Cycling Alpha Cells in Regenerative Drug-Treated Human Pancreatic Islets Serve As Key Beta Cell Progenitors

Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP1 receptor agonists (GLP1) or TGF? superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. We performed single cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone, or with GLP1 or LY. We identify Cycling Alpha Cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that Cycling Alpha Cells may serve as precursor cells that transdifferentiate into beta cells. In addition to shedding light onto the mechanisms of action of DYRK1A inhibitors, our findings suggest that the proper target for regenerative drugs in human islets may be Cycling Alpha Cells. Overall design: Cadaveric human islets were subject to beta cell regenerative drug treatment for 96 hours which was followed by scRNA-seq experiments. DMSO (control), Harmine (10µM), Harmine + GLP1RA (GLP), and Harmine + LY364947 (LY) treatments.