A discovery-based proteomics approach identifies protein disulphide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetesResearch in context
Farooq Syed,
Divya Singhal,
Koen Raedschelders,
Preethi Krishnan,
Robert N. Bone,
Madeline R. McLaughlin,
Jennifer E. Van Eyk,
Raghavendra G. Mirmira,
Mei-Ling Yang,
Mark J. Mamula,
Huanmei Wu,
Xiaowen Liu,
Carmella Evans-Molina
Affiliations
Farooq Syed
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, USA, 46202; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut St, Indianapolis, IN, USA, 46202
Divya Singhal
Department of Biochemistry and Molecular Biology, University of Calgary, 2500 University Drive NW, Alberta, Canada, T2N1N4
Koen Raedschelders
Advanced Clinical Biosystems Research Institute, Precision Health, Barbra Streisand Women's Heart Center at the Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Suite A9227, Los Angeles, CA, USA, 90048
Preethi Krishnan
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, USA, 46202; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut St, Indianapolis, IN, USA, 46202
Robert N. Bone
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, USA, 46202; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut St, Indianapolis, IN, USA, 46202
Madeline R. McLaughlin
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, USA, 46202
Jennifer E. Van Eyk
Advanced Clinical Biosystems Research Institute, Precision Health, Barbra Streisand Women's Heart Center at the Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., Suite A9227, Los Angeles, CA, USA, 90048
Raghavendra G. Mirmira
Kovler Diabetes Center, University of Chicago, 900 E 57th St, Chicago, IL, USA, 60637
Mei-Ling Yang
Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA, 06510
Mark J. Mamula
Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA, 06510
Huanmei Wu
Department of BioHealth Informatics, Indiana University–Purdue University Indianapolis, 535 W. Michigan Street, Indianapolis, IN, USA, 46202; Department of Health Services Administration and Policy, Temple University College of Public Health, 1101 W. Montgomery Ave, Philadelphia, PA, USA, 19122
Xiaowen Liu
Deming Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA, 70112
Carmella Evans-Molina
Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, USA, 46202; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut St, Indianapolis, IN, USA, 46202; Department of Medicine, Indiana University School of Medicine, 340 W 10th St, Indianapolis, IN, USA, 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr, Indianapolis, IN, USA, 46202; Richard L. Roudebush VA Medical Center, Indiana University School of Informatics and Computing, 1481 W 10th St, Indianapolis, IN, USA, 46202; Corresponding author. Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN, 46202, USA.
Summary: Background: Stress responses within the β cell have been linked with both increased β cell death and accelerated immune activation in type 1 diabetes (T1D). At present, information on the timing and scope of these responses as well as disease-related changes in islet β cell protein expression during T1D development is lacking. Methods: Data independent acquisition-mass spectrometry was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. Findings: In islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in stress mitigation and maintenance of β cell function, followed by loss of expression of protective proteins that heralded diabetes onset. EIF2 signalling and the unfolded protein response, mTOR signalling, mitochondrial function, and oxidative phosphorylation were commonly modulated pathways in both NOD mice and NOD-SCID mice rendered acutely diabetic by T cell adoptive transfer. Protein disulphide isomerase A1 (PDIA1) was upregulated in NOD islets and pancreatic sections from human organ donors with autoantibody positivity or T1D. Moreover, PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to non-diabetic controls. Interpretation: We identified a core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of β cell stress in T1D. Funding: NIH (R01DK093954, DK127308, U01DK127786, UC4DK104166, R01DK060581, R01GM118470, and 5T32DK101001-09). VA Merit Award I01BX001733. JDRF (2-SRA-2019-834-S-B, 2-SRA-2018-493-A-B, 3-PDF-20016-199-A-N, 5-CDA-2022-1176-A-N, and 3-PDF-2017-385-A-N).
