| 1. |
- Saksida, Tamara, et al.
(författare)
-
Galectin-3 deficiency protects pancreatic islet cells from cytokine-triggered apoptosis in vitro
- 2013
-
Ingår i: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541. ; 228:7, s. 1568-1576
-
Tidskriftsartikel (refereegranskat)abstract
- Beta cell apoptosis is a hallmark of diabetes. Since we have previously shown that galectin-3 deficient (LGALS3/) mice are relatively resistant to diabetes induction, the aim of this study was to examine whether beta cell apoptosis depends on the presence of galectin-3 and to delineate the underlying mechanism. Deficiency of galectin-3, either hereditary or induced through application of chemical inhibitors, -lactose or TD139, supported survival and function of islet beta cells compromised by TNF-+IFN-+IL-1 stimulus. Similarly, inhibition of galectin-3 by -lactose or TD139 reduced cytokine-triggered apoptosis of beta cells, leading to conclusion that endogenous galectin-3 propagates beta apoptosis in the presence of an inflammatory milieu. Exploring apoptosis-related molecules expression in primary islet cells before and after treatment with cytokines we found that galectin-3 ablation affected the expression of major components of mitochondrial apoptotic pathway, such as BAX, caspase-9, Apaf, SMAC, caspase-3, and AIF. In contrast, anti-apoptotic molecules Bcl-2 and Bcl-XL were up-regulated in LGALS3/ islet cells when compared to wild-type (WT) counterparts (C57BL/6), resulting in increased ratio of anti-apoptotic versus pro-apoptotic molecules. However, Fas-triggered apoptotic pathway as well as extracellular signal-regulated kinase 1/2 (ERK1/2) was not influenced by LGALS-3 deletion. All together, these results point to an important role of endogenous galectin-3 in beta cell apoptosis in the inflammatory milieu that occurs during diabetes pathogenesis and implicates impairment of mitochondrial apoptotic pathway as a key event in protection from beta cell apoptosis in the absence of galectin-3. J. Cell. Physiol. 228: 15681576, 2013. (c) 2012 Wiley Periodicals, Inc.
|
|
| 2. |
- Saksida, Tamara, et al.
(författare)
-
Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid-induced apoptosis
- 2012
-
Ingår i: Immunology and Cell Biology. - : Wiley. - 0818-9641 .- 1440-1711. ; 90:7, s. 688-698
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 3. |
- Stojanovic, Ivana, et al.
(författare)
-
Macrophage migration inhibitory factor (MIF) enhances palmitic acid- and glucose-induced murine beta cell dysfunction and destruction in vitro.
- 2012
-
Ingår i: Growth Factors. - : Informa UK Limited. - 0897-7194 .- 1029-2292. ; 30:6, s. 385-393
-
Tidskriftsartikel (refereegranskat)abstract
- Although several reports suggest a potentially deleterious role of macrophage migration inhibitory factor (MIF) in type 2 diabetes (T2D) pathology, it is still unclear how this pro-inflammatory cytokine acts on pancreatic beta cells. The aim of the present study was to evaluate MIF effects on murine beta cells in the in vitro settings mimicking T2D-associated conditions. Results indicate that recombinant MIF further increased apoptosis of pancreatic islets or MIN6 cells upon exposure to palmitic acid or glucose. This was accompanied by upregulation of several pro-apoptotic molecules. Furthermore, MIF potentiated nutrient-induced islet cell dysfunction, as revealed by lower glucose oxidation rate, ATP content, and depolarized mitochondrial membrane. The final outcome was potentiation of mitochondrial apoptotic pathway. The observed upregulation of nutrient-induced islet cell dysfunction and apoptosis by MIF implicates that silencing MIF may be beneficial for maintaining integrity of endocrine pancreas in obesity-associated T2D.
|
|
