title: Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration.
abstract: Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy.
authors.affiliation: University Grenoble Alpes, LBFA , F-38000 Grenoble, France.
authors.forename: D
authors.initials: D
authors.lastname: Detaille
authors.affiliation: University Grenoble Alpes, LBFA, F-38000 Grenoble, France; INSERM, U1055, F-38000 Grenoble, France.
authors.forename: G
authors.initials: G
authors.lastname: Vial
authors.affiliation: University Grenoble Alpes, LBFA, F-38000 Grenoble, France; INSERM, U1055, F-38000 Grenoble, France.
authors.forename: A-L
authors.initials: AL
authors.lastname: Borel
authors.affiliation: University Grenoble Alpes, LBFA, F-38000 Grenoble, France; INSERM, U1055, F-38000 Grenoble, France.
authors.forename: C
authors.initials: C
authors.lastname: Cottet-Rouselle
authors.affiliation: Poxel , F-69000 Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Hallakou-Bozec
authors.affiliation: Poxel , F-69000 Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Bolze
authors.affiliation: Poxel , F-69000 Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Fouqueray
authors.affiliation: University Grenoble Alpes, LBFA, F-38000 Grenoble, France; INSERM, U1055, F-38000 Grenoble, France.
authors.forename: E
authors.identifier: 0000-0002-5204-9477
authors.initials: E
authors.lastname: Fontaine