Targeted pharmacological therapy restores β-cell function for diabetes remission

• DOI: 10.1038/s42255-020-0171-3
• Publication Date: 2020-02-20T16:02:52Z
• Authors: Stephan Sachs; Aimée Bastidas-Ponce; Sophie Tritschler; Mostafa Bakhti; Anika Böttcher; Miguel A. Sánchez...; 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 Yang; Brian Finan; Richard D. DiMarchi; Matthias H. Tschöp; Fabian J. Theis; Susanna M. Hofmann; Timo D. Müller; Heiko Lickert
• Keywords: Cell therapy

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.