Targeted pharmacological therapy restores β-cell function for diabetes remission

Stephan Sachs, Aimée Bastidas-Ponce, Sophie Tritschler, Mostafa Bakhti, Anika Böttcher, Miguel A. Sánchez-Garrido, Marta Tarquis-Medina, Maximilian Kleinert, Katrin Fischer, Sigrid Jall, Alexandra Harger, Erik Bader, Sara Roscioni, Siegfried Ussar, Annette Feuchtinger, Burcak Yesildag, Aparna Neelakandhan, Christine B. Jensen, Marion Cornu, Bin YangBrian Finan, Richard D. DiMarchi, Matthias H. Tschöp, Fabian J. Theis, Susanna M. Hofmann, Timo D. Müller, Heiko Lickert

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)192-209
Number of pages18
JournalNature Metabolism
Volume2
Issue number2
DOIs
StatePublished - 1 Feb 2020

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