Low Level Pro-inflammatory Cytokines Decrease Connexin36 Gap Junction Coupling in Mouse and Human Islets through Nitric Oxide-mediated Protein Kinase Cδ
Open accessAbstract
Pro-inflammatory cytokines contribute to the decline in islet function during the development of diabetes. Cytokines can disrupt insulin secretion and calcium dynamics; however, the mechanisms underlying this are poorly understood. Connexin36 gap junctions coordinate glucose-induced calcium oscillations and pulsatile insulin secretion across the islet. Loss of gap junction coupling disrupts these dynamics, similar to that observed during the development of diabetes. This study investigates the mechanisms by which pro-inflammatory cytokines mediate gap junction coupling. Specifically, as cytokine-induced NO can activate PKCδ, we aimed to understand the role of PKCδ in modulating cytokine-induced changes in gap junction coupling. Isolated mouse and human islets were treated with varying levels of a cytokine mixture containing TNF-α, IL-1β, and IFN-γ. Islet dysfunction was measured by insulin secretion, calcium dynamics, and gap junction coupling. Modulators of PKCδ and NO were applied to determine their respective roles in modulating gap junction coupling. High levels of cytokines caused cell death and decreased insulin secretion. Low levels of cytokine treatment disrupted calcium dynamics and decreased gap junction coupling, in the absence of disruptions to insulin secretion. Decreases in gap junction coupling were dependent on NO-regulated PKCδ, and altered membrane organization of connexin36. This study defines several mechanisms underlying the disruption to gap junction coupling under conditions associated with the development of diabetes. These mechanisms will allow for greater understanding of islet dysfunction and suggest ways to ameliorate this dysfunction during the development of diabetes.
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Cytokine cocktail pretreatment reduces Gjd2 expression, and Gjd2 is downregulated in δ-cells of pre-diabetic adult NOD mice, correlating with increased somatostatin secretion.
“In agreement with a previous report15, cytokine cocktail pretreatment reduced the expression of Gjd2 (Extended Data Fig. 5c), which encodes the gap junction protein connexin-36”
From Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes (2024) · cites this paper as [15]
The Results section, “Pro-inflammatory Cytokines Decrease Membrane Cx36 and Alter Plaque Organization” (page unavailable), reports that cytokine treatment decreased membrane-localized connexin-36 protein and gap-junction coupling. It does not establish reduced Gjd2 gene expression; the copy also does not report Gjd2 downregulation in δ-cells of pre-diabetic NOD mice or a correlation with somatostatin secretion. (LLM, conf=0.85)
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“5c), which encodes the gap junction protein connexin-36, expressed in both β-cells and δ-cells 15,16 .”
- Authors
- Farnsworth, N. L., Walter, R. L., Hemmati, A., Westacott, M. J., & Benninger, R. K. P.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- Benninger, Richard K.P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 291
- Issue
- 7
- Pages
- 3184-3196
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4751367
- OpenAlex
- W2258402864
- Cited by
- 48
- References
- 70
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 11 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 8 · 2016: 2
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R00 DK085145, R01 DK102950, R01 DK106412, F32 DK102276)
- Juvenile Diabetes Research Foundation (5-CDA-2014–198-A-N)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- inflammatory cytokines, connexin 36, electrical coupling, nitric oxide, protein kinase C delta, pancreatic islets, insulin secretion, calcium dynamics, TNF-α, IL-1β, interferon-gamma, islet dysfunction, diabetes mellitus
- MeSH terms
- Insulin Secretion, Gap Junction delta-2 Protein, Animals, Cell Survival, Enzyme Activation, Enzyme Inhibitors, Humans, Insulin, Interferon-gamma, Islets of Langerhans, Mice, Inbred C57BL, Nitric Oxide, Prediabetic State, Recombinant Proteins, Tissue Banks, Tumor Necrosis Factor-alpha, Cytokines, Gap Junctions, Connexins, Calcium Signaling, Tissue Culture Techniques, Protein Kinase C-delta, Interleukin-1beta
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