Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes

Cell Rep. 2021 Aug 3;36(5):109490. doi: 10.1016/j.celrep.2021.109490.

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.

Keywords: AKT; MST1; MTORC1; PHLPP1/2; T2D; apoptosis; beta cell; insulin; pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2; type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Survival
  • Diabetes Mellitus, Type 2 / enzymology*
  • Diabetes Mellitus, Type 2 / pathology*
  • Diet, High-Fat
  • Female
  • Gene Deletion
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Insulin Secretion
  • Insulin-Secreting Cells / enzymology*
  • Insulin-Secreting Cells / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Knockout
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Biosynthesis
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Stress, Physiological
  • Up-Regulation

Substances

  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • PHLPP1 protein, human
  • PHLPP1 protein, mouse
  • PHLPP2 protein, human
  • PHLPP2 protein, mouse
  • Phosphoprotein Phosphatases