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

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• 作者：Renecia A. Watkins^a ; Carmella Evans-Molina^b ; ^c ; ^d ; ^e ; Jennifer K. Terrell^a ; Kathleen H. Day^b ; Lynette Guindon^f ; Ivan A. Restrepo^a ; Raghavendra G. Mirmira^a ; ^b ; ^c ; ^d ; ^e ; Janice S. Blum^f ; Linda A. DiMeglio^a ; ^e ; ^{dimeglio@iu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：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 di
• 刊名：Translational Research
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：168
• 期：Complete
• 页码：96-106.e1
• 全文大小：1387 K

文摘

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.