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Search: id:"swepub:oai:lup.lub.lu.se:255954a2-08f3-46b5-a197-b2ffb34d41bc" > A Syntenic Cross Sp...

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  • Peiris, HeshanFlinders University (author)

A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes

  • Article/chapterEnglish2016

Publisher, publication year, extent ...

  • 2016-05-19
  • Public Library of Science (PLoS),2016

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:255954a2-08f3-46b5-a197-b2ffb34d41bc
  • https://lup.lub.lu.se/record/255954a2-08f3-46b5-a197-b2ffb34d41bcURI
  • https://doi.org/10.1371/journal.pgen.1006033DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.

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  • Duffield, Michael D.Flinders University (author)
  • Fadista, JoaoLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups(Swepub:lu)med-jft (author)
  • Jessup, Claire F.University of Adelaide (author)
  • Kashmir, VinderFlinders University (author)
  • Genders, Amanda J.Deakin University (author)
  • McGee, Sean L.Baker IDI Heart and Diabetes Institute (author)
  • Martin, Alyce M.Flinders University (author)
  • Saiedi, MadihaFlinders University (author)
  • Morton, NicholasUniversity of Edinburgh (author)
  • Carter, RoderickUniversity of Edinburgh (author)
  • Cousin, Michael A.University of Edinburgh (author)
  • Kokotos, Alexandros C.University of Edinburgh (author)
  • Oskolkov, NikolayLund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups(Swepub:lu)fkem-nyo (author)
  • Volkov, PetrLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups(Swepub:lu)med-pvo (author)
  • Hough, Tertius A.Mary Lyon Centre Pathology (author)
  • Fisher, Elizabeth M CUniversity College London (author)
  • Tybulewicz, Victor L JImperial College London (author)
  • Busciglio, JorgeUniversity of California System (author)
  • Coskun, Pinar E.University of California System (author)
  • Becker, AnnUniversity of California System (author)
  • Belichenko, Pavel V.University of California System (author)
  • Mobley, William C.University of California System (author)
  • Ryan, Michael T.Monash University (author)
  • Chan, Jeng YieGarvan Institute of Medical Research (author)
  • Laybutt, D. RossGarvan Institute of Medical Research (author)
  • Coates, P. TobyRoyal Adelaide Hospital (author)
  • Yang, SijunWuhan University (author)
  • Ling, CharlotteLund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,Diabetes - epigenetik,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups,Diabetes - Epigenetics(Swepub:lu)endo-cl0 (author)
  • Groop, LeifLund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,Translationell muskelforskning,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups,Translational Muscle Research(Swepub:lu)endo-lgr (author)
  • Pritchard, Melanie A.Monash University (author)
  • Keating, Damien J.South Australian Health and Medical Research Institute (author)
  • Flinders UniversityTranslationell muskelforskning (creator_code:org_t)

Related titles

  • In:PLoS Genetics: Public Library of Science (PLoS)12:51553-73901553-7404

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