Targeted pharmacological therapy restores β-cell function for diabetes remission
| Autor: | Aparna Neelakandhan, Matthias H. Tschöp, Mostafa Bakhti, Katrin Fischer, Aimée Bastidas-Ponce, Sophie Tritschler, Miguel A. Sánchez-Garrido, Anika Böttcher, Stephan Sachs, Erik Bader, Susanna M. Hofmann, Sara S. Roscioni, Fabian J. Theis, Siegfried Ussar, Brian Finan, Heiko Lickert, Annette Feuchtinger, Sigrid Jall, Burcak Yesildag, Richard D. DiMarchi, Marta Tarquis-Medina, Alexandra Harger, Maximilian Kleinert, Marion Cornu, Christine B. Jensen, Bin Yang, Timo D. Müller |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
β cell function
Pharmacological therapy Polypharmacology Endocrinology Diabetes and Metabolism medicine.medical_treatment 030209 endocrinology & metabolism Pharmacology Protein degradation Streptozocin Diabetes Mellitus Experimental Mice 03 medical and health sciences 0302 clinical medicine Glucagon-Like Peptide 1 Insulin-Secreting Cells Physiology (medical) Diabetes mellitus Internal Medicine Animals Homeostasis Humans Hypoglycemic Agents Insulin Medicine 030304 developmental biology 0303 health sciences geography geography.geographical_feature_category biology business.industry Regeneration (biology) Remission Induction Estrogens Cell Biology medicine.disease Islet 3. Good health Insulin receptor biology.protein Cancer research Experimental pathology business |
| Zdroj: | Nat. Metab. 2, 192-209 (2020) Sachs, S, Bastidas-Ponce, A, Tritschler, S, Bakhti, M, Böttcher, A, Sánchez-Garrido, M A, Tarquis-Medina, M, Kleinert, M, Fischer, K, Jall, S, Harger, A, Bader, E, Roscioni, S, Ussar, S, Feuchtinger, A, Yesildag, B, Neelakandhan, A, Jensen, C B, Cornu, M, Yang, B, Finan, B, DiMarchi, R D, Tschöp, M H, Theis, F J, Hofmann, S M, Müller, T D & Lickert, H 2020, ' Targeted pharmacological therapy restores β-cell function for diabetes remission ', Nature Metabolism, vol. 2, no. 2, pp. 192-209 . https://doi.org/10.1038/s42255-020-0171-3 Nature Metabolism |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|