The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells
(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.
(Less)
- author
- organization
-
- Diabetes - Molecular Metabolism (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Stem Cell Center
- Endocrine Cell Differentiation and Function (research group)
- Diabetes - Islet Patophysiology (research group)
- Translational Muscle Research (research group)
- publishing date
- 2021-02-22
- type
- 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
- 2024-09-19 17:31:40
@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}}, }