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Cited by 353Endoplasmic Reticulum Stress and DiseasePancreatic function and diabetesDiabetes and associated disorders

Islet β-Cell Endoplasmic Reticulum Stress Precedes the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse Model

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Tersey, Sarah A., Nishiki, Yurika, Templin, Andrew T., Cabrera, Susanne M., Stull, Natalie D., Colvin, Stephanie C., Evans-Molina, Carmella, Rickus, Jenna L. +2 more·2012·Diabetes
DOI 10.2337/db11-1293PMC PMC3314371
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Abstract

Type 1 diabetes is preceded by islet β-cell dysfunction, but the mechanisms leading to β-cell dysfunction have not been rigorously studied. Because immune cell infiltration occurs prior to overt diabetes, we hypothesized that activation of inflammatory cascades and appearance of endoplasmic reticulum (ER) stress in β-cells contributes to insulin secretory defects. Prediabetic nonobese diabetic (NOD) mice and control diabetes-resistant NOD-SCID and CD1 strains were studied for metabolic control and islet function and gene regulation. Prediabetic NOD mice were relatively glucose intolerant and had defective insulin secretion with elevated proinsulin:insulin ratios compared with control strains. Isolated islets from NOD mice displayed age-dependent increases in parameters of ER stress, morphologic alterations in ER structure by electron microscopy, and activation of nuclear factor-κB (NF-κB) target genes. Upon exposure to a mixture of proinflammatory cytokines that mimics the microenvironment of type 1 diabetes, MIN6 β-cells displayed evidence for polyribosomal runoff, a finding consistent with the translational initiation blockade characteristic of ER stress. We conclude that β-cells of prediabetic NOD mice display dysfunction and overt ER stress that may be driven by NF-κB signaling, and strategies that attenuate pathways leading to ER stress may preserve β-cell function in type 1 diabetes.

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  • Inflammatory cytokines, hypoxia, and hyperglycemia can all induce an ER stress response in β cells that leads to cell dysfunction and apoptosis.

    “Inflammatory cytokines, hypoxia, and hyperglycemia can all induce an ER stress response in β cells that leads to cell dysfunction and apoptosis.”

    From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [129]

    The Abstract and Discussion report that proinflammatory cytokines are associated with ER-stress responses in β cells and that ER stress may contribute to impaired insulin secretion. They do not establish hypoxia or hyperglycemia as ER-stress triggers, or show that the resulting ER stress leads to apoptosis. (LLM, conf=0.86)

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References 43 · Cited by 353

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Authors
Tersey, S. A., Nishiki, Y., Templin, A. T., Cabrera, S. M., Stull, N. D., Colvin, S. C., Evans-Molina, C., Rickus, J. L., Maier, B., & Mirmira, R. G.
Affiliations
  • Indiana University Indianapolis (US)
  • Indiana University School of Medicine (US)
  • The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
  • Purdue University West Lafayette (US)
Corresponding author
Mirmira, Raghavendra G.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2012-03-14
Volume
61
Issue
4
Pages
818-827
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db11-1293
PMC
PMC3314371
OpenAlex
W2138846538
Cited by
353
References
43
Citations by year
2026: 13 · 2025: 23 · 2024: 18 · 2023: 15 · 2022: 30 · 2021: 34 · 2020: 27 · 2019: 21 · 2018: 17 · 2017: 28 · 2016: 29 · 2015: 27 · 2014: 34 · 2013: 24 · 2012: 11
FWCI
14.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Purdue e-Pubs (Purdue University System) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (F32DK094489, T32DK065549, R01DK083583, R01DK093954)
  • National Center for Research Resources (UL1RR025761)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
type 1 diabetes, endoplasmic reticulum stress, beta-cell dysfunction, prediabetes, NOD mice, NF-κB signaling, proinsulin/insulin ratio, insulin secretion, inflammatory cytokines, insulitis, MIN6 cells
MeSH terms
Aging, Animals, Blood Glucose, Diabetes Mellitus, Type 1, Endoplasmic Reticulum, Female, Stress, Physiological, Mice, Inbred NOD, Glucose Intolerance, Insulin-Secreting Cells, Mice

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