title: A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes.
abstract: 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.
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Heshan
authors.initials: H
authors.lastname: Peiris
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Duffield
authors.affiliation: Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Islet Biology Laboratory, Department of Anatomy and Histology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Claire F
authors.identifier: 0000-0003-1184-6653
authors.initials: CF
authors.lastname: Jessup
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Vinder
authors.initials: V
authors.lastname: Kashmir
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Genders
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.|Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Alyce M
authors.initials: AM
authors.lastname: Martin
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Madiha
authors.initials: M
authors.lastname: Saiedi
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Morton
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Roderick
authors.initials: R
authors.lastname: Carter
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cousin
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alexandros C
authors.identifier: 0000-0003-4024-9866
authors.initials: AC
authors.lastname: Kokotos
authors.affiliation: Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Oskolkov
authors.affiliation: Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: Petr
authors.initials: P
authors.lastname: Volkov
authors.affiliation: Mary Lyon Centre Pathology, MRC Harwell, Harwell Oxford Science Park, Oxford, United Kingdom.
authors.forename: Tertius A
authors.initials: TA
authors.lastname: Hough
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.affiliation: Francis Crick Institute, Mill Hill, London, United Kingdom.|Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.affiliation: Department of Neurobiology and Behaviour, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Jorge
authors.initials: J
authors.lastname: Busciglio
authors.affiliation: Department of Neurobiology and Behaviour, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Pinar E
authors.initials: PE
authors.lastname: Coskun
authors.affiliation: Department of Neurosciences School of Medicine, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Becker
authors.affiliation: Department of Neurosciences School of Medicine, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Belichenko
authors.affiliation: Department of Neurosciences School of Medicine, University of California, San Diego, San Diego, California, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: Jeng Yie
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
authors.affiliation: Clinical and Experimental Transplantation Group, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia.
authors.forename: P Toby
authors.initials: PT
authors.lastname: Coates
authors.affiliation: Animal Experiment Center, Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China.
authors.forename: Sijun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
authors.affiliation: Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Pritchard
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.|South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Keating
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000782:Aneuploidy; D000818:Animals; D002135:Calcium-Binding Proteins; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D000255:Adenosine Triphosphate; D005947:Glucose