Blaz Lupse, 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, Amin Ardestani
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...
August 3, 2021: Cell Reports