Reduced expression level of protein phosphatase, PPM1E, serves to maintain insulin secretion in type 2 diabetes

Abstract

<p>Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase expression overall was changed in T2D, and that of <em>PPM1E</em> was most markedly downregulated. <em>PPM1E</em> expression correlated inversely with HbA1c. Silencing of <em>PPM1E</em> increased glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells and/or islets from T2D patients while <em>PPM1E</em> overexpression decreased GSIS. Increased GSIS following <em>PPM1E</em> silencing was associated with decreased oxidative stress, elevated cytosolic Ca2+ levels and ATP/ADP ratio, increased hyperpolarization of the inner mitochondrial membrane and phosphorylation of CaMKII, AMPK and acetyl-coA carboxylase. Silencing of <em>PPM1E</em>, however, did not change insulin content. Increased GSIS, cell viability, and activation of AMPK upon metformin treatment in β-cells were observed upon <em>PPM1E</em> silencing. Thus, protein dephosphorylation via PPM1E abrogates GSIS. Consequently, reduced <em>PPM1E</em> expression in T2D may be a compensatory response of β-cells to uphold insulin secretion under metabolic duress. Targeting PPM1E in β-cells may thus represent a novel therapeutic strategy for treatment of T2D.</p>