Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling
Open accessAbstract
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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Obesity is frequently characterized by systemic inflammation, and preclinical evidence links systemic inflammation to β-cell dysfunction.
“Obesity is frequently characterized by systemic inflammation and preclinical evidence links systemic inflammation to β-cell dysfunction63,64.”
From Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future (2014) · cites this paper as [63]
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Additional file 1 of A Practical Guide to Rodent Islet Isolation and Assessment Revisited
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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)
- PMC
- PMC2948622
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- 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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