title: Potential of protein phosphatase inhibitor 1 as biomarker of pancreatic β-cell injury in vitro and in vivo.
abstract: 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.
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Benedicte
authors.initials: B
authors.lastname: Brackeva
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ling
authors.forename: Gertjan
authors.initials: G
authors.lastname: Kramer
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.forename: Bart
authors.initials: B
authors.lastname: Keymeulen
authors.forename: Daniel
authors.initials: D
authors.lastname: Pipeleers
authors.forename: Frans
authors.initials: F
authors.lastname: Gorus
authors.forename: Geert A
authors.initials: GA
authors.lastname: Martens
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051381:Rats
chemical_list: D015415:Biomarkers; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C021042:protein phosphatase inhibitor-1; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
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