The genomic and molecular landscape of a rare type of benign pancreatic tumor has provided scientists with insights into the genes and pathways involved in beta cell regeneration, which could represent a starting point for developing new approaches to diabetes therapy that replace lost insulin-producing beta cells. “For the first time, we have a genomic recipe—an actual wiring diagram in molecular terms that demonstrates how beta cells replicate,” claims Andrew Stewart, M.D., director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, who led the research.

“When you think of tumor genomics, you're thinking of breast cancer or colon cancer, leukemia, etc.,” he notes. “No one is thinking of doing genomics on tumors that don't really kill people. So the real innovation here is that we collected benign tumors that don't metastasize and don't cause great harm, and we're trying to use these benign tumors that have beta cell regeneration going on in them, as the only reasonable source of genomic information on how to make beta cells regenerate.”

Type 1 diabetes is characterized by a loss of insulin-producing beta cells, so a priority for diabetes research is the development of new treatments that can increase the number of healthy beta cells. Insulimonas are small, nonmalignant pancreatic beta cell carcinomas that overproduce insulin. Reasoning that the tumors would exhibit genomic mechanisms that underpin beta cell expansion, the Icahn School of Medicine team and colleagues in the U.S. and U.K., first carried out whole-exome sequencing and RNA sequencing of 38 human insulinomas. They then carried out network analysis of the data to computationally model relevant molecular events in insulinoma, relative to normal adult and juvenile human beta cells. “Our primary intent was to employ an integrative genomics approach to identify mitogenic mechanisms with potential application for human beta cell expansion,” the authors write in their published paper in Nature Communications, which is entitled “Insights into Beta Cell Regeneration for Diabetes via Integration of Molecular Landscapes in Human Insulinomas.”


The key is knowing how to look, not just where to look, adds co-author Carmen Argmann, Ph.D., associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai. “In this case, we looked at millions of data points collected in rare human insulinomas to try and find an answer to a common disease, diabetes. We then computationally created two molecular pictures from that data, one from the insulinoma and one for the normal beta cell, and identified the critical differences that will hopefully lead to new ways to expand beta cell mass in diabetes patients.” The researchers next plan to look for clinical applications of their findings in partnership with Sema4, a genomic testing firm spun out of the Mount Sinai Health System. Sema4 is an interdisciplinary partnership of scientists, doctors, engineers, and genetic counselors that focuses on merging big data analytics with clinical diagnostics to aid disease treatment, diagnosis, and prevention.

Work by Dr. Stewart’s team had previously shown that the developmental plant-derived compound  harmine promotes beta cell regeneration and proliferation at levels that might be relevant to diabetes therapy. The latest results highlight the targets of harmine as a potential pathway for beta cell regeneration, as well as identifying a number of new potential pathways for diabetes therapy. “Collectively, this study provides a novel and complex lens through which to view insulinoma and its relationship to normal beta cell function …” the authors conclude. “Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.”

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