Targeted pharmacological therapy restores β-cell function for diabetes remission.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
31
07
2019
accepted:
15
01
2020
entrez:
23
7
2020
pubmed:
23
7
2020
medline:
20
1
2021
Statut:
ppublish
Résumé
Dedifferentiation of insulin-secreting β cells in the islets of Langerhans has been proposed to be a major mechanism of β-cell dysfunction. Whether dedifferentiated β cells can be targeted by pharmacological intervention for diabetes remission, and ways in which this could be accomplished, are unknown as yet. Here we report the use of streptozotocin-induced diabetes to study β-cell dedifferentiation in mice. Single-cell RNA sequencing (scRNA-seq) of islets identified markers and pathways associated with β-cell dedifferentiation and dysfunction. Single and combinatorial pharmacology further show that insulin treatment triggers insulin receptor pathway activation in β cells and restores maturation and function for diabetes remission. Additional β-cell selective delivery of oestrogen by Glucagon-like peptide-1 (GLP-1-oestrogen conjugate) decreases daily insulin requirements by 60%, triggers oestrogen-specific activation of the endoplasmic-reticulum-associated protein degradation system, and further increases β-cell survival and regeneration. GLP-1-oestrogen also protects human β cells against cytokine-induced dysfunction. This study not only describes mechanisms of β-cell dedifferentiation and regeneration, but also reveals pharmacological entry points to target dedifferentiated β cells for diabetes remission.
Identifiants
pubmed: 32694693
doi: 10.1038/s42255-020-0171-3
pii: 10.1038/s42255-020-0171-3
doi:
Substances chimiques
Estrogens
0
Hypoglycemic Agents
0
Insulin
0
Streptozocin
5W494URQ81
Glucagon-Like Peptide 1
89750-14-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
192-209Commentaires et corrections
Type : ErratumIn
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