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Sachs, S. ; Bastidas-Ponce, A. ; Tritschler, S. ; Bakhti, M. ; Böttcher, A. ; Sánchez-Garrido, M.A. ; Tarquis Medina, M. ; Kleinert, M. ; Fischer, K. ; Jall, S. ; Harger, A. ; Bader, E. ; Roscioni, S. ; Ussar, S. ; Feuchtinger, A. ; Yesildag, B.* ; Neelakandhan, A.* ; Jensen, C.B.* ; Cornu, M.* ; Yang, B.* ; Finan, B.* ; DiMarchi, R.D.* ; Tschöp, M.H. ; Theis, F.J. ; Hofmann, S.M. ; Müller, T.D. ; Lickert, H.

Targeted pharmacological therapy restores β-cell function for diabetes remission.

Nat. Metab. 2, 192-209 (2020)
Postprint DOI Verlagsversion bestellen
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 2, Heft: 2, Seiten: 192-209 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed