Anti-proliferative effect of pro-inflammatory cytokines in cultured β cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1
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Pancreatic β-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of β-cell mass loss by pro-inflammatory cytokine-induced apoptosis, influences of a pro-inflammatory environment on β-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic β cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-bromo-2′-deoxyuridine label respectively, in the presence–absence of varying concentrations of glucose, pro-inflammatory cytokines, and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines interleukin (IL)-1β, interferon (IFN)-γ, and tumour necrosis factor-α (TNF-α) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in β-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased β-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and β-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic β cells as well as to delay the development of overt diabetes.
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GLP-1-based therapies show anti-inflammatory effects on the liver, vascular system including aorta and vein endothelial cells, brain, kidney, lung, testis, and skin by reducing the production of inflammatory cytokines and infiltration of immune cells in the tissues.
“emerging data suggest that GLP-1-based therapies also showed anti-inflammatory effects on the liver, vascular system including aorta and vein endothelial cells, brain, kidney, lung, testis, and skin by reducing the production of inflammatory cytokines and infiltration of immune cells in the tissues [17, 21–25].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [22]
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- Authors
- Blandino-Rosano, M., Perez-Arana, G., Mellado-Gil, J. M., Segundo, C., & Aguilar-Diosdado, M.
- Affiliations
- Hospital Universitario Puerta del Mar (ES)
- Venue
- Journal of Molecular Endocrinology
- Publisher
- Bioscientifica
- Published
- 2008-05-15
- Volume
- 41
- Issue
- 1
- Pages
- 35-44
- ISSN
- 0952-5041 (ISSN-L)
- 1479-6813
- OpenAlex
- W2160357177
- Cited by
- 82
- References
- 61
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 2 · 2019: 3 · 2018: 1 · 2017: 7 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 10 · 2012: 8
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk
- 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
- inflammatory cytokines, beta-cell proliferation, glucagon-like peptide-1, ERK signaling, beta-cell apoptosis, type 1 diabetes, IL-1β, interferon-gamma, TNF-α, glucose, pancreatic islets, beta cell regeneration, ERK1/2 phosphorylation
- MeSH terms
- Animals, Cells, Cultured, Glucose, Male, Cytokines, Rats, Wistar, Inflammation Mediators, Cell Culture Techniques, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 3, Cell Proliferation, Insulin-Secreting Cells, Rats, Glucagon-Like Peptide 1
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