eli Lilly and Company, Merck, AstraZeneca, Abbott, Dexcom, Janssen, and Pfizer.

Congratulations to Drs. Stitzel, Parker and Sethupathy for this important paper that embodies what we envisioned when we created the Pathway to Stop Diabetes program—bringing brilliant minds together to pursue innovative approaches to understanding the full scope and complexity of diabetes. Given that type 2 diabetes is a progressive disorder, and pancreatic dysfunction is one of the major pathophysiologic factors, this research is truly significant and provides essential data supporting the next logical experimental steps in unraveling the interactions of genetics and pancreatic dysfunction,” said the ADA’s Chief Scientific, Medical and Mission Officer William T. Cefalu, MD.

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