Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes.
Adolescent
Adult
Aged
Animals
Biphenyl Compounds
/ pharmacology
Bridged Bicyclo Compounds, Heterocyclic
/ pharmacology
Cellular Senescence
/ drug effects
Child
Child, Preschool
Cohort Studies
Diabetes Mellitus, Type 1
/ metabolism
Female
Fibroblasts
Humans
Hyperglycemia
/ metabolism
Insulin-Secreting Cells
/ metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Nitrophenols
/ pharmacology
Piperazines
/ pharmacology
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Sulfonamides
/ pharmacology
THP-1 Cells
Young Adult
DNA damage
SASP
beta cells
cellular senescence
senolytics
type 1 diabetes
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
07 05 2019
07 05 2019
Historique:
received:
25
03
2018
revised:
08
07
2018
accepted:
23
01
2019
pubmed:
26
2
2019
medline:
14
7
2020
entrez:
26
2
2019
Statut:
ppublish
Résumé
Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. Immune-mediated beta cell destruction drives the disease, but whether beta cells actively participate in the pathogenesis remains unclear. Here, we show that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP). Senescent beta cells upregulated pro-survival mediator Bcl-2, and treatment of NOD mice with Bcl-2 inhibitors selectively eliminated these cells without altering the abundance of the immune cell types involved in the disease. Significantly, elimination of senescent beta cells halted immune-mediated beta cell destruction and was sufficient to prevent diabetes. Our findings demonstrate that beta cell senescence is a significant component of the pathogenesis of T1D and indicate that clearance of senescent beta cells could be a new therapeutic approach for T1D.
Identifiants
pubmed: 30799288
pii: S1550-4131(19)30021-X
doi: 10.1016/j.cmet.2019.01.021
pii:
doi:
Substances chimiques
ABT-737
0
Biphenyl Compounds
0
Bridged Bicyclo Compounds, Heterocyclic
0
Nitrophenols
0
Piperazines
0
Proto-Oncogene Proteins c-bcl-2
0
Sulfonamides
0
venetoclax
N54AIC43PW
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1045-1060.e10Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK121794
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.