Blaz Lupse
Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes
Lupse, Blaz; Annamalai, Karthika; Ibrahim, Hazem; Kaur, Supreet; Geravandi, Shirin; Sarma, Bhavishya; Pal, Anasua; Awal, Sushil; Joshi, Arundhati; Rafizadeh, Sahar; Madduri, Murali Krishna; Khazaei, Mona; Liu, Huan; Yuan, Ting; He, Wei; Gorrepati, Kanaka Durga Devi; Azizi, Zahra; Qi, Qi; Ye, Keqiang; Oberholzer, Jose; Maedler, Kathrin; Ardestani, Amin
Authors
Karthika Annamalai
Hazem Ibrahim
Supreet Kaur
Shirin Geravandi
Bhavishya Sarma
Anasua Pal
Sushil Awal
Arundhati Joshi
Sahar Rafizadeh
Murali Krishna Madduri
Mona Khazaei
Huan Liu
Ting Yuan
Wei He
Kanaka Durga Devi Gorrepati
Zahra Azizi
Qi Qi
Keqiang Ye
Jose Oberholzer
Kathrin Maedler
Dr Amin Ardestani A.Ardestani@hull.ac.uk
Senior Lecturer
Abstract
Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to β-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate β-cell death. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control β-cell apoptosis. Genetic inhibition of PHLPPs markedly improves β-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our study presents PHLPPs as targets for functional regenerative therapy of pancreatic β cells in diabetes.
Citation
Lupse, B., Annamalai, K., Ibrahim, H., Kaur, S., Geravandi, S., Sarma, B., …Ardestani, A. (2021). Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes. Cell reports, 36(5), Article 109490. https://doi.org/10.1016/j.celrep.2021.109490
Journal Article Type | Article |
---|---|
Acceptance Date | Jul 14, 2021 |
Online Publication Date | Aug 3, 2021 |
Publication Date | Aug 3, 2021 |
Deposit Date | Jan 4, 2024 |
Publicly Available Date | Jan 8, 2024 |
Journal | Cell Reports |
Print ISSN | 2211-1247 |
Electronic ISSN | 2211-1247 |
Publisher | Cell Press |
Peer Reviewed | Peer Reviewed |
Volume | 36 |
Issue | 5 |
Article Number | 109490 |
DOI | https://doi.org/10.1016/j.celrep.2021.109490 |
Keywords | Beta cell; Type 2 diabetes; T2D; Pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2; PHLPP1/2; Apoptosis; MST1; AKT; MTORC1; Insulin |
Public URL | https://hull-repository.worktribe.com/output/4461543 |
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Copyright Statement
© 2021 The Authors.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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