Targeted pharmacological therapy restores β-cell function for diabetes remission

Sachs S, Bastidas-Ponce A, Tritschler S, Bakhti M, Boettcher A, Sanchez-Garrido MA, Tarquis-Medina M, Kleinert M, Fischer K, Jall S, Harger A, Bader E, Roscioni S, Ussar S, Feuchtinger A, Yesildag B, Neelakandhan A, Jensen CB, Cornu M, Yang B, Finan B, Dimarchi RD, Tschoep MH, Theis FJ, Hofmann SM, Muller TD, Lickert H (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Nature Metabolism Nature Research

Book Volume: 2

Pages Range: 192-209

Journal Issue: 2

DOI: 10.1038/s42255-020-0171-3

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.

Involved external institutions

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Deutsches Zentrum für Diabetesforschung e.V. (DZD) DE Germany (DE) InSphero AG CH Switzerland (CH) Novo Nordisk A/S DK Denmark (DK) Novo Nordisk US United States (USA) (US)

How to cite

APA:

Sachs, S., Bastidas-Ponce, A., Tritschler, S., Bakhti, M., Boettcher, A., Sanchez-Garrido, M.A.,... Lickert, H. (2020). Targeted pharmacological therapy restores β-cell function for diabetes remission. Nature Metabolism, 2(2), 192-209. https://dx.doi.org/10.1038/s42255-020-0171-3

MLA:

Sachs, Stephan, et al. "Targeted pharmacological therapy restores β-cell function for diabetes remission." Nature Metabolism 2.2 (2020): 192-209.

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