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)To read this article in full you will need to make a payment
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References
- Redefining the clinical remission period in children with type 1 diabetes.Pediatr Diabetes. 2004; 5: 16-19
- ‘The honeymoon phase’ in children with type 1 diabetes mellitus: frequency, duration, and influential factors.Pediatr Diabetes. 2006; 7: 101-107
- New definition for the partial remission period in children and adolescents with type 1 diabetes.Diabetes Care. 2009; 32: 1384-1390
- Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model.Diabetes. 2012; 61: 818-827
- Restoration of the unfolded protein response in pancreatic beta cells protects mice against type 1 diabetes.Sci Transl Med. 2013; 5: 211ra156
- Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes.Diabetologia. 2012; 55: 2417-2420
- The binary switch between life and death of endoplasmic reticulum-stressed beta cells.Curr Opin Endocrinol Diabetes Obes. 2010; 17: 107-112
- Endoplasmic reticulum stress, pancreatic beta-cell degeneration, and diabetes.Cold Spring Harb Perspect Med. 2012; 2: a007666
- ER stress in pancreatic beta cells: the thin red line between adaptation and failure.Sci Signal. 2010; 3: pe7
- Endoplasmic reticulum stress and pancreatic beta-cell death.Trends Endocrinol Metab. 2011; 22: 266-274
- Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?.Antioxid Redox Signal. 2007; 9: 2277-2294
- Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.Proc Natl Acad Sci U S A. 2011; 108: 8885-8890
- Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The Childhood Diabetes in Finland Study Group.J Clin Endocrinol Metab. 1994; 79: 1570-1575
- Exposure of human islets to cytokines can result in disproportionately elevated proinsulin release.J Clin Invest. 1999; 104: 67
- Dual role of heat shock proteins as regulators of apoptosis and innate immunity.J Innate Immun. 2010; 2: 238-247
- GRP94: an HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum.Biochim Biophys Acta. 2012; 1823: 774-787
- Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data.Diabetes. 2012; 61: 2066-2073
- Guide for the care and use of laboratory animals.8th ed. The National Academies Press, Washington, DC2011
- An improved method for isolation of mouse pancreatic islets.Transplantation. 1985; 40: 437
- Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet β cell.J Biol Chem. 2014; 289: 32798-32810
- The bias due to incomplete matching.Biometrics. 1985; 41: 103-116
- Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset.Diabetes. 2010; 59: 679-685
- The role of inflammation in insulitis and beta-cell loss in type 1 diabetes.Nat Rev Endocrinol. 2009; 5: 219-226
- Determinants of clinical remission in recent-onset IDDM.Diabetes Care. 1993; 16: 125-132
- Proinsulin levels and the proinsulin: c-peptide ratio complement autoantibody measurement for predicting type 1 diabetes.Diabetologia. 2005; 48: 2322-2329
- Increased proinsulin levels as an early indicator of B-cell dysfunction in non-diabetic twins of type 1 (insulin-dependent) diabetic patients.Diabetologia. 1988; 31: 182-184
- Abnormal proinsulin/C-peptide ratio in juvenile diabetes.Acta Diabetol Lat. 1982; 19: 351-358
- Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of type 1 (insulin-dependent) diabetes mellitus.Diabetologia. 1990; 33: 36-42
- Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha.Mol Cell Biol. 2002; 22: 8506-8513
- Cdc37/Hsp90 protein-mediated regulation of IRE1α protein activity in endoplasmic reticulum stress response and insulin synthesis in INS-1 cells.J Biol Chem. 2012; 287: 6266-6274
- Interaction of Nck1 and PERK phosphorylated at Y561 negatively modulates PERK activity and PERK regulation of pancreatic β-cell proinsulin content.Mol Biol Cell. 2014; 25: 702-711
- Oxidative stress induces monocyte necrosis with enrichment of cell-bound albumin and overexpression of endoplasmic reticulum and mitochondrial chaperones.PLoS One. 2013; 8: e59610
- Type 1 diabetes alters anti-hsp90 autoantibody isotype.J Autoimmun. 2003; 20: 237-245
- Secreted heat shock protein 90alpha induces colorectal cancer cell invasion through CD91/LRP-1 and NF-kappaB-mediated integrin alphaV expression.J Biol Chem. 2010; 285: 25458-25466
- Elevated HSP27, HSP70 and HSP90 alpha in chronic obstructive pulmonary disease: markers for immune activation and tissue destruction.Clin Lab. 2009; 55: 31-40
- Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes.J Biol Chem. 2004; 279: 42351-42354
- Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function.J Clin Invest. 1992; 90: 1263
- Direct autocrine action of insulin on β-cells: does it make physiological sense?.Diabetes. 2013; 62: 2157-2163
- Effectiveness of early intensive therapy on β-cell preservation in type 1 diabetes.Diabetes Care. 2013; 36: 4030-4035
- Effect of insulin resistance and hyperglycemia on proinsulin release in a primate model of diabetes mellitus.J Clin Endocrinol Metab. 1992; 74: 192-197
- Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance.Diabetologia. 1987; 30: 698-702
- Role of hsp90 in systemic lupus erythematosus and its clinical relevance.Autoimmune Dis. 2012; 2012: 728605
- Aberrant expression and secretion of heat shock protein 90 in patients with bullous pemphigoid.PLoS One. 2013; 8: e70496
Article info
Publication history
Published online: September 03, 2015
Accepted:
August 28,
2015
Received in revised form:
August 12,
2015
Received:
April 29,
2015
Identification
Copyright
© 2016 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
