200-OR: Targeting β-Cell Senescence and Secondary Senescence—Therapeutic Potential of JAK Inhibitors in Diabetes

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Introduction and Objective: Cellular senescence is a stress response marked by the upregulation of antiapoptotic pathways, loss of function, and secretome remodeling (SASP). Pancreatic β-cells undergo senescence with age and insulin resistance, while their targeted removal improves glucose homeostasis, demonstrating the role of β-cell senescence in diabetes progression. However, β-cell senescence can also promote β-cell survival and function. Thus, a better understanding of the phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies.Methods: scRNASeq of human and mouse islets revealed senescent subopulations and their transcriptional signatures. A p21Cip1-tdTom reporter mouse was developed through CRISPR editing and their islets isolated and used for flow cytometry, insulin secretion assays and protein content. siRNA against p21Cip1 was used for knockdown and downstream analysis of function and transcription. Inhibitors of JAK1/2 and JAK 2/3 were used on mouse and human islets to assess their effects on insulin secretion and senescence status.Results: Subpopulations of senescent β-cells, identified through the expression of Cdkn1a (encoding p21Cip1) and Cdkn2a (encoding p16Ink4a) had distinct transcriptional and functional identities. The predominant senescent β-cell subpopulation expressed Cdkn1a and was characterized by a lack of function, and transcription of SASP factors. The SASP from the Cdkn1a+ subpopulation induced secondary senescence and dysfunction in neighboring cells. JAK inhibitors counteracted secondary senescence, decreased SASP secretion and restored function in human islets from donors with insulin resistance and Type 2 Diabetes.Conclusion: The main subpopulation of senescent β-cells expressed Cdkn1a and led to secondary senescence, loss of function, and loss of transcriptional identity in neighboring cells. This was attenuated with JAK inhibitors

Disclosure

P. Carapeto: None. K. Iwasaki: None. H. Pan: None. C. Cahill: None. F. Hela: None. S. Le: None. C. Aguayo-Mazzucato: Consultant; Novo Nordisk.

Funding

This study was supported by Institutional Startup Funds to CAM, National Institutes of Health grants 1R01DK132535 to CAM, P30 DK036836 to Joslin Diabetes Center (Cores), Thomas J Beatson Jr Foundation grant 2020-010 and the Richard and Susan Smith Family Foundation Award to CAM. SL is funded by NIH R25DK140752. KI is a Iacocca Postdoctoral Fellow.



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