What question did this study set out to answer?

This research aims to explore whether targeting senescent pancreatic beta-cells can restore their proliferative capacity, potentially aiding diabetes treatment.

June 7, 2026

2671-P: Restoration of Proliferation in Rodent and Human β-Cells by Targeting Senescence

Key Points

This research aims to explore whether targeting senescent pancreatic beta-cells can restore their proliferative capacity, potentially aiding diabetes treatment.
Administered combinations of senolytic and senomorphic drugs to MIN6 and INS1 beta-cell lines.
Evaluated proliferation through EdU incorporation and flow cytometry in both rodent and human pancreatic islets.
Used harmine treatment to induce proliferation in mouse and primary islets.
DQ with baricitinib increased proliferation in INS1 cells from 1% to 32% (n=12).
DQ also increased proliferation in human islets from 6% to 25% (n=8 technical replicates from 2 donors).
Deletion of p16 did not alter proliferation rates.

Abstract

Introduction and Objective: The high price of insulin has led to dangerous underuse of the drug. Targeting β -cell failure through restoring proliferation could provide insulin independence to people with diabetes. In response to stressors, cells may become senescent, ceasing to proliferate and influencing neighboring cells to also become dysfunctional. Senescent pancreatic β-cells accumulate in people with T2D. Senolytics can induce apoptosis of senescent cells while senomorphics target senescence associated secretory phenotype (SASP) factors to suppress secondary senescence. We determined whether senolytic and senomorphic drugs significantly restored the proliferative capacity of pancreatic β-cells. Methods: Different combinations of each senomorphic drug (momelotonib, tofacitinib, or baricitinib) and senolytic drugs (dasatinib and quercetin, DQ) were administered to MIN6 and INS1 β -cell lines. Differences in proliferation between control and experimental groups were evaluated with EdU incorporation through flow cytometry. These treatments and evaluation were repeated in islets from humans, C57Bl6 mice and INK ATTAC mice where specific deletion of senescence marker and effector p16 can be induced. Mouse and primary islets were treated with harmine to induce proliferation given their low basal division rate. Results: DQ with baricitinib significantly increased proliferation in INS1 cells from 1% to 32% (n=12). DQ significantly increased proliferation in human islets from 6% to 25% (n=8 technical replicates from 2 donors). Deletion of p16 did not change proliferation rates. Conclusion: Targeting senescent cells can restore the proliferative capacity of rodent and human beta cells. Further mechanistic studies will address the effects on beta cell mass and the role of senotherapies in vivo. Disclosure A. Adebayo: None. K. Iwasaki: None. J. Hollister-Lock: None. S. Le: None. C. Aguayo-Mazzucato: Consultant; Ended; Novo Nordisk, Sanofi.

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