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

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 168; pp. 96 - 106.e1
• Main Authors: Watkins, Renecia A., Evans-Molina, Carmella, Terrell, Jennifer K., Day, Kathleen H., Guindon, Lynette, Restrepo, Ivan A., Mirmira, Raghavendra G., Blum, Janice S., DiMeglio, Linda A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2016
• Subjects: Adolescent; Aging; Animals; Biomarkers; Blood Glucose; C-Peptide - blood; C-Peptide - metabolism; Case-Control Studies; Child; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Female; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Insulin-Secreting Cells - metabolism; Internal Medicine; Male; Mice; Proinsulin - genetics; Proinsulin - metabolism; Stress, Physiological - physiology; NOD; HSP; nPOD; LLD; BiP; ER; GAD65; mIAA; TID; FPIR; C-peptide; UPR; CHOP; PI; HbA1c; BMI; IA-2; islet antigen 2; heat shock protein; first phase insulin response; insulin autoantibody; binding of immunoglobulin protein; type 1 diabetes; body mass index; CCAAT/enhancer-binding protein homologous protein; insulin connecting peptide; glutamic acid decarboxylase 65; proinsulin; unfolded protein response; lower limit of detection; nonobese diabetic; hemoglobin A1c; Network of Pancreatic Organ Donors with Diabetes; endoplasmic reticulum
• ISSN: 1931-5244; 1878-1810
• DOI: 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.