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    Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice


    Martin, Darren S. and Leonard, Siobhán and Devine, Robert and Redondo, Clara and Kinsella, Gemma K. and Breen, Conor and McEneaney, Victoria and Rooney, Mary F. and Munsey, Tim S. and Porter, Richard K. and Sivaprasadarao, Asipu and Stephens, John C. and Findlay, John B. C. (2016) Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice. Journal of Molecular Endocrinology, 56. pp. 261-271. ISSN 0952-5041

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    Abstract

    Metformin is the main drug of choice for treating type 2 diabetes, yet the therapeutic regimens and side effects of the compound are all undesirable and can lead to reduced compliance. The aim of this study was to elucidate the mechanism of action of two novel compounds which improved glucose handling and weight gain in mice on a high-fat diet. Wildtype C57Bl/6 male mice were fed on a high-fat diet and treated with novel, anti-diabetic compounds. Both compounds restored the glucose handling ability of these mice. At a cellular level, these compounds achieve this by inhibiting complex I activity in mitochondria, leading to AMP-activated protein kinase activation and subsequent increased glucose uptake by the cells, as measured in the mouse C2C12 muscle cell line. Based on the inhibition of NADH dehydrogenase (IC50 27 μmol L−1), one of these compounds is close to a thousand fold more potent than metformin. There are no indications of off target effects. The compounds have the potential to have a greater anti-diabetic effect at a lower dose than metformin and may represent a new anti-diabetic compound class. The mechanism of action appears not to be as an insulin sensitizer but rather as an insulin substitute.

    Item Type: Article
    Additional Information: This is the postprint version of the published article, which is available at doi: 10.1530/JME-15-0225. This work was supported by Science Foundation Ireland (www.sfi.ie), grant number 08/IN.1/B1900 TIDA Feasibility Study; Higher Education Authority under the PRTLI Cycle 5 BioAT Programme and Government of Ireland Postgraduate Scholarship from the Irish Research Council.
    Keywords: type 2 diabetes; metformin; complex I; NADH dehydrogenase; AMPK; insulin resistance; ATP;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 7699
    Identification Number: https://doi.org/10.1530/JME-15-0225
    Depositing User: Dr John Stephens
    Date Deposited: 10 Jan 2017 15:05
    Journal or Publication Title: Journal of Molecular Endocrinology
    Publisher: Bioscientifica Ltd.
    Refereed: Yes
    Funders: Science Foundation Ireland (SFI), Higher Education Aithority (HEA)
    URI:

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