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A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes
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نویسنده
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peiris h. ,duffield m.d. ,fadista j. ,jessup c.f. ,kashmir v. ,genders a.j. ,mcgee s.l. ,martin a.m. ,saiedi m. ,morton n. ,carter r. ,cousin m.a. ,kokotos a.c. ,oskolkov n. ,volkov p. ,hough t.a. ,fisher e.m.c. ,tybulewicz v.l.j. ,busciglio j. ,coskun p.e. ,becker a. ,belichenko p.v. ,mobley w.c. ,ryan m.t. ,chan j.y. ,laybutt d.r. ,coates p.t. ,yang s. ,ling c. ,groop l. ,pritchard m.a. ,keating d.j.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 5
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چکیده
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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. © 2016 peiris et al.
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آدرس
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department of human physiology and centre for neuroscience,flinders university,adelaide,sa, Australia, department of human physiology and centre for neuroscience,flinders university,adelaide,sa, Australia, lund university diabetes centre,malmö, Sweden, islet biology laboratory,department of anatomy and histology and centre for neuroscience,flinders university,adelaide,sa,australia,discipline of medicine,university of adelaide,adelaide,sa, Australia, department of human physiology and centre for neuroscience,flinders university,adelaide,sa, Australia, metabolic remodelling laboratory,metabolic research unit,school of medicine,deakin university,geelong, Australia, 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, department of human physiology and centre for neuroscience,flinders university,adelaide,sa, Australia, department of human physiology and centre for neuroscience,flinders university,adelaide,sa, Australia, queen’s medical research institute,university of edinburgh,edinburgh, United Kingdom, queen’s medical research institute,university of edinburgh,edinburgh, United Kingdom, centre for integrative physiology,university of edinburgh,edinburgh, United Kingdom, centre for integrative physiology,university of edinburgh,edinburgh, United Kingdom, lund university diabetes centre,malmö, Sweden, lund university diabetes centre,malmö, Sweden, mary lyon centre pathology,mrc harwell,harwell oxford science park,oxford, United Kingdom, department of neurodegenerative disease,ucl institute of neurology,london, United Kingdom, francis crick institute,mill hill,london,united kingdom,department of medicine,imperial college london,london, United Kingdom, department of neurobiology and behaviour,university of california,irvine,ca, United States, department of neurobiology and behaviour,university of california,irvine,ca, United States, department of neurosciences school of medicine,university of california,san diego,ca, United States, department of neurosciences school of medicine,university of california,san diego,ca, United States, department of neurosciences school of medicine,university of california,san diego,ca, United States, department of biochemistry and molecular biology,monash university,melbourne,vic, Australia, diabetes and metabolism division,garvan institute of medical research,darlinghurst,sydney,nsw, Australia, diabetes and metabolism division,garvan institute of medical research,darlinghurst,sydney,nsw, Australia, clinical and experimental transplantation group,royal adelaide hospital,north terrace,adelaide,sa, Australia, animal experiment center,animal biosafety level-iii laboratory,wuhan university,wuhan, China, lund university diabetes centre,malmö, Sweden, lund university diabetes centre,malmö, Sweden, department of biochemistry and molecular biology,monash university,melbourne,vic, Australia, department of human physiology and centre for neuroscience,flinders university,adelaide,sa,australia,south australian health and medical research institute,adelaide, Australia
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Authors
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