title: Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes.
abstract: 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.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Renecia A
authors.initials: RA
authors.lastname: Watkins
authors.affiliation: 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.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Terrell
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Kathleen H
authors.initials: KH
authors.lastname: Day
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Lynette
authors.initials: L
authors.lastname: Guindon
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Restrepo
authors.affiliation: 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.
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind. Electronic address: dimeglio@iu.edu.
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
mesh_terms: D000293:Adolescent; D000375:Aging; D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide; D018841:HSP90 Heat-Shock Proteins; D011384:Proinsulin