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

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., Pal, A., Awal, S., Joshi, A., Rafizadeh, S., Madduri, M. K., Khazaei, M., Liu, H., Yuan, T., He, W., Gorrepati, K. D. D., Azizi, Z., Qi, Q., Ye, K., Oberholzer, J., …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