Targeted pharmacological therapy restores β-cell function for diabetes remission

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Dokumenter

  • Stephan Sachs
  • Aimée Bastidas-Ponce
  • Sophie Tritschler
  • Mostafa Bakhti
  • Anika Böttcher
  • Miguel A Sánchez-Garrido
  • Marta Tarquis-Medina
  • 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

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.

OriginalsprogEngelsk
TidsskriftNature Metabolism
Vol/bind2
Udgave nummer2
Sider (fra-til)192-209
Antal sider18
ISSN2522-5812
DOI
StatusUdgivet - 2020

Bibliografisk note

CURIS 2020 NEXS 087

ID: 238369497