title: Rutin suppresses human-amylin/hIAPP misfolding and oligomer formation in-vitro, and ameliorates diabetes and its impacts in human-amylin/hIAPP transgenic mice.
abstract: Pancreatic islet β-cells secrete the hormones insulin and amylin, and defective β-cell function plays a central role in the pathogenesis of type-2 diabetes (T2D). Human amylin (hA, also termed hIAPP) misfolds and forms amyloid aggregates whereas orthologous mouse amylin does neither. Furthermore, hA elicits apoptosis in cultured β-cells and β-cell death in ex-vivo islets. In addition, hA-transgenic mice that selectively express hA in their β-cells, manifest β-cell apoptosis and progressive islet damage that leads to diabetes closely resembling that in patients with T2D. Aggregation of hA is thus linked to the causation of diabetes. We employed time-dependent thioflavin-T spectroscopy and ion-mobility mass spectrometry to screen potential suppressors of hA misfolding for anti-diabetic activity. We identified the dietary flavonol rutin as an inhibitor of hA-misfolding and measured its anti-diabetic efficacy in hA-transgenic mice. In vitro, rutin bound hA, suppressed misfolding, disaggregated oligomers and reverted hA-conformation towards the physiological. In hA-transgenic mice, measurements of glucose, fluid-intake, and body-weight showed that rutin-treatment slowed diabetes-progression by lowering of rates of elevation in blood glucose (P = 0.030), retarding deterioration from symptomatic diabetes to death (P = 0.014) and stabilizing body-weight (P < 0.0001). In conclusion, rutin treatment suppressed hA-aggregation in vitro and doubled the lifespan of diabetic mice (P = 0.011) by a median of 69 days compared with vehicle-treated control-diabetic hA-transgenic mice.
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Aitken
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand.
authors.forename: Kerry M
authors.initials: KM
authors.lastname: Loomes
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics, CMFT, Manchester Academic Health Sciences Centre, and Institute of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Riba-Garcia
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics, CMFT, Manchester Academic Health Sciences Centre, and Institute of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Unwin
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand.
authors.forename: Gordana
authors.initials: G
authors.lastname: Prijic
authors.affiliation: Michael Barber Centre, Manchester Institute of Biotechnology, University of Manchester, UK.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Phillips
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand; Department of Surgery, Faculty of Medical & Health Sciences, University of Auckland, New Zealand.
authors.forename: Anthony R J
authors.initials: ARJ
authors.lastname: Phillips
authors.affiliation: Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Joint School of Biological Sciences, Guangzhou Institute of Biomedicine and Health, Guangzhou Medical University, Guangzhou, China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand.
authors.forename: Sally D
authors.initials: SD
authors.lastname: Poppitt
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: Michael Barber Centre, Manchester Institute of Biotechnology, University of Manchester, UK.
authors.forename: Perdita E
authors.initials: PE
authors.lastname: Barran
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics, CMFT, Manchester Academic Health Sciences Centre, and Institute of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK; School of Social & Community Medicine, Faculty of Health Sciences, University of Bristol, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Dowsey
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics, CMFT, Manchester Academic Health Sciences Centre, and Institute of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK. Electronic address: g.cooper@auckland.ac.nz.
authors.forename: Garth J S
authors.initials: GJS
authors.lastname: Cooper
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding / Q000187:drug effects*; D057165:Proteostasis Deficiencies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012431:Rutin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000682:Amyloid; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D012431:Rutin
keywords: Amylin; Ion-mobility mass-spectrometry; Rutin; Transgenic mice; Type-2 diabetes