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Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes

  • Renecia A. Watkins
    Affiliations
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind
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  • Carmella Evans-Molina
    Affiliations
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind

    Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Ind

    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Ind

    Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind
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  • Jennifer K. Terrell
    Affiliations
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind
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  • Kathleen H. Day
    Affiliations
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind
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  • Lynette Guindon
    Affiliations
    Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind
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  • Ivan A. Restrepo
    Affiliations
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind
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  • Raghavendra G. Mirmira
    Affiliations
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind

    Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind

    Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Ind

    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Ind

    Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind
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  • Janice S. Blum
    Affiliations
    Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind
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  • Linda A. DiMeglio
    Correspondence
    Reprint requests: Linda A. DiMeglio, Indiana University School of Medicine, Rm 5960, 705 Riley Hospital Drive, Indianapolis, IN 46202
    Affiliations
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind

    Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind
    Search for articles by this author
Published:September 03, 2015DOI:https://doi.org/10.1016/j.trsl.2015.08.010
      Rapid evaluation of therapies designed to preserve β cells in persons with type 1 diabetes (T1D) is hampered by limited availability of sensitive β-cell health biomarkers. In particular, biomarkers elucidating the presence and degree of β-cell stress are needed. We characterized β-cell secretory activity and stress in 29 new-onset T1D subjects (10.6 ± 3.0 years, 55% male) at diagnosis and then 8.2 ± 1.2 weeks later at first clinic follow-up. We did comparisons with 16 matched healthy controls. We evaluated hemoglobin A1c (HbA1c), β-cell function (random C-peptide [C] and proinsulin [PI]), β-cell stress (PI:C ratio), and the β-cell stress marker heat shock protein (HSP)90 and examined these parameters' relationships with clinical and laboratory characteristics at diagnosis. Mean diagnosis HbA1c was 11.3% (100 mmol/mol) and 7.6% (60 mmol/mol) at follow-up. C-peptide was low at diagnosis (P < 0.001 vs controls) and increased at follow-up (P < 0.001) to comparable with controls. PI did not differ from controls at diagnosis but increased at follow-up (P = 0.003) signifying increased release of PI alongside improved insulin secretion. PI:C ratios and HSP90 concentrations were elevated at both time points. Younger subjects had lower C-peptide and greater PI, PI:C, and HSP90. We also examined islets isolated from prediabetic nonobese diabetic mice and found that HSP90 levels were increased ∼4-fold compared with those in islets isolated from matched CD1 controls, further substantiating HSP90 as a marker of β-cell stress in T1D. Our data indicate that β-cell stress can be assessed using PI:C and HSP90. This stress persists after T1D diagnosis. Therapeutic approaches to reduce β-cell stress in new-onset T1D should be considered.

      Abbreviations:

      BiP (binding of immunoglobulin protein), BMI (body mass index), CHOP (CCAAT/enhancer-binding protein homologous protein), C-peptide (insulin connecting peptide), ER (endoplasmic reticulum), FPIR (first phase insulin response), GAD65 (glutamic acid decarboxylase 65), HbA1c (hemoglobin A1c), HSP (heat shock protein), mIAA (insulin autoantibody), IA-2 (islet antigen 2), LLD (lower limit of detection), nPOD (Network of Pancreatic Organ Donors with Diabetes), NOD (nonobese diabetic), PI (proinsulin), TID (type 1 diabetes), UPR (unfolded protein response)
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