Cited by 83Pancreatic function and diabetesDiabetes and associated disordersEndoplasmic Reticulum Stress and Disease

Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling

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Dula, Stacey B., Jecmenica, Mladen, Wu, Runpei, Jahanshahi, Pooya, Verrilli, Gretchen M., Carter, Jeffrey D., Brayman, Kenneth L., Nunemaker, Craig S.·2010·Cell Calcium

Abstract

In obesity and the early stages of type 2 diabetes (T2D), proinflammatory cytokines are mildly elevated in the systemic circulation. This low-grade systemic inflammation exposes pancreatic islets to these circulating cytokines at much lower levels than seen within the islet during insulitis. These low-dose effects have not been well described. We examined mouse islets treated overnight with a low-dose cytokine combination commonly associated with inflammation (TNF-alpha, IL-1 beta, and IFN-gamma). We then examined islet function primarily using intracellular calcium ([Ca(2+)](i)), a key component of insulin secretion and cytokine signaling. Cytokine-treated islets demonstrated several features that suggested dysfunction including excess [Ca(2+)](i) in low physiological glucose (3mM), reduced responses to glucose stimulation, and disrupted [Ca(2+)](i) oscillations. Interestingly, islets taken from young db/db mice showed similar disruptions in [Ca(2+)](i) dynamics as cytokine-treated islets. Additional studies of control islets showed that the cytokine-induced elevation in basal [Ca(2+)](i) was due to both greater calcium influx through L-type-calcium-channels and reduced endoplasmic reticulum (ER) calcium storage. Many of these cytokine-induced disruptions could be reproduced by SERCA blockade. Our data suggest that chronic low-grade inflammation produces circulating cytokine levels that are sufficient to induce beta-cell dysfunction and may play a contributing role in beta-cell failure in early T2D.

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Crossref · 10.1016/j.ceca.2010.07.007

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  1. [79]Spinas GA Palmer JP Mandrup-Poulsen T Andersen H Nielsen JH Nerup J The bimodal effect of interleukin 1 on rat pancreatic beta-cells--stimulation followed by inhibition--depends upon dose, duration of exposure, and ambient glucose concentration Acta Endocrinol 119 1988 307 311 3051828

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Authors
Dula, S. B., Jecmenica, M., Wu, R., Jahanshahi, P., Verrilli, G. M., Carter, J. D., Brayman, K. L., & Nunemaker, C. S.
Affiliations
University of Virginia (US)
Venue
Cell Calcium
Publisher
Elsevier BV
Published
2010-08
Volume
48
Issue
2-3
Pages
133-142
ISSN
0143-4160 (ISSN-L)
OpenAlex
W1965785955
Cited by
83
References
82
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 2 · 2018: 8 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 10 · 2012: 1
FWCI
5.74
Type
journal article
Language
en
Open access
Locations
  • Cell Calcium (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p30dk063609-05)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-063609, P30-DK-063609, K01DK081621)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
low-grade inflammation, pancreatic islets, beta-cell dysfunction, intracellular calcium, calcium handling, inflammatory cytokines, TNF-α, IL-1β, interferon-gamma, calcium oscillations, L-type calcium channels, SERCA, type 2 diabetes, obesity, db/db mice, insulin secretion
MeSH terms
Acidosis, Animals, Calcium, Diabetes Mellitus, Type 2, Endoplasmic Reticulum, Glucose, Islets of Langerhans, Male, Mice, Inbred C57BL, Mice, Transgenic, Cytokines, Inflammation Mediators, Calcium Signaling, Calcium Channels, L-Type, Insulin-Secreting Cells, Mice, Sarcoplasmic Reticulum Calcium-Transporting ATPases

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