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  • br Results br Discussion In this study

    2019-07-24


    Results
    Discussion In this study we discovered that LPS-triggered TLR4 activation induces β-cell dysfunction, apoptosis and a pro-inflammatory response through IL-1β, IL-6, TNF and IL-8 production in human islets. While LPS-induced IL-6 was partially responsible for β-cell dysfunction, in confirmation with what we have shown before in rodent islets [30], IL-8 from α-cells was responsible for monocyte migration to islets during TLR4-activation-induced islet inflammation. Such complex cellular TLR4 response in islets is further potentiated in obese individuals, with more IL-1β, IL-6 and IL-8 expression and a tendency to more islet macrophage accumulation, which may be the prerequisite for a higher vulnerability of obese individuals to later development of β-cell damage und diabetes.
    Experimental procedures
    Transparency document
    Acknowledgements This work was supported by the JDRF and the German Research Foundation (DFG). We would like to thank Katrischa Hennekens for excellent technical assistance and Payal Shah for help with the analyses (all Uni Bremen) and Melanie Braun and Lutz Schmidt (Asklepios Klinik Hamburg) for providing the human buffy coats. We thank Julie Kerr-Conte and Francois Pattou, European Genomic Institute for Diabetes, INSERM UMR 1190, Lille, France for the high quality human islet isolations. Human islets were also provided through the JDRF award 31-2008-416 (ECIT Islet for Basic Research program) and from the Integrated Islet Distribution Program (IIDP): Human Islets for Research funded through a contract from the National Institute of Diabetes and Kidney and Digestive Diseases (NIDDK) and the JDRF.
    Introduction Mitochondria play a vital role in a myriad of processes involved in metabolism, cellular bioenergetics, and metabolic cell signaling [[1], [2], [3], [4]]. The mitochondrial oxidative phosphorylation (OXPHOS) system, which comprises complexes I–IV and ATP synthase (CV), is the major contributor to cellular Ifenprodil hemitartrate production and sustains most mitochondrial functions. The dysfunction of complex I (CI) (OMIM 252010) of the OXPHOS system, is the most common defect in mitochondrial energy metabolism, often resulting in progressive, severe multi-system deterioration. Due to the extreme complexity and heterogeneous nature (genetically and clinically) of human CI deficiency, the underlying pathogenic mechanisms thereof remain poorly understood [5,6]. Current studies on mouse models of CI dysfunction, such as the whole-body Ndufs4−/− (knockout) mouse, attempt to better comprehend mitochondrial disease. The nuclear DNA-encoded NDUFS4 protein is essential to CI assembly, stability, and activity [7,8]. Ndufs4−/− mice present with symptoms similar to human CI deficiency at around postnatal day (P) 35 and develop a progressive Leigh-like phenotype, including developmental delays, failure to thrive, lethargy, ophthalmoplegia, locomotor impairment, hearing loss, as well as progressive ataxia, and necrotizing encephalomyopathy leading to early death (P50–60) [[9], [10], [11]]. Since the development of whole-body Ndufs4−/− mice, several conditional knockouts (neuronal, glial, cardiac, hematopoietic, and hepatic) have been developed in order to gain insight into tissue-specific consequences of CI dysfunction (reviewed by Toracco et al. [12]). However, due to the main interest in the predominant neurological phenotype of this disease model, limited information is available on skeletal muscle-specific consequences of the Ndufs4 knockout. A recent study by Foriel and colleagues [13] highlighted the involvement of skeletal muscle in Ndufs4 knockout pathology. The authors reported similarities between the phenotypes of skeletal muscle-specific and whole-body Ndufs4 knockout Drosophila, such as reduced lifespan, feeding difficulties, locomotor impairment, and climbing defects. Given the important, often underappreciated, role of the muscular system in health and disease [14], as well as its integration and interdependence with the nervous system [15], it is imperative to elucidate the effects of a Ndufs4 knockout on muscle metabolism. Skeletal muscle not only facilitates breathing and locomotion but also plays an essential role in various systemic, energy-demanding processes such as whole-body protein metabolism, glucose, and fatty acid consumption, thermoregulation, immunity, as well as the maintenance of adequate bone strength and density [[14], [15], [16]]. As Ndufs4−/− mice display weight loss [9], a significant decrease in body fat [11], decreases in body temperature [9], as well as systemic inflammation and osteoporosis [10], it can be hypothesized that aberrant skeletal muscle metabolism might also play an important role in murine Ndufs4−/− phenotypes.