Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

Abstract

As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators b-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for b-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 b-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 b-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, b-cell function was not entirely preserved in the absence of MIF judging by low glucose oxidation and depolarized mitochondrial membrane. In conclusion, the observed considerable preservation of b-cells from nutrient-induced apoptosis might implicate MIF as a potential therapeutic target in the later stage of obesity-associated T2D.

Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

“…5G). Deficiency of macrophage migration inhibitory factor-1 (MIF-1) has been shown to protect pancreatic islets from palmitic acid-induced apoptosis (40). Yet whereas we detected lower levels of MIF-1 in whole pancreases of Ghrelin Ϫ/Ϫ :ob/ob mice, we observed higher levels of ChREBP in Ghsr Ϫ/Ϫ :ob/ob mice (Fig.…”

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

“…The involvement of other NEFA-dependent signals in the promotion of beta cell dysfunction and death has also been proposed. These include activation of Erk-1/2 [32], NF-κB [33], protein-kinase C (PKC)-δ [34], endoplasmic reticulum (ER) stress [35], calpain-10 [36] and ceramide formation [37], and induction of sterol regulatory element-binding protein [38], macrophage migration inhibitory factor [39], cell death-inducing DNA fragmentation factor a-like effector A [40] and cell death-inducing DFF45-like effector b [41]. NEFA-mediated inhibition of Akt activity [42] has also been implicated.…”

“…Wollheim, University of Geneva, Geneva, Switzerland) were grown as previously described [15]. Murine glucagon-secreting alpha-TC1-6 cells (passage [35][36][37][38][39][40]; a gift from Professor F. Purrello, University of Catania, Catania, Italy) were grown in monolayer at 37°C in a humidified incubator gassed with 5% CO 2 , in DMEM containing 4 mmol/l L-glutamine supplemented with 0.02% BSA, 3 g/l glucose, 10% heat-inactivated FBS, 100 IU/ml penicillin, 100 μg/ml streptomycin, 0.1 mmol/l non-essential amino acids (all from Gibco Invitrogen, Paisley, UK) and 15 mmol/ l HEPES (pH 7.4).…”

Monocyte chemoattractant protein 1 and macrophage migration inhibitory factor in children with type 1 diabetes

“…MIF is an important molecule to the development of T1DM complications such as cardiac dysfunction, and diabetic foot disease [21,22]. It is known to promote inflammatory cytokine and palmitic acid-induced pancreatic islet apoptosis [23,24].…”