Targeted Pharmacological Therapy Restores Β-Cell Function for Diabetes Remission

MCML Authors

Fabian Theis

Prof. Dr.

Principal Investigator

Mathematical Modelling of Biological Systems

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.

article

---

Nature Metabolism

2. Feb. 2020.

---

Authors

S. Sachs • A. Bastidas-Ponce • S. Tritschler • M. Bakhti • A. Böttcher • M. A. Sánchez-Garrido • M. Tarquis-Medina • M. Kleinert • K. Fischer • S. Jall • A. Harger • E. Bader • S. Roscioni • S. Ussar • A. Feuchtinger • B. Yesildag • A. Neelakandhan • C. B. Jensen • M. Cornu • B. Yang • B. Finan • R. D. DiMarchi • M. H. Tschöp • F. J. Theis • S. M. Hofmann • T. D. Müller • H. Lickert

---

Links

DOI

---

Research Area

 C2 | Biology