title: Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model.
abstract: Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice.
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France Center for European Nutrition and Health, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France guillaume.vial@inserm.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Chauvin
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bendridi
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Durand
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Meugnier
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Madec
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bernoud-Hubac
authors.affiliation: Plateforme de lipidomique, Université de Bourgogne, Centre Hospitalier Universitaire le Bocage, Dijon, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pais de Barros
authors.affiliation: INSERM U1055, Laboratoire de Bioénergétique Fondamentale et Appliquée (LBFA) et SFR Biologie Environnementale et Systémique (BEeSy), Grenoble, France Joseph Fourier University, Grenoble, France Grenoble University Hospital, Grenoble, France.
authors.forename: Éric
authors.initials: É
authors.lastname: Fontaine
authors.affiliation: Service Maladies Héréditaires du Métabolisme, Centre de Biologie et Pathologie Est, Centre Hospitalier Universitaire de Lyon et UMR, Bron, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva
authors.affiliation: Poxel SA, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hallakou-Bozec
authors.affiliation: Poxel SA, Lyon, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bolze
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France Center for European Nutrition and Health, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France Endocrinology, Diabetology, and Nutrition Service, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.affiliation: INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France Center for European Nutrition and Health, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France Endocrinology, Diabetology, and Nutrition Service, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D014227:Triazines / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D014227:Triazines; C575881:imeglimin