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      Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition

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          SUMMARY

          SIRT3 is a nicotinamide adenine dinucleotide (NAD +)- dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial metabolism, could be susceptible to SIRT3-mediated effects. We used CRISPR/Cas9 technology to manipulate SIRT3 expression in β cells, resulting in widespread SIRT3-dependent changes in acetylation of key metabolic enzymes but no appreciable changes in glucose- or pyruvate-stimulated insulin secretion or metabolomic profile during glucose stimulation. Moreover, these broad changes in the SIRT3-targeted acetylproteome did not affect responses to nutritional or ER stress. We also studied mice with global SIRT3 knockout fed either standard chow (STD) or high-fat and high-sucrose (HFHS) diets. Only when chronically fed HFHS diet do SIRT3 KO animals exhibit a modest reduction in insulin secretion. We conclude that broad changes in mitochondrial protein acetylation in response to manipulation of SIRT3 are not sufficient to cause changes in islet function or metabolism.

          In Brief

          Peterson et al. report that ablation of SIRT3 in 832/13 β cells dramatically alters the mitochondrial acetylproteome but does not affect insulin secretion, metabolomic profile, or β cell survival. Moreover, SIRT3 knockout causes a modest reduction in insulin secretion in mice fed a high-fat and high-sucrose but not a standard chow diet.

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          Universal and confident phosphorylation site localization using phosphoRS.

          An algorithm for the assignment of phosphorylation sites in peptides is described. The program uses tandem mass spectrometry data in conjunction with the respective peptide sequences to calculate site probabilities for all potential phosphorylation sites. Tandem mass spectra from synthetic phosphopeptides were used for optimization of the scoring parameters employing all commonly used fragmentation techniques. Calculation of probabilities was adapted to the different fragmentation methods and to the maximum mass deviation of the analysis. The software includes a novel approach to peak extraction, required for matching experimental data to the theoretical values of all isoforms, by defining individual peak depths for the different regions of the tandem mass spectrum. Mixtures of synthetic phosphopeptides were used to validate the program by calculation of its false localization rate versus site probability cutoff characteristic. Notably, the empirical obtained precision was higher than indicated by the applied probability cutoff. In addition, the performance of the algorithm was compared to existing approaches to site localization such as Ascore. In order to assess the practical applicability of the algorithm to large data sets, phosphopeptides from a biological sample were analyzed, localizing more than 3000 nonredundant phosphorylation sites. Finally, the results obtained for the different fragmentation methods and localization tools were compared and discussed.
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            Glucolipotoxicity: fuel excess and beta-cell dysfunction.

            Glucotoxicity, lipotoxicity, and glucolipotoxicity are secondary phenomena that are proposed to play a role in all forms of type 2 diabetes. The underlying concept is that once the primary pathogenesis of diabetes is established, probably involving both genetic and environmental forces, hyperglycemia and very commonly hyperlipidemia ensue and thereafter exert additional damaging or toxic effects on the beta-cell. In addition to their contribution to the deterioration of beta-cell function after the onset of the disease, elevations of plasma fatty acid levels that often accompany insulin resistance may, as glucose levels begin to rise outside of the normal range, also play a pathogenic role in the early stages of the disease. Because hyperglycemia is a prerequisite for lipotoxicity to occur, the term glucolipotoxicity, rather than lipotoxicity, is more appropriate to describe deleterious effects of lipids on beta-cell function. In vitro and in vivo evidence supporting the concept of glucotoxicity is presented first, as well as a description of the underlying mechanisms with an emphasis on the role of oxidative stress. Second, we discuss the functional manifestations of glucolipotoxicity on insulin secretion, insulin gene expression, and beta-cell death, and the role of glucose in the mechanisms of glucolipotoxicity. Finally, we attempt to define the role of these phenomena in the natural history of beta-cell compensation, decompensation, and failure during the course of type 2 diabetes.
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              Metabolic signaling in fuel-induced insulin secretion.

              The pancreatic islet β cell senses circulating levels of calorigenic nutrients to secrete insulin according to the needs of the organism. Altered insulin secretion is linked to various disorders such as diabetes, hypoglycemic states, and cardiometabolic diseases. Fuel stimuli, including glucose, free fatty acids, and amino acids, promote insulin granule exocytosis primarily via their metabolism in β cells and the production of key signaling metabolites. This paper reviews our current knowledge of the pathways involved in both positive and negative metabolic signaling for insulin secretion and assesses the role of established and candidate metabolic coupling factors, keeping recent developments in focus. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                31 July 2018
                03 July 2018
                15 August 2018
                : 24
                : 1
                : 209-223.e6
                Affiliations
                [1 ]Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA
                [2 ]Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
                [3 ]Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
                [4 ]Lead Contact
                Author notes
                [* ]Correspondence: chris.newgard@ 123456duke.edu

                AUTHOR CONTRIBUTIONS

                B.S.P., J.E.C., M.D.H., and C.B.N. designed the studies. B.S.P. and J.E.C. performed the experiments. P.A.G. performed the proteomics analyses. O.I. performed the metabolomics analyses. B.S.P. and C.B.N. wrote the paper. B.S.P., J.E.C., O.I., P.A.G., M.D.H., and C.B.N. edited the paper.

                Article
                NIHMS981697
                10.1016/j.celrep.2018.05.088
                6093627
                29972782
                24f9a3ba-e70b-43e6-8c04-65b1303a6ed2

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology
                Cell biology

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