Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors
Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no clinically available effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP-1 receptor agonists (GLP-1) or transforming growth factor β (TGF-β) superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. Here we perform single-cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone or with GLP-1 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. Collectively, in addition to enhancing expression of beta cell phenotypic genes in beta cells, our findings suggest that regenerative drugs may be targeting cycling alpha cells in human islets.
Authors
- Adolfo Garcı́a-Ocaña (ORCID: https://orcid.org/0000-0002-6883-6176)
- Deniz Demircioğlu (ORCID: https://orcid.org/0000-0001-7857-0407)
- Randy B. Kang (ORCID: https://orcid.org/0000-0002-2541-4344)
- Esra Karaköse (ORCID: https://orcid.org/0000-0002-6940-5909)
- Geming Lu (ORCID: https://orcid.org/0000-0002-1322-3997)
- Andrew F. Stewart (ORCID: https://orcid.org/0000-0001-7866-5959)
- Xuedi Wang (ORCID: https://orcid.org/0009-0002-0709-8349)
- Carmen Argmann (ORCID: https://orcid.org/0000-0002-1110-8012)
- Saul Carcamo (ORCID: https://orcid.org/0000-0002-1510-1045)
- Donald K. Scott (ORCID: https://orcid.org/0000-0002-1414-9223)
- Robert Sebra (ORCID: https://orcid.org/0000-0001-9267-2426)
- Luca Lambertini (ORCID: https://orcid.org/0000-0003-3326-219X)
- Peng Wang (ORCID: https://orcid.org/0000-0002-2549-2780)
- Dan Hasson (ORCID: https://orcid.org/0000-0001-7943-1636)
- Olivia Wood
Institutions
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101832
- Citations
- 12
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 6.87
Funders
- Icahn School of Medicine at Mount Sinai
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences