The use of proteomics to elucidate the protective effects of GLP-1 on cytokine-mediated beta-cell dysfunction and death
Year: 2011
Type: article
Abstract: Background/Aims: Type 1 diabetes (T1D) is characterized by cytokine-mediated β-cell destruction, resulting in life-long insulin dependency for the patient. The incretin hormone glucagon-like peptide-1 (GLP-1) plays a key role in regulation of insulin secretion and glucose homeostasis. Few reports have described the effects of incretin-based agents in T1D. The aim of this study was to investigate the protective effects of GLP-1 on cytokine-mediated β-cell destruction and the underlying mechanisms of action. Methods: Whole human islets were incubated with IL-1β (50U/ml) and IFN- (1000U/ml) either alone or in combination with GLP-1 (10nM). Apoptosis and insulin secretion were measured after 72 h of culture. In parallel alterations in protein profile were measured after 24 h of incubation by 2-dimensional difference gel electrophoresis (2D-DIGE). Results: Cytokines induced a significant decrease in insulin secretion (n=3, p<0.05) and increase in apoptosis (n=3, p<0.05), an effect which was almost completely restored by addition of GLP-1. 2D-DIGE analysis resulted in a differential expression of 68, 24 or 41 spots upon stimulation with cytokines, GLP-1 or the combination, respectively (n=4, p<0.05); of which we have by now identified 55% by MALDI-TOF/TOF. Preliminary data indicate that proteins of different classes, such as ER stress, RNA metabolism, cytoskeleton and islet regeneration are altered by cytokine treatment. Interestingly, Islet of Langerhans regenerating protein (REG1A) and Regenerating islet lectin 1-beta precursor (REG1B) were present in different isoforms, which were altered by the cytokines in opposite direction, suggesting a role for post-translational modified forms in cytokine-mediated destruction. GLP-1 could to a great extent restore the cytokine-induced alterations of REG1A and REG1B. Conclusions: GLP-1 was able to protect human islets against cytokine-mediated β-cell dysfunction and death. This protective effect was accompanied by changes in proteome profile, such as restoration of REG1A and REG1B, providing a better insight in the underlying mechanisms of GLP-1 action, a prerequisite for moving towards clinical applications in T1D.
Source: Lirias
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2521166250