title: Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice.
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 27µmolL(-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.
authors.affiliation: Department of BiologyMaynooth University, Maynooth, Ireland darren.martin@nuim.ie.
authors.forename: Darren S D
authors.initials: DS
authors.lastname: Martin
authors.affiliation: Department of BiologyMaynooth University, Maynooth, Ireland.
authors.forename: Siobhán
authors.initials: S
authors.lastname: Leonard
authors.affiliation: Department of ChemistryMaynooth University, Maynooth, Ireland.
authors.forename: Robert
authors.initials: R
authors.lastname: Devine
authors.affiliation: School of Biochemistry and Molecular BiologyUniversity of Leeds, Leeds, UK.
authors.forename: Clara
authors.initials: C
authors.lastname: Redondo
authors.affiliation: School of Food Science and Environmental HealthCollege of Sciences and Health, Dublin Institute of Technology, Dublin, Ireland.
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Kinsella
authors.affiliation: Department of BiologyMaynooth University, Maynooth, Ireland.
authors.forename: Conor J
authors.initials: CJ
authors.lastname: Breen
authors.affiliation: Department of BiologyMaynooth University, Maynooth, Ireland.
authors.forename: Victoria
authors.initials: V
authors.lastname: McEneaney
authors.affiliation: School of Biochemistry & ImmunologyTrinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Rooney
authors.affiliation: School of Biomedical SciencesUniversity of Leeds, Leeds, UK.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Munsey
authors.affiliation: School of Biochemistry & ImmunologyTrinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Porter
authors.affiliation: School of Biomedical SciencesUniversity of Leeds, Leeds, UK.
authors.forename: Asipu
authors.initials: A
authors.lastname: Sivaprasadarao
authors.affiliation: Department of ChemistryMaynooth University, Maynooth, Ireland.
authors.forename: John C
authors.initials: JC
authors.lastname: Stephens
authors.affiliation: Department of BiologyMaynooth University, Maynooth, Ireland School of Biochemistry and Molecular BiologyUniversity of Leeds, Leeds, UK.
authors.forename: John B C
authors.initials: JB
authors.lastname: Findlay
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D059305:Diet, High-Fat; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010101:Oxygen Consumption; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D010879:Piperazines; C000617571:RTC-1 compound; D013876:Thiophenes; D009243:NAD; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D042967:Electron Transport Complex I; D005947:Glucose
keywords: AMPK; ATP; NADH dehydrogenase; complex I; insulin resistance; metformin; type 2 diabetes