
Hindrik Mulder
Principal investigator

The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells
Author
Summary, in English
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.
Department/s
- Diabetes - Molecular Metabolism
- EXODIAB: Excellence of Diabetes Research in Sweden
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Stem Cell Center
- Endocrine Cell Differentiation and Function
- Diabetes - Islet Patophysiology
- Genomics, Diabetes and Endocrinology
Publishing year
2021-02-22
Language
English
Publication/Series
Metabolism: Clinical and Experimental
Document type
Journal article
Publisher
Elsevier
Topic
- Cell and Molecular Biology
- Endocrinology and Diabetes
Status
Published
Research group
- Diabetes - Molecular Metabolism
- Endocrine Cell Differentiation and Function
- Diabetes - Islet Patophysiology
- Genomics, Diabetes and Endocrinology
ISBN/ISSN/Other
- ISSN: 1532-8600