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Biochem Biophys Res Commun. 2017 Jan 22;482(4):625-631. doi: 10.1016/j.bbrc.2016.11.083. Epub 2016 Nov 16.

Rutin suppresses human-amylin/hIAPP misfolding and oligomer formation in-vitro, and ameliorates diabetes and its impacts in human-amylin/hIAPP transgenic mice.

Author information

1
School of Biological Sciences, University of Auckland, New Zealand.
2
School of Biological Sciences, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand.
3
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.
4
Michael Barber Centre, Manchester Institute of Biotechnology, University of Manchester, UK.
5
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.
6
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.
7
College of Pharmacy, Jinan University, Guangzhou, China.
8
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.
9
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.

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.

KEYWORDS:

Amylin; Ion-mobility mass-spectrometry; Rutin; Transgenic mice; Type-2 diabetes

PMID:
27865831
DOI:
10.1016/j.bbrc.2016.11.083
[Indexed for MEDLINE]

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