Targeted pharmacological therapy restores β-cell function for diabetes remission
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Sachs et al_Nature Metabolism_2020_Vol 2(2)_192-209
Forlagets udgivne version, 16,3 MB, PDF-dokument
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.
Originalsprog | Engelsk |
---|---|
Tidsskrift | Nature Metabolism |
Vol/bind | 2 |
Udgave nummer | 2 |
Sider (fra-til) | 192-209 |
Antal sider | 18 |
ISSN | 2522-5812 |
DOI | |
Status | Udgivet - 2020 |
Bibliografisk note
CURIS 2020 NEXS 087
Author correction to this article: https://doi.org/10.1038/s42255-020-0201-1
Antal downloads er baseret på statistik fra Google Scholar og www.ku.dk
ID: 238369497