Martin, Darren S., Leonard, Siobhán, Devine, Robert, Redondo, Clara, Kinsella, Gemma K., Breen, Conor, McEneaney, Victoria, Rooney, Mary F., Munsey, Tim S., Porter, Richard K., Sivaprasadarao, Asipu, 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 |
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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: | 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) |
Related URLs: | |
URI: | https://mu.eprints-hosting.org/id/eprint/7699 |
Use Licence: | This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here |
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