# The role of senescent beta cells in T1D and T2D

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $758,532

## Abstract

U01 Application: The role of senescent beta cells in T1D and T2D
Abstract
Recent studies including our own suggest a marked increase in β-cells expressing key components of cellular
senescence in islets from Type 1 diabetes (T1D) and Type 2 diabetic (T2D) patients, implicating β-cell
senescence as a critical contributor to islet dysfunction. Recently, it was reported that ablation of senescent
cells by non-specific senolysis in mouse models of T1D and T2D improved diseease outcome. However, these
studies did not determine which senescent cell type was relevant to the beneficial effect, nor did they address
to what extent senescence occurs in the human endocrine pancreas before and during the development of
T1D and T2D. To close this knowledge gap, in Specific Aim 1 we will determine the prevalence, transcription
signatures and epigenomic landscapes of β-cell senescence in T1D, pre-T1D and T2D donors using
immunostaining, imaging mass cytometry, single cell RNAseq, single cell ATACseq, DNA methylome
determination and Cut-and-Tag analysis for key histone marks. In addition, we will evaluate the hypothesis that
irreparable damage to telomeres drives senescence in β-cells, a possible scenario that could provide a
mechanism for senescence to occur in islet cells of diabetic patients. In Specific Aim 2, we will test whether
metabolic and/or inflammatory stressors drive senescence in human β-cells and determine the effect of
senescence on β-cell function using scRNAseq and secretome analysis. We will evaluate if induction of
senescence and the senescence-associated secretory phenotype (SASP) in human islet cells is p16
dependent, employing the pseudo-islets approach and using our hyperglycemic xeno-transplantation model to
assess the direct effect of senolytics on human islet function. In Specific Aim 3, we will employ a novel
transgenic mouse, the ‘SenKiller’ model, to enable cell-type specific and inducible ablation of senescent cells in
any lineage including β-cells. Using this mouse model in combination with the appropriate β-cell specific Cre
driver, we will provide a definitive answer to the question if senescent β-cells are critical in the development of
glucose intolerance in models of T2D and islet autoimmunity in models of T1D. Together, this proposal will
determine the occurrence of senescence among islet cells from T1D and T2D donors using large cohorts and
multiple experimental modalities, explore the natural drivers of senescence and consequences to islet function
as well as secretion of pro-inflammatory substances, and employ novel mouse models to unequivocally
determine if elimination of senescent b-cells impacts diabetes progression in mouse models of T1D and T2D.
The data generated here will address burning questions in the field, namely, is senescence increased in islets
from diabetic patients, and are these cells important in the overall pathophysiology of T1D and T2D. These
critical questions will have therapeutic relevance regardin...

## Key facts

- **NIH application ID:** 10583684
- **Project number:** 1U01DK134995-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** KLAUS H KAESTNER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $758,532
- **Award type:** 1
- **Project period:** 2022-09-19 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10583684

## Citation

> US National Institutes of Health, RePORTER application 10583684, The role of senescent beta cells in T1D and T2D (1U01DK134995-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10583684. Licensed CC0.

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