Intra-islet insulin synthesis defects are associated with endoplasmic reticulum stress and loss of beta cell identity in human diabetes.
Dedifferentiation
ER stress
Pancreatic islets
Proinsulin
Type 2 diabetes
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
05
08
2022
accepted:
07
09
2022
pubmed:
25
10
2022
medline:
5
1
2023
entrez:
24
10
2022
Statut:
ppublish
Résumé
Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear. In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers. We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression. Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.
Identifiants
pubmed: 36280617
doi: 10.1007/s00125-022-05814-2
pii: 10.1007/s00125-022-05814-2
pmc: PMC9807540
doi:
Substances chimiques
Insulin
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
354-366Subventions
Organisme : Ministero dell'Università e della Ricerca
ID : PRIN 201793XZ5A_006
Informations de copyright
© 2022. The Author(s).
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