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The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells

Cataldo, Luis Rodrigo LU orcid ; Vishnu, Neelanjan LU ; Singh, Tania LU ; Bertonnier-Brouty, Ludivine LU ; Bsharat, Sara LU ; Luan, Cheng LU ; Renström, Erik LU ; Prasad, Rashmi B LU ; Fex, Malin LU and Mulder, Hindrik LU orcid , et al. (2021) In Metabolism: Clinical and Experimental
Abstract

The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target of type 2 diabetes drugs aiming to enhance insulin secretion. Here we show that the protein phosphatase 1 inhibitor protein 1A (PPP1R1A), is expressed in β-cells and that its expression is reduced in dysfunctional β-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and β-cell function. We observed a strong correlation of MAFA and PPP1R1A mRNA levels in human islets, moreover, PPP1R1A mRNA levels were reduced in type 2 diabetic islets and positively correlated with GLP1-mediated GSIS... (More)

The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target of type 2 diabetes drugs aiming to enhance insulin secretion. Here we show that the protein phosphatase 1 inhibitor protein 1A (PPP1R1A), is expressed in β-cells and that its expression is reduced in dysfunctional β-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and β-cell function. We observed a strong correlation of MAFA and PPP1R1A mRNA levels in human islets, moreover, PPP1R1A mRNA levels were reduced in type 2 diabetic islets and positively correlated with GLP1-mediated GSIS amplification. PPP1R1A silencing in β-cell lines impaired GSIS amplification, PKA-target protein phosphorylation, mitochondrial coupling efficiency and also the expression of critical β-cell marker genes like MafA, Pdx1, NeuroD1 and Pax6. Our results demonstrate that the β-cell transcription factor MafA is required for PPP1R1A expression and that reduced β-cell PPP1R1A levels impaired β-cell function and contributed to β-cell dedifferentiation during type 2 diabetes. Loss of PPP1R1A in type 2 diabetic β-cells may explains the unresponsiveness of type 2 diabetic patients to GLP1R-based treatments.

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Contribution to journal
publication status
published
subject
in
Metabolism: Clinical and Experimental
article number
154734
publisher
Elsevier
external identifiers
  • scopus:85102079538
  • pmid:33631146
ISSN
1532-8600
DOI
10.1016/j.metabol.2021.154734
language
English
LU publication?
yes
id
b92b6c1e-49ff-4307-8f97-5b7beeff9ace
date added to LUP
2021-03-09 13:49:21
date last changed
2024-06-13 08:15:48
@article{b92b6c1e-49ff-4307-8f97-5b7beeff9ace,
  abstract     = {{<p>The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target of type 2 diabetes drugs aiming to enhance insulin secretion. Here we show that the protein phosphatase 1 inhibitor protein 1A (PPP1R1A), is expressed in β-cells and that its expression is reduced in dysfunctional β-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and β-cell function. We observed a strong correlation of MAFA and PPP1R1A mRNA levels in human islets, moreover, PPP1R1A mRNA levels were reduced in type 2 diabetic islets and positively correlated with GLP1-mediated GSIS amplification. PPP1R1A silencing in β-cell lines impaired GSIS amplification, PKA-target protein phosphorylation, mitochondrial coupling efficiency and also the expression of critical β-cell marker genes like MafA, Pdx1, NeuroD1 and Pax6. Our results demonstrate that the β-cell transcription factor MafA is required for PPP1R1A expression and that reduced β-cell PPP1R1A levels impaired β-cell function and contributed to β-cell dedifferentiation during type 2 diabetes. Loss of PPP1R1A in type 2 diabetic β-cells may explains the unresponsiveness of type 2 diabetic patients to GLP1R-based treatments.</p>}},
  author       = {{Cataldo, Luis Rodrigo and Vishnu, Neelanjan and Singh, Tania and Bertonnier-Brouty, Ludivine and Bsharat, Sara and Luan, Cheng and Renström, Erik and Prasad, Rashmi B and Fex, Malin and Mulder, Hindrik and Artner, Isabella}},
  issn         = {{1532-8600}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Elsevier}},
  series       = {{Metabolism: Clinical and Experimental}},
  title        = {{The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells}},
  url          = {{http://dx.doi.org/10.1016/j.metabol.2021.154734}},
  doi          = {{10.1016/j.metabol.2021.154734}},
  year         = {{2021}},
}