Potential of Protein Phosphatase Inhibitor 1 as Biomarker of pancreatic beta cell injury in vitro and in vivo

  1. Geert A. Martens1,2
  1. 1Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, Belgium
  2. 2Department of Clinical Chemistry & Radioimmunology, Universitair Ziekenhuis Brussel
  3. 3Department of Medical Biochemistry, Academisch Medisch Centrum, Amsterdam, The Netherlands
  4. 4Gene Expression Unit, Department Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven, Belgium
  1. Corresponding author: Geert A. Martens, geert.martens{at}uzbrussel.be

Abstract

There is a need for plasma-based tests that can directly measure the extent of beta cell injury in vivo, in patients receiving islet grafts and in animal models. Here we propose protein phosphatase 1, regulatory (inhibitor) subunit 1A (PPP1R1A) as novel biomarker for acute beta cell destruction. LC-MS/MS proteome analysis of FACS-purified beta cells, tissue-comparative Western blotting and immunohistochemistry indicated relatively high molar abundance and selectivity of PPP1R1A in beta cells. PPP1R1A was discharged into the extracellular space of chemically-injured rat and human islets in vitro, proportionate to the extent of beta cell death. Streptozotocin injection in rats led to a progressive PPP1R1A depletion from the cytoplasm of disintegrating beta cells, and a marked surge in plasma levels detectable by an affinity capture method. A similar massive PPP1R1A discharge in blood was also detected in 3 patients immediately after intraportal islet transplantation. Our findings provide first proof-of-principle for PPP1R1A as real-time biomarker of beta cell destruction in animal models and patients, and warrant development of more sensitive methods for its further validation in clinical trials.

  • Received October 30, 2012.
  • Accepted March 26, 2013.

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