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Cheng Luan

Research engineer

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

Author

  • Luis Rodrigo Cataldo
  • Neelanjan Vishnu
  • Tania Singh
  • Ludivine Bertonnier-Brouty
  • Sara Bsharat
  • Cheng Luan
  • Erik Renström
  • Rashmi B Prasad
  • Malin Fex
  • Hindrik Mulder
  • Isabella Artner

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 in 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