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

Peiris, Heshan (author)
Flinders University
Duffield, Michael D. (author)
Flinders University
Fadista, Joao (author)
Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups
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Jessup, Claire F. (author)
University of Adelaide
Kashmir, Vinder (author)
Flinders University
Genders, Amanda J. (author)
Deakin University
McGee, Sean L. (author)
Baker IDI Heart and Diabetes Institute
Martin, Alyce M. (author)
Flinders University
Saiedi, Madiha (author)
Flinders University
Morton, Nicholas (author)
University of Edinburgh
Carter, Roderick (author)
University of Edinburgh
Cousin, Michael A. (author)
University of Edinburgh
Kokotos, Alexandros C. (author)
University of Edinburgh
Oskolkov, Nikolay (author)
Lund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups
Volkov, Petr (author)
Lund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups
Hough, Tertius A. (author)
Mary Lyon Centre Pathology
Fisher, Elizabeth M C (author)
University College London
Tybulewicz, Victor L J (author)
Imperial College London
Busciglio, Jorge (author)
University of California System
Coskun, Pinar E. (author)
University of California System
Becker, Ann (author)
University of California System
Belichenko, Pavel V. (author)
University of California System
Mobley, William C. (author)
University of California System
Ryan, Michael T. (author)
Monash University
Chan, Jeng Yie (author)
Garvan Institute of Medical Research
Laybutt, D. Ross (author)
Garvan Institute of Medical Research
Coates, P. Toby (author)
Royal Adelaide Hospital
Yang, Sijun (author)
Wuhan University
Ling, Charlotte (author)
Lund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,Diabetes - epigenetik,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups,Diabetes - Epigenetics
Groop, Leif (author)
Lund 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
Pritchard, Melanie A. (author)
Monash University
Keating, Damien J. (author)
South Australian Health and Medical Research Institute
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 (creator_code:org_t)
2016-05-19
2016
English.
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:5
Related links:
http://dx.doi.org/10... (free)
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

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