Potential of Protein Phosphatase Inhibitor 1 As Biomarker of Pancreatic β-Cell Injury In Vitro and In Vivo
- Lei Jiang1,
- Benedicte Brackeva1,2,
- Zhidong Ling1,
- Gertjan Kramer3,
- Johannes M. Aerts3,
- Frans Schuit4,
- Bart Keymeulen1,
- Daniel Pipeleers1,
- Frans Gorus1,2 and
- Geert A. Martens1,2⇑
- 1Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- 2Department of Clinical Chemistry and Radioimmunology, Universitair Ziekenhuis Brussel, Brussels, Belgium
- 3Department of Medical Biochemistry, Academisch Medisch Centrum, Amsterdam, the Netherlands
- 4Gene Expression Unit, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Leuven, Belgium
- Corresponding author: Geert A. Martens, .
There is a need for plasma-based tests that can directly measure the extent of β-cell injury in vivo in patients receiving islet grafts and in animal models. In this study, we propose protein phosphatase 1, regulatory (inhibitor) subunit 1A (PPP1R1A) as a novel biomarker for acute β-cell destruction. Liquid chromatography–tandem mass spectrometry proteome analysis of fluorescence-activated cell sorter–purified β-cells, tissue-comparative Western blotting, and immunohistochemistry indicated relatively high molar abundance and selectivity of PPP1R1A in β-cells. PPP1R1A was discharged into the extracellular space of chemically injured rat and human islets in vitro, proportionate to the extent of β-cell death. Streptozotocin injection in rats led to a progressive PPP1R1A depletion from the cytoplasm of disintegrating β-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 three patients immediately after intraportal islet transplantation. Our findings provide first proof-of-principle for PPP1R1A as real-time biomarker of β-cell destruction in animal models and patients and warrant development of more sensitive methods for its further validation in clinical trials.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1507/-/DC1.
- Received October 30, 2012.
- Accepted March 26, 2013.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.