2. Academic Validation
  3. Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model

Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model

  • Diabetes. 2015 Jun;64(6):2254-64. doi: 10.2337/db14-1220.
Guillaume Vial 1,  Marie-Agnès Chauvin 2,  Nadia Bendridi 2,  Annie Durand 2,  Emmanuelle Meugnier 2,  Anne-Marie Madec 2,  Nathalie Bernoud-Hubac 2,  Jean-Paul Pais de Barros 3,  Éric Fontaine 4,  Cécile Acquaviva 5,  Sophie Hallakou-Bozec 6,  Sébastien Bolze 6,  Hubert Vidal 7,  Jennifer Rieusset 7
Affiliations

Affiliations

  • 1 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.
  • 2 INSERM U1060, Faculté de Médecine Lyon-Sud, Oullins, France.
  • 3 Plateforme de lipidomique, Université de Bourgogne, Centre Hospitalier Universitaire le Bocage, Dijon, France.
  • 4 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.
  • 5 Service Maladies Héréditaires du Métabolisme, Centre de Biologie et Pathologie Est, Centre Hospitalier Universitaire de Lyon et UMR, Bron, France.
  • 6 Poxel SA, Lyon, France.
  • 7 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.
PMID: 25552598 DOI: 10.2337/db14-1220
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.

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