Targeted pharmacological therapy restores β-cell function for diabetes remission
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Targeted pharmacological therapy restores β-cell function for diabetes remission. / Sachs, Stephan; Bastidas-Ponce, Aimée; Tritschler, Sophie; Bakhti, Mostafa; Böttcher, Anika; Sánchez-Garrido, Miguel A; Tarquis-Medina, Marta; Kleinert, Maximilian; Fischer, Katrin; Jall, Sigrid; Harger, Alexandra; Bader, Erik; Roscioni, Sara; Ussar, Siegfried; Feuchtinger, Annette; Yesildag, Burcak; Neelakandhan, Aparna; Jensen, Christine B; Cornu, Marion; Yang, Bin; Finan, Brian; DiMarchi, Richard D; Tschöp, Matthias H; Theis, Fabian J; Hofmann, Susanna M.; Müller, Timo D; Lickert, Heiko.
In: Nature Metabolism, Vol. 2, No. 2, 2020, p. 192-209.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 238369497