p21-senescent cells drive pancreatic islet dysfunction through targetable paracrine signaling in type 2 diabetes
Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodelling of the cellular secretory profile. In humans, pancreatic β-cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β-cell senescence to islet dysfunction remains unknown and thus, the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β-cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics, and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21+ β-cells induced secondary senescence in neighbouring cells, characterized by dysfunction and loss of identity. Janus kinase inhibitors (JAKi) counteracted the induction of secondary senescence and restored β-cell function in islets from humans with T2D and in high-fat diet-fed mice. These findings reveal the critical role of p21+ β-cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.
Authors
- Jillian L. Woodworth
- Cristina Aguayo‐Mazzucato (ORCID: https://orcid.org/0000-0001-5402-1382)
- Paul Robson (ORCID: https://orcid.org/0000-0002-0191-3958)
- Maya Jackson
- Kanako Iwasaki (ORCID: https://orcid.org/0000-0003-1671-3980)
- Vesna D. Garovic (ORCID: https://orcid.org/0000-0001-6891-0578)
- Sara Espinoza (ORCID: https://orcid.org/0000-0002-5902-650X)
- Nicolas Musi (ORCID: https://orcid.org/0000-0003-4242-2888)
- Sergii Domanskyi (ORCID: https://orcid.org/0000-0002-6847-6019)
- George A. Kuchel (ORCID: https://orcid.org/0000-0001-8387-7040)
- Francisco Cigarroa (ORCID: https://orcid.org/0000-0002-7432-8880)
- Francesko Hela (ORCID: https://orcid.org/0000-0002-9977-1221)
- Stephanie Sanjines
- Cristian Abarca (ORCID: https://orcid.org/0000-0003-1968-2761)
- Juliana Alcoforado Diniz (ORCID: https://orcid.org/0000-0001-8699-8219)
- Christopher Cahill
- Tamara Tchkonia
- Dylan Baker
- Priscila Carapeto (ORCID: https://orcid.org/0000-0002-8987-9116)
- Sandra Le
- Alejandro Pena (ORCID: https://orcid.org/0009-0008-4335-2635)
- Ayush Midha
- Jeffrey H. Chuang
- James L. Kirkland
- Hui Pan (ORCID: https://orcid.org/0000-0001-5748-7217)
- Sebastian Pena
Institutions
- Cedars-Sinai Medical Center (US)
- Joslin Diabetes Center (US)
- Mayo Clinic (US)
- The University of Texas at San Antonio Health Science Center (US)
- Urology San Antonio (US)
- Jackson Laboratory (US)
- Mayo Clinic in Arizona (US)
- Hypertension Institute (US)
- Universidad Cristiana Autónoma de Nicaragua (NI)
- Mayo Clinic in Florida (US)
- UConn Health (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2026-06-09
- DOI
- https://doi.org/10.1172/jci.insight.197310
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Richard and Susan Smith Family Foundation
- Joslin Diabetes Center
- Juvenile Diabetes Research Foundation Canada
- Diabetes Canada
- Noaber Foundation
- University of Alberta
- National Institutes of Health
- Diabetes Research Center
- Canadian Institutes of Health Research
- National Institute on Aging
- National Institute of Diabetes and Digestive and Kidney Diseases