Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 35-44 |
| Number of pages | 10 |
| Journal | Journal of Molecular Endocrinology |
| Volume | 41 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - Jul 1 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Molecular Biology
- Endocrinology
Cite this
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. / Blandino Rosano, Manuel; Perez-Arana, G.; Mellado-Gil, J. M.; Segundo, Carmen; Aguilar-Diosdado, Manuel.
In: Journal of Molecular Endocrinology, Vol. 41, No. 1-2, 01.07.2008, p. 35-44.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Anti-proliferative effect of pro-inflammatory cytokines in cultured β cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition
T2 - Protective role of glucagon-like peptide -1
AU - Blandino Rosano, Manuel
AU - Perez-Arana, G.
AU - Mellado-Gil, J. M.
AU - Segundo, Carmen
AU - Aguilar-Diosdado, Manuel
PY - 2008/7/1
Y1 - 2008/7/1
N2 - 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.
AB - 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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U2 - 10.1677/JME-07-0154
DO - 10.1677/JME-07-0154
M3 - Article
VL - 41
SP - 35
EP - 44
JO - Journal of Molecular Endocrinology
JF - Journal of Molecular Endocrinology
SN - 0952-5041
IS - 1-2
ER -