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Reduced Expression Level of Protein Phosphatase PPM1E Serves to Maintain Insulin Secretion in Type 2 Diabetes

Gheibi, Sevda LU ; Cataldo, Luis Rodrigo LU orcid ; Hamilton, Alexander LU ; Huang, Mi LU ; Kalamajski, Sebastian LU ; Fex, Malin LU and Mulder, Hindrik LU orcid (2023) In Diabetes 72(4). p.455-466
Abstract

Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of the type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase expression overall was changed in T2D, and that of PPM1E was the most markedly downregulated. PPM1E expression correlated inversely with HbA1c. Silencing of PPM1E increased glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells and/or islets from patients with T2D, whereas PPM1E overexpression decreased... (More)

Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of the type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase expression overall was changed in T2D, and that of PPM1E was the most markedly downregulated. PPM1E expression correlated inversely with HbA1c. Silencing of PPM1E increased glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells and/or islets from patients with T2D, whereas PPM1E overexpression decreased GSIS. Increased GSIS after PPM1E silencing was associated with decreased oxidative stress, elevated cytosolic Ca2+ levels and ATP to ADP ratio, increased hyperpo-larization of the inner mitochondrial membrane, and phosphorylation of CaMKII, AMPK, and acetyl-CoA car-boxylase. Silencing of PPM1E, however, did not change insulin content. Increased GSIS, cell viability, and activation of AMPK upon metformin treatment in β-cells were observed upon PPM1E silencing. Thus, protein de-phosphorylation via PPM1E abrogates GSIS. Conse-quently, reduced PPM1E expression in T2D may be a compensatory response of β-cells to uphold insulin secretion under metabolic duress. Targeting PPM1E in β-cells may thus represent a novel therapeutic strategy for treatment of T2D.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
72
issue
4
pages
12 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:36662636
  • scopus:85150752427
ISSN
0012-1797
DOI
10.2337/db22-0472
language
English
LU publication?
yes
additional info
Funding Information: Funding. This study was supported by grants from the Swedish Research Council (2021-01777), the Novo Nordisk, Hjelt, Stiftelsen Lars Hiertas Minne, and Albert Påhlsson’s Foundations, and the Royal Physiographic Society of Lund. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. S.G. contributed to the study conceptualization, methodology, investigation, writing the original draft, review and editing of the manuscript, and visualization. L.R.C., A.H., M.H., and S.K. contributed to the study methodology and investigation. M.F. and H.M. contributed to the study conceptualization, methodology, resources, reviewing and editing the manuscript, supervision, and funding acquisition. S.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Preliminary results of this study were presented at the virtual 57th Annual Meeting of the European Association for the Study of Diabetes, 27 September to October 2021. Publisher Copyright: © 2023 by the American Diabetes Association. Readers may use this article.
id
9904234b-b1bf-4eb5-a5fd-59606d8c92cd
date added to LUP
2023-04-28 08:48:59
date last changed
2024-06-15 02:18:07
@article{9904234b-b1bf-4eb5-a5fd-59606d8c92cd,
  abstract     = {{<p>Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of the type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase expression overall was changed in T2D, and that of PPM1E was the most markedly downregulated. PPM1E expression correlated inversely with HbA<sub>1c</sub>. Silencing of PPM1E increased glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells and/or islets from patients with T2D, whereas PPM1E overexpression decreased GSIS. Increased GSIS after PPM1E silencing was associated with decreased oxidative stress, elevated cytosolic Ca<sup>2+</sup> levels and ATP to ADP ratio, increased hyperpo-larization of the inner mitochondrial membrane, and phosphorylation of CaMKII, AMPK, and acetyl-CoA car-boxylase. Silencing of PPM1E, however, did not change insulin content. Increased GSIS, cell viability, and activation of AMPK upon metformin treatment in β-cells were observed upon PPM1E silencing. Thus, protein de-phosphorylation via PPM1E abrogates GSIS. Conse-quently, reduced PPM1E expression in T2D may be a compensatory response of β-cells to uphold insulin secretion under metabolic duress. Targeting PPM1E in β-cells may thus represent a novel therapeutic strategy for treatment of T2D.</p>}},
  author       = {{Gheibi, Sevda and Cataldo, Luis Rodrigo and Hamilton, Alexander and Huang, Mi and Kalamajski, Sebastian and Fex, Malin and Mulder, Hindrik}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{4}},
  pages        = {{455--466}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Reduced Expression Level of Protein Phosphatase PPM1E Serves to Maintain Insulin Secretion in Type 2 Diabetes}},
  url          = {{http://dx.doi.org/10.2337/db22-0472}},
  doi          = {{10.2337/db22-0472}},
  volume       = {{72}},
  year         = {{2023}},
}