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.

Elevations in the Fasting Serum Proinsulin–to–C-Peptide Ratio Precede the Onset of Type 1 Diabetes

“…In human subjects, elevations in the PI:C ratio are present in those with type 1 and type 2 diabetes (8,26). Moreover, reductions in the PI:C ratio have been associated with improved β-cell function in both disorders.…”

A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes

“…The top hit was monorden (radicicol), which inhibits heat shock protein 90 (Hsp90), a molecular chaperone responsible for polypeptide maturation, rematuration, and folding of denatured proteins (44). Hsp90 is upregulated in response to pancreatic β cell stress in T1D (45,46). Inhibitors of Hsp90 promote ubiquitin-proteasome-mediated degradation of their protein substrates, block NF-κB activity, and interfere with MHC class II-mediated islet antigen presentation (44,47,48).…”

Remission Phase in Paediatric Type 1 Diabetes: New Understanding and Emerging Biomarkers

“…The latter method is the most widely used in clinical research and intervention studies to monitor changes in β-cell function in T1D patients, although an agreement should be reached to standardize this test. Other proposed biomarkers of β-cell function in humans are proinsulin levels in serum or mediators of β-cell stress such as the proinsulin/C-peptide ratio and the measurement of the heat shock protein 90 (Hsp90) [28]. …”