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

Manuel Blandino Rosano, G. Perez-Arana, J. M. Mellado-Gil, Carmen Segundo, Manuel Aguilar-Diosdado

Research output: Contribution to journalArticle

61 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)35-44
Number of pages10
JournalJournal of Molecular Endocrinology
Volume41
Issue number1-2
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

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Glucagon-Like Peptide 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Cultured Cells
Cytokines
Islets of Langerhans
Type 1 Diabetes Mellitus
Glucose
Cell Proliferation
Apoptosis
In Situ Nick-End Labeling
Bromodeoxyuridine
Interleukin-1
Interferons
Regeneration
Diabetes Mellitus
Homeostasis
Cell Death
Tumor Necrosis Factor-alpha
Western Blotting

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 journalArticle

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