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Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid-induced apoptosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2012 (English)In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 90, no 7, 688-698 p.Article in journal (Refereed) Published
Abstract [en]

As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators beta-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for beta-cell function associated with T2D and obesity in humans is macrophage migration inhibitory factor (MIF). Therefore, the aim of this study was to explore MIF expression in vivo during development of obesity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 mice and whether MIF inhibition could affect beta-cell apoptosis and dysfunction induced by palmitic acid (PA) in vitro. Indeed, increase in systemic and locally produced MIF correlated well with the weight gain, triglyceride upregulation, glucose intolerance and insulin resistance, which developed in HFD-fed mice. In in vitro settings PA dose-dependently induced MIF secretion before apoptosis development in islets. Further, mif gene deletion, mRNA silencing or protein inhibition rescued beta-cells from PA-induced apoptosis as measured by MTT assay and histone-DNA enzyme linked immuno sorbent assay. Protection from induced apoptosis was mediated by altered activation of caspase pathway and correlated with changes in the level of Bcl-2 family members. Further, MIF inhibition conveyed a significant resistance to PA-induced downregulation of insulin and PDX-1 expression and ATP content. However, beta-cell function was not entirely preserved in the absence of MIF judging by low glucose oxidation and depolarized mitochondria! membrane. In conclusion, the observed considerable preservation of beta-cells from nutrient-induced apoptosis might implicate MIF as a potential therapeutic target in the later stage of obesity-associated T2D.

Place, publisher, year, edition, pages
2012. Vol. 90, no 7, 688-698 p.
Keyword [en]
apoptosis, beta-cells, macrophage migration inhibitory factor, obesity, palmitic acid, type 2 diabetes
National Category
Medical and Health Sciences Immunology in the medical area
URN: urn:nbn:se:uu:diva-181419DOI: 10.1038/icb.2011.89ISI: 000307611700005OAI: oai:DiVA.org:uu-181419DiVA: diva2:557589
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2013-12-18Bibliographically approved

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Sandler, Stellan
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