TY - JOUR

T1 - Targeted pharmacological therapy restores β-cell function for diabetes remission

AU - Sachs, Stephan

AU - Bastidas-Ponce, Aimée

AU - Tritschler, Sophie

AU - Bakhti, Mostafa

AU - Böttcher, Anika

AU - Sánchez-Garrido, Miguel A

AU - Tarquis-Medina, Marta

AU - Kleinert, Maximilian

AU - Fischer, Katrin

AU - Jall, Sigrid

AU - Harger, Alexandra

AU - Bader, Erik

AU - Roscioni, Sara

AU - Ussar, Siegfried

AU - Feuchtinger, Annette

AU - Yesildag, Burcak

AU - Neelakandhan, Aparna

AU - Jensen, Christine B

AU - Cornu, Marion

AU - Yang, Bin

AU - Finan, Brian

AU - DiMarchi, Richard D

AU - Tschöp, Matthias H

AU - Theis, Fabian J

AU - Hofmann, Susanna M.

AU - Müller, Timo D

AU - Lickert, Heiko

N1 - A correction to this publication has been published at: https://doi.org/10.1038/s42255-020-0201-1

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1038/s42255-020-0171-3

DO - 10.1038/s42255-020-0171-3

M3 - Journal article

C2 - 32694693

AN - SCOPUS:85079823155

VL - 2

SP - 192

EP - 209

JO - Nature Metabolism

JF - Nature Metabolism

SN - 2522-5812

IS - 2

ER -