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  • VH-298 br Conclusion The following are the supplementary dat

    2019-07-24


    Conclusion The following are the supplementary data related to this article.
    Transparency document
    Acknowledgements This study was funded by the European Foundation for the Study of Diabetes (EFSD)/Novo Nordisk (2015–2017) and by the Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica (grants PRIN, PON 01_02460 and POR 03PE_00060_8 Campania Bioscience). This study was supported in part by the FLAGSHIP "InterOmics" Project ASPIRE, funded and supported by the Italian MIUR and CNR organizations. ML and LP are the recipients of the SID/FO.DI.RI.-MSD ITALIA 2017 Research Fellowship. TF was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB1118). We are grateful to M. Brownlee (Albert Einstein College of Medicine, Bronx, NY, USA) for having enable us to use the Glo1-KD mice. We thank Antonio D'Andrea for his technical support.
    Introduction Type 2 Diabetes (T2D) is strongly associated with obesity and characterized by chronic insulin resistance, progressive failure of pancreatic β-cells, and finally hyperglycaemia [1]. The association of T2D with inflammatory mediators, such as IL-1β, IL-6, IL-8, TNF as well as circulating acute-phase proteins is highlighted in several prospective and retrospective cohort studies [[2], [3], [4], [5]]. Such measures of chronic, low-grade, sterile VH-298 can predict type 2 diabetes progression. Pro-inflammatory cytokines and chemokines can independently cause insulin resistance in peripheral insulin-sensing tissues like fat, liver and muscle [5,6] and progressive β-cell failure. This ultimately shifts metabolism from relative insulin insufficiency - due to the greater insulin demand in obesity - to definite insulin deficiency [7] and on the level of the β-cell from compensation to decompensation [8,9]. Toll-like receptor (TLR)-4 signaling is one of the major pro-inflammatory pathways activated by exogenous pathogen-related or endogenous danger-related molecules. Circulating levels of the classical TLR4 ligand – LPS are elevated in obese and T2D individuals as well as in rodent obesity/diabetes models, recently termed as “metabolic endotoxemia” [10,11]. The implicated mechanism is attributed to the “leaky gut”; associated with alterations in the gut microbiota composition during obesity, causing perturbations of tight junction proteins. This results in an elevation in gut permeability, allowing more gut microbe-derived LPS to enter the circulation [10,12]. Other TLR4 ligands/agonists, including CXCL10, HMGB1, S100A8, hyaluronan, are also elevated in the serum of T2D patients [[13], [14], [15]]. TLR4-deficiency or its pharmacological or genetic inhibition ameliorates obesity- or lipid-induced insulin resistance in mouse models and in humans [[16], [17], [18], [19], [20]]. Saturated fatty acids, particularly palmitate, have also been connected to TLR4 activation in the context of obesity and T2D [16,[21], [22], [23]]. However, palmitate is not a direct agonist for TLR4 [24,25], and indirectly activates TLR4 through the hepato-adipokine fetuin-A [24]. The whole TLR4 complex is not only expressed in cells of the immune system; relatively high expression was found in endocrine cells of pancreatic islets [14,26] and thus, a direct role of TLR4 in islet inflammation was proposed. Indeed, TLR4 activation contributes to β-cell failure; stimulation of isolated rodent islets by TLR4 ligands impairs β-cell function and survival [[26], [27], [28], [29], [30]]. In purified human β-cells and isolated human/rodent islets, LPS treatment reduces insulin gene expression [28,29], which confirms a direct TLR4 effect on the level of the β-cell. The intra- and inter-islet cellular cross talk may accelerate inflammation by paracrine and endocrine effects of inflammatory mediators. Islet resident and infiltrated immune cells can induce mouse islet inflammation and dysfunction in ex vivo conditions [30]. Therefore, research on intact islets, where the islet microenvironment and the crosstalk between different islet cell populations is preserved, will identify the impact of inflammatory stimuli on islet function and cellular viability, rather than working with isolated cell types, which suffer per se from a poor survival due to the loss of their natural integrity and cellular communication [31]. Hence, in this present study, we investigated whether and through which inflammatory mediators TLR4-triggered inflammation and the islet's cellular inflammatory interplay affect β-cell function and viability.