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

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 beta-cells and that its expression is reduced in dysfunctional beta-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and beta-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 INS1 (832/13) beta-cells impaired GSIS amplification, PKA-target protein phosphorylation, mitochondrial coupling efficiency and also the expression of critical beta-cell marker genes like MafA, Pdx1, NeuroD1 and Pax6. Our results demonstrate that the beta-cell transcription factor MafA is required for PPP1R1A expression and that reduced beta-cell PPP1R1A levels impaired beta-cell function and contributed to beta-cell dedifferentiation during type 2 diabetes. Loss of PPP1R1A in type 2 diabetic beta-cells may explains the unresponsiveness of type 2 diabetic patients to GLP1R-based treatments. (C) 2021 The Author(s). Published by Elsevier Inc.